Introduction to Neuroscience

Neurotransmitters

So far, we have focused on how neurons generate and propagate electrical signals and how those signals cross the synapse. We now turn to the “chemical vocabulary” of the nervous system: neurotransmitters. Different neurons speak in slightly different chemical dialects, releasing particular transmitter molecules that act on specific receptors. These combinations of transmitter and receptor endow each neural circuit with its own characteristic mode of signaling, time-course, and function.

What Is a Neurotransmitter?

Definition. A neurotransmitter is a chemical messenger released by a presynaptic neuron at the synapse that binds to specific receptors on a postsynaptic cell (neuron, muscle fiber, or gland) and changes that cell’s membrane potential or intracellular signaling state.

Classically, a substance is considered a neurotransmitter if it satisfies several criteria:

• It is synthesized in the neuron (often in the soma or terminal) and present in the presynaptic terminal.
• It is released in response to presynaptic depolarization and Ca²⁺-dependent exocytosis.
• It acts on specific receptors in the postsynaptic membrane to produce a physiological effect.
• There is a mechanism for its removal or inactivation (e.g., reuptake, enzymatic breakdown).
• Its effects can be mimicked by exogenous application of the substance or by drugs that activate its receptors.

Not all signaling molecules in the nervous system are classical neurotransmitters. Some, such as hormones and neuromodulators, act at longer distances or over longer time scales. Others, like gaseous transmitters, diffuse freely rather than being packaged into vesicles. Nonetheless, the core idea remains: chemical signals allow neurons to influence one another’s electrical activity and gene expression.

Families of Neurotransmitters

Neurotransmitters can be grouped into several broad families based on their chemistry and synthesis:

1. Small-molecule neurotransmitters
   • Amino acid transmitters: glutamate, GABA, glycine.
   • Monoamines: dopamine (DA), norepinephrine (NE), serotonin (5-HT), and others.
   • Acetylcholine (ACh): a “one-of-a-kind” transmitter in its own category.


2. Neuropeptides
   • Short chains of amino acids (e.g., substance P, endorphins, enkephalins, neuropeptide Y).
   • Often co-released with a small-molecule transmitter and act as modulators with slower, longer-lasting effects.


3. Atypical (non-classical) transmitters
   • Gases such as nitric oxide (NO) and carbon monoxide (CO), which diffuse freely and act retrogradely.
   • Endocannabinoids, lipid-derived messengers that often travel from postsynaptic to presynaptic cell.

Each family has its own style of signaling. Small molecules typically mediate fast, point-to-point synaptic communication; peptides and atypical transmitters tend to modulate activity over wider regions and longer time scales.

“Workhorse” vs. “Boutique” Transmitters

One useful way to think about neurotransmitters is to distinguish between those that are nearly ubiquitous—used everywhere in the brain—and those that are more specialized in specific circuits.

Workhorse transmitters are used by enormous numbers of synapses and form the basic excitatory–inhibitory backbone of neural signaling:

• Glutamate – the primary fast excitatory transmitter in the CNS.
• GABA (and glycine in the spinal cord and brainstem) – the primary fast inhibitory transmitters.

Boutique transmitters are associated with particular neural pathways and psychological functions:

• Acetylcholine (ACh)
• Dopamine (DA)
• Norepinephrine (NE, noradrenaline)
• Serotonin (5-HT)
• Various peptide transmitters (e.g., opioids, oxytocin, vasopressin, CCK, NPY).

The “workhorses” are involved in most synaptic computations in the cortex, hippocampus, and cerebellum, mediating fast EPSPs and IPSPs. The “boutique” transmitters ride on top of this background activity, tuning the overall responsiveness and mode of processing of entire circuits (e.g., “alert and vigilant” vs. “calm and sleepy”).

Glutamate and GABA: The Core Excitatory–Inhibitory Balance

Glutamate is the principal excitatory neurotransmitter in the CNS. When glutamate binds to its postsynaptic receptors, it typically allows cations (Na⁺, sometimes Ca²⁺) to enter the cell, producing EPSPs and bringing the membrane potential closer to threshold.

Major glutamate receptor types include:

• AMPA receptors – ionotropic; mediate fast EPSPs.
• NMDA receptors – ionotropic; voltage- and ligand-gated, permeable to Ca²⁺; crucial for synaptic plasticity.
• Kainate receptors – ionotropic; also contribute to fast excitation.
• mGluRs (metabotropic glutamate receptors) – GPCRs that modulate excitability and plasticity.

GABA (γ-aminobutyric acid) is the primary inhibitory transmitter in the adult brain. Activation of GABA receptors usually leads to Cl⁻ influx or K⁺ efflux, generating IPSPs and making neurons less likely to fire an action potential.

Major GABA receptor types include:

• GABA_A receptors – ionotropic; Cl⁻ channels that mediate fast inhibition.
• GABA_B receptors – metabotropic; activate G proteins that open K⁺ channels and/or close Ca²⁺ channels.

Many psychoactive drugs (e.g., benzodiazepines, barbiturates, alcohol) act in part by enhancing GABA_A-mediated inhibition, tilting the balance of excitation and inhibition toward less overall neural activity.

Cholinergic Systems (Acetylcholine)

Acetylcholine (ACh) is the first neurotransmitter to have been discovered and remains one of the most important. In the peripheral nervous system, ACh is the transmitter at the neuromuscular junction (causing skeletal muscle contraction) and at many autonomic synapses. In the brain, ACh is produced by several key groups of neurons whose axons project widely.

Major cholinergic pathways include:

• Basal forebrain cholinergic system – neurons in the nucleus basalis, medial septum, and related regions project to cortex and hippocampus and are critical for attention, learning, and memory.
• Brainstem cholinergic nuclei – neurons in the pedunculopontine and laterodorsal tegmental nuclei project to thalamus and basal ganglia and are involved in arousal and REM sleep.

Examples of ACh function in the brain.

• Nicotinic ACh receptors (ionotropic) contribute to short-term memory and reward circuitry. Nicotine from tobacco is an agonist at these receptors—this is one reason tobacco products are so strongly addictive.
• Muscarinic ACh receptors (metabotropic) support cognition and cortical processing. Drugs that block muscarinic receptors can produce confusion, memory problems, and even hallucinations.

Degeneration of basal forebrain cholinergic neurons is a hallmark of Alzheimer’s disease, and many current treatments for Alzheimer’s attempt to enhance cholinergic signaling (e.g., by inhibiting acetylcholinesterase).

Dopaminergic Pathways

Dopamine (DA) is a monoamine transmitter with several discrete pathways in the brain. These pathways support diverse functions including motor control, motivation, and reinforcement learning.

The Mesostriatal Dopamine Pathway

The mesostriatal (or nigrostriatal) DA pathway originates in the substantia nigra of the midbrain and projects primarily to the striatum (caudate nucleus and putamen).

Functions.

• Critical for motor control and the initiation of voluntary movements.
• Modulates activity in basal ganglia circuits that select and sequence actions.

Loss of dopaminergic neurons in the substantia nigra → striatum pathway leads to Parkinson’s disease, a disorder characterized by bradykinesia (slowness of movement), resting tremor, rigidity, and postural instability. Treatments such as L-DOPA attempt to restore dopamine levels in this circuit.

The Mesolimbocortical Dopamine Pathway

The mesolimbocortical DA pathway originates in the ventral tegmental area (VTA) of the midbrain and projects to:

• the nucleus accumbens and other parts of the limbic system (ventral striatum), and
• the prefrontal cortex.

Functions.

• Central to reward and reinforcement learning (signal for “better than expected” outcomes).
• Involved in motivation, goal-directed behavior, and aspects of cognition.
• Heavily implicated in addiction; many drugs of abuse increase dopamine in this pathway.

Abnormalities in dopaminergic signaling in mesolimbocortical circuits have been linked to schizophrenia and other psychotic disorders. Many antipsychotic medications work by blocking or partially blocking D₂-family DA receptors.

Noradrenergic Pathways (Norepinephrine)

Norepinephrine (NE), also known as noradrenaline, is a monoamine transmitter used both in the peripheral sympathetic nervous system and in the brain.

Central noradrenergic neurons are concentrated primarily in the locus coeruleus (LC) in the pons, as well as in a few other brainstem nuclei. Axons from the LC project broadly throughout the cortex, hippocampus, cerebellum, and spinal cord.

Functions of NE in the brain.

• Arousal and vigilance – NE helps maintain wakefulness and alertness.
• Attention – modulates the ability to focus on salient stimuli.
• Mood – alterations in NE signaling are linked to depression and anxiety.
• Sexual behavior and stress responses – coordinates physiological changes in challenging situations.

In the body, NE is a key mediator of the fight-or-flight response, increasing heart rate, blood pressure, and redirecting blood flow to muscles.

Serotonergic Pathways (Serotonin)

Serotonin (5-hydroxytryptamine, 5-HT) is another monoamine transmitter with cell bodies primarily in the raphe nuclei of the brainstem. From there, serotonergic fibers project widely throughout the brain and spinal cord.

Functions of 5-HT.

• Regulation of sleep–wake cycles and dreaming.
• Modulation of mood, including anxiety and depression.
• Influence on sexual behavior and appetite.
• Participation in cognitive functions such as learning and decision-making.

Many antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs; e.g., Prozac), act by increasing 5-HT levels in the synaptic cleft. By blocking the serotonin transporter, they prolong and enhance activation of postsynaptic 5-HT receptors.

Neuropeptides and Other Boutique Transmitters

Neuropeptides include a large and diverse set of signaling molecules:

• Opioid peptides (e.g., endorphins, enkephalins, dynorphins) – modulate pain, reward, and stress.
• Oxytocin and vasopressin – involved in social behavior, bonding, and fluid balance.
• Neuropeptide Y (NPY), CCK, substance P – implicated in feeding, anxiety, and nociception.

Peptide transmitters are often co-released with a classical transmitter (e.g., glutamate, GABA) and act via metabotropic receptors to modulate circuit function rather than to drive fast EPSPs or IPSPs.

Identifying and Naming Neurotransmitter Receptors

Every neurotransmitter must bind to a receptor to exert its effects. Receptors are typically named according to:

• The transmitter they bind (e.g., glutamate receptors vs. ACh receptors).
• Whether they are ionotropic (ligand-gated ion channels) or metabotropic (G protein–coupled receptors).
• Their specific pharmacology—for example, which drugs activate (agonists) or block (antagonists) them.

In many cases, a receptor subtype is named after a synthetic drug that selectively activates it. For instance:

• NMDA receptor – a glutamate receptor subtype named after the agonist N-methyl-D-aspartate.
• AMPA receptor – named after the agonist AMPA.
• Nicotinic and muscarinic ACh receptors – named after nicotine and muscarine, respectively.

Major Transmitter Receptor Families (Selected Examples)

The table below summarizes several important transmitter systems, their main receptor families, and broad functional roles.

Note: Each transmitter family contains multiple receptor subtypes with distinct distributions and functions. This diversity allows a relatively small set of chemical messengers to support a vast repertoire of neural computations and behaviors.

A Glimpse of Neuropharmacology

Finally, because neurotransmitters act through specific receptors and transporters, they provide numerous targets for drugs. Neuropharmacology is the study of how drugs affect the nervous system and behavior. At synapses, drugs can:

• Act as agonists, activating receptors (e.g., nicotine at nicotinic ACh receptors).
• Act as antagonists, blocking receptors (e.g., many antipsychotics at D₂ receptors).
• Alter neurotransmitter synthesis, storage, or release.
• Block reuptake transporters (e.g., SSRIs for 5-HT, cocaine for DA/NE).
• Inhibit enzymatic breakdown (e.g., acetylcholinesterase inhibitors for ACh).

Because the same transmitter can have very different effects in different brain regions and receptor contexts, drug actions are both powerful and complex. Understanding the underlying transmitter systems and their receptor families is therefore essential for making sense of how psychoactive drugs—from therapeutic medications to drugs of abuse—alter brain function and behavior.

Neuropharmacology I: Drugs and Neurotransmitters

We have seen that neurons use a rich chemical vocabulary—neurotransmitters—to communicate. These transmitters act through specific receptors to excite, inhibit, or modulate their targets. Neuropharmacology asks a closely related question:

Roles of Neurotransmitters in the Brain (Recap)

Recall that each neuron usually releases one, or mostly one, primary neurotransmitter from all of its axon terminals. This “chemical identity” shapes how it participates in a circuit.

We distinguished between:

• Workhorse transmitters – nearly ubiquitous.
  • Glutamate: fast excitation / depolarization.
  • GABA (and glycine in spinal cord and brainstem): fast inhibition / hyperpolarization.
• Boutique transmitters – associated with specific circuits/functions.
  • Acetylcholine (ACh)
  • Dopamine (DA)
  • Norepinephrine (NE; noradrenaline)
  • Serotonin (5-HT)
  • Peptide neurotransmitters (e.g., opioids, CCK, NPY)

Workhorse transmitters carry the bulk of fast synaptic traffic, whereas boutique transmitters act more like “settings” or “modes” for large-scale circuits—tuning arousal, mood, reward, and motivation.

Review of Major Boutique Transmitter Systems

Cholinergic Pathways and ACh Functions

Acetylcholine (ACh) neurons form several key pathways in the brain:

• Basal forebrain cholinergic system (nucleus basalis, medial septum): projects to cortex and hippocampus; important for attention, learning, and memory.
• Brainstem cholinergic nuclei (pedunculopontine and laterodorsal tegmental nuclei): project to thalamus and basal ganglia; regulate arousal and sleep–wake states.

Examples of ACh function in the brain.

• Nicotinic ACh receptors (ionotropic): contribute to reward circuitry.
  • Nicotine binds these receptors and enhances dopaminergic reward signaling.
  • Hence, tobacco products are powerfully addictive.
• Muscarinic ACh receptors (metabotropic): support cognition and cortical processing.
  • Muscarinic receptor blockers (e.g., certain plant alkaloids and medications) can produce confusion, memory impairments, and even hallucinations.

Dopaminergic Pathways and Their Functions

Dopamine (DA) neurons are clustered in midbrain nuclei and send their axons to specific targets, forming distinct pathways.

Mesostriatal (nigrostriatal) pathway.

• Cell bodies in the substantia nigra.
• Axons project to the striatum (caudate + putamen).
• Supports motor control and the initiation of voluntary movement.

Loss of dopaminergic neurons in the substantia nigra → striatum pathway leads to Parkinson’s disease, characterized by:

• Bradykinesia (slowness of movement)
• Resting tremor
• Rigidity and postural instability

Mesolimbocortical pathway.

• Originates in the ventral tegmental area (VTA).
• Projects to the limbic system (especially nucleus accumbens) and prefrontal cortex.

Functions of DA in this pathway.

• Reward and reinforcement – signals “better than expected” outcomes.
• Learning and motivation – helps assign value to actions and cues.
• Addiction – many drugs of abuse increase dopamine in these regions.

Abnormal dopaminergic signaling in this pathway is associated with schizophrenia and related psychotic disorders. Many antipsychotics act as antagonists at dopamine receptors, especially of the D₂ family.

Noradrenergic Pathways and NE Functions

Norepinephrine (NE), also called noradrenaline, is produced by neurons in the locus coeruleus and a few other brainstem nuclei. Their fibers project broadly throughout the brain.

Functions of NE.

• Arousal and vigilance – keeps the cortex “awake” and responsive.
• Attention and alertness – enhances responses to salient stimuli.
• Mood regulation – disturbances in NE can contribute to depression and anxiety.
• Sexual behavior and stress responses – coordinates physiological readiness.

Serotonergic Pathways and 5-HT Functions

Serotonin (5-HT) cell bodies are mainly found in the raphe nuclei of the brainstem. Serotonergic fibers project widely to cortex, limbic system, and spinal cord.

Functions of 5-HT.

• Regulation of sleep and circadian rhythms.
• Modulation of mood and anxiety.
• Influence on sexual behavior and appetite.

Antidepressants such as Prozac are selective serotonin reuptake inhibitors (SSRIs). They increase 5-HT in the synaptic cleft by blocking its reuptake, thereby enhancing postsynaptic 5-HT receptor activity.

Identifying and Naming Neurotransmitter Receptors (Recap)

To understand how drugs act, we must first understand the receptors they bind. For any given receptor, we ask:

• Which neurotransmitter does it bind?
  – e.g., glutamate receptor vs. acetylcholine receptor.
• What kind of receptor is it?
  – Ionotropic (ligand-gated ion channel) or metabotropic (G protein–coupled receptor).
• What is its specific pharmacology?
  – Which drugs (agonists/antagonists) bind to it, and how strongly?

Many receptor subtypes are named after synthetic drugs that selectively activate them:

• NMDA and AMPA receptors (glutamate) – named after the agonists N-methyl-D-aspartate and AMPA, respectively.
• Nicotinic vs. muscarinic ACh receptors – named after nicotine and muscarine.

Why Is Neuropharmacology So Useful?

Neuropharmacology is powerful because it provides tools and treatments:

• There are drugs that target almost any step in neural signaling:
  • Receptors (direct agonists/antagonists)
  • Transporters (reuptake inhibitors)
  • Enzymes (breakdown inhibitors)
  • Ion channels, second-messenger pathways, gene transcription, etc.
• Many of these drugs are natural products discovered long ago (e.g., plant alkaloids, toxins, venoms).
• We use drugs as experimental probes to selectively manipulate molecules and circuits and infer their functions.
• We use drugs as therapies to treat a wide range of neurological and psychiatric conditions.

What Is a Drug?

Definition. In neuropharmacology, a drug is an exogenous substance (coming from outside the body) that has biological activity in the nervous system and is not a normal food or nutrient.

Drugs are usually specific chemicals with definable molecular targets, such as:

• a particular receptor subtype,
• a transporter,
• an ion channel, or
• an enzyme involved in transmitter synthesis or degradation.

Drugs differ in their modes of activity:

• Agonist – a drug that activates a receptor (mimics or enhances the effect of the endogenous ligand).
• Antagonist – a drug that blocks or reduces activation of a receptor by other ligands.

Basic Pharmacology Vocabulary

Definition. A ligand is any substance that binds to a receptor, whether endogenous (e.g., a neurotransmitter) or exogenous (e.g., a drug or toxin).

We can classify ligands by how they influence receptor activity:

• Agonist – initiates or enhances the normal effects of the receptor.
• Antagonist – reduces receptor activation by other ligands; has little or no effect on its own in the absence of the endogenous ligand.

More refined categories (useful later) include:

• Partial agonist – activates the receptor, but produces a smaller effect than a full agonist, even at full occupancy.
• Inverse agonist – reduces the receptor’s baseline activity below its resting level.
• Allosteric modulator – binds at a site distinct from the ligand-binding site and alters the receptor’s response (positively or negatively) to the endogenous ligand.

Modes of Binding: Competitive vs. Noncompetitive Antagonists

To understand how drugs block receptors, we consider where and how they bind.

Competitive antagonists.

• Bind to the same site on the receptor as the endogenous ligand.
• “Compete” with the ligand for binding; increasing the concentration of the endogenous ligand can overcome blockade.
• Typically shift the dose–response curve to the right (need more agonist for the same effect), without changing the maximal possible effect.

Noncompetitive antagonists.

• Bind to a different (allosteric) site or otherwise prevent receptor activation even when the agonist is bound.
• Block receptor function in a way that cannot be overcome simply by adding more agonist.
• Often reduce the maximum effect achievable by the agonist.

In all cases, the endogenous ligand is the “reference” that tells us what the receptor is normally supposed to do. Drugs then mimic, enhance, or interfere with this natural signaling.

The Dose–Response Curve (DRC)

How do we quantify how strongly a drug acts? A central tool is the dose–response curve.

Definition. A dose–response curve (DRC) plots the magnitude or percentage of response as a function of the drug dose.

Typically:

• Dose is plotted on a logarithmic (log) scale on the x-axis.
• Response (% of subjects responding, or mean effect size) is on the y-axis.
• The curve has a characteristic sigmoidal (S-shaped) form.

ED₅₀ (effective dose 50) is the dose at which 50% of subjects show a defined response (or where the effect reaches 50% of its maximum in a given preparation). It is a standard measure of potency: lower ED₅₀ means greater potency.

Two key features of a DRC:

• Potency – how much drug is needed for a given effect (linked to ED₅₀).
• Efficacy – the maximum effect the drug can produce, regardless of dose.

Therapeutic Index

Every drug has two faces: benefit and risk. We care about the doses that produce the desired therapeutic effects and the doses that cause toxicity or death.

Definitions.

• ED₅₀ – dose at which 50% of subjects show a therapeutic effect.
• TD₅₀ – dose at which 50% of subjects show toxicity.
• LD₅₀ – dose at which 50% of subjects die.

Therapeutic index is a measure of safety—it reflects the separation between the effective dose range and the toxic/lethal dose range. Intuitively:

Conceptually:

• Wide therapeutic index – large difference between average therapeutic and lethal/toxic doses.
  • Safer; dosing errors are less likely to be catastrophic.
• Narrow therapeutic index – small difference between therapeutic and toxic doses.
  • Requires close monitoring; small changes in dose or metabolism can push the patient into toxicity.

Drug Tolerance

Over time, the same dose of a drug may produce less effect. This phenomenon is called tolerance.

Definition. Drug tolerance is a decrease in the effect of a drug following repeated administration, such that higher doses are required to achieve the same response.

Types of tolerance:

• Metabolic tolerance
  • Organ systems (especially liver, kidneys) become more efficient at eliminating the drug.
  • Result: less drug reaches the brain for the same administered dose.
• Functional tolerance
  • Target tissues (e.g., neurons) become less responsive to the drug.
  • Often involves changes in receptor number or signaling.

Mechanisms of Tolerance in Neurons

Recall that the effect of a neurotransmitter or drug depends on how many receptors are present and how strongly they signal. Neurons can adapt by changing receptor expression:

• Down-regulation in response to chronic agonist exposure
  • If a receptor is persistently activated (e.g., by a drug that acts as an agonist), neurons may reduce the number of receptors on the cell surface.
  • Result: the same drug concentration produces less effect → tolerance.
• Up-regulation in response to chronic antagonist exposure
  • If receptors are chronically blocked by an antagonist, neurons may increase the number of receptors.
  • Result: heightened sensitivity; if the antagonist is suddenly removed, normal levels of neurotransmitter can produce exaggerated responses (rebound phenomena).

These changes shift the dose–response curve over time. A dose that was once effective may become subtherapeutic (tolerance), or a dose that was once safe may become toxic if metabolic capacity is lost.

Summary: Agonistic and Antagonistic Actions of Drugs

Putting it all together:

• Endogenous ligands (neurotransmitters, neuromodulators) normally bind their receptors and produce specific effects.
• Agonist drugs mimic or enhance those effects by activating the same receptors (or by increasing the availability of the endogenous ligand).
• Antagonist drugs block or dampen receptor activation, reducing the effect of the endogenous ligand.
• Over repeated exposure, the body adjusts through metabolic and functional tolerance, especially via receptor up- and down-regulation.

In the subsequent steps of our journey, we will apply these principles to specific drug classes—how they act on particular neurotransmitter systems, what they reveal about brain function, and how they are used (and misused) in clinical and everyday settings.

Neuropharmacology II: Classes of Psychoactive Drugs

In the previous section, we built the conceptual toolkit of neuropharmacology: we defined neurotransmitters, receptors, agonists and antagonists, dose–response curves, therapeutic index, and tolerance. We saw that drugs can mimic, enhance, or block the actions of endogenous ligands, and that repeated exposure can drive the nervous system to adapt.

We now put those concepts to work by examining specific classes of psychoactive drugs—substances that alter mood, perception, cognition, and behavior by targeting particular neurotransmitter systems. As we do so, keep asking:

Major Classes of Psychoactive Drugs

Psychoactive drugs can be grouped (roughly) by their primary psychological effects and main targets:

• Opiates / opioids – powerful analgesics (painkillers); act on endogenous opioid receptors.
• Stimulants – increase wakefulness, alertness, and energy; act on monoamine and other systems.
• Hallucinogens / psychedelics – alter perception and cognition; often act on serotonin (5-HT), but also other systems.

In every case, there is a tension between therapeutic potential and risk (addiction, toxicity, and long-term harm). Neuropharmacology aims to understand both sides.

Opiates / Opioids

Opiates are drugs derived from the opium poppy; opioids more broadly include natural, semi-synthetic, and fully synthetic drugs that act on the same receptors as endogenous opioid peptides (e.g., endorphins, enkephalins).

Examples.

• Natural/semi-synthetic: morphine, codeine, heroin.
• Prescription painkillers: oxycodone, hydrocodone, others.
• Synthetic opioids: fentanyl and analogs (very potent).

Mechanism of Action

Opioids are generally agonists at opioid receptors (μ, κ, δ), which are metabotropic (GPCRs) widely expressed in the brain and spinal cord. Activation of these receptors:

• Reduces neuronal excitability (via opening K⁺ channels and/or closing Ca²⁺ channels).
• Decreases transmission of pain signals in the spinal cord and brainstem → analgesia.
• Engages reward circuits in the mesolimbic system → euphoria and high addiction liability.

Clinical and Adverse Effects

Clinically, opioids are used as:

• Analgesics – for acute severe pain (e.g., post-surgical, cancer-related pain).
• Anesthetics adjuncts – in surgical settings.

However, they also cause:

• Respiratory depression – suppression of brainstem respiratory centers; this is the primary cause of death in overdose.
• Constipation, nausea, sedation, and tolerance.
• Dependence and addiction – with compulsive use despite harm.

Tolerance to opioids can develop rapidly. A particularly dangerous scenario is when a person stops using (e.g., during treatment), loses tolerance, and then relapses at their previous high dose—greatly increasing the risk of fatal overdose.

The Opioid Crisis and Harm Reduction

In many countries, especially the United States, there has been a major opioid epidemic:

• Over-prescription of opioid painkillers and diversion into the black market fueled widespread use.
• Potent synthetic opioids such as fentanyl, which is much stronger than morphine, significantly increased overdose risk.

A key life-saving tool is naloxone (Narcan), a competitive opioid receptor antagonist. It rapidly displaces opioids from μ-receptors and can reverse opioid-induced respiratory depression if given in time. Making naloxone widely available (e.g., nasal sprays) is an important harm-reduction strategy.

Stimulants

Stimulant drugs increase wakefulness, alertness, and often produce a sense of energy and confidence. They act by increasing activity in excitatory or modulatory systems, particularly acetylcholine, glutamate, and monoamines (dopamine, norepinephrine).

Common examples:

• Caffeine
• Nicotine
• Cocaine
• Amphetamines (including methamphetamine and related compounds)

All stimulants can produce tolerance and sometimes dependence; some (particularly cocaine and amphetamines) have high addiction potential and serious health risks.

Mechanisms (Brief Overview)

Different stimulants act at different targets:

• Caffeine – blocks adenosine receptors (adenosine normally promotes sleep), indirectly increasing neural activity and catecholamine release.
• Nicotine – agonist at nicotinic ACh receptors; enhances attention and reinforces mesolimbic dopamine signaling → highly addictive.
• Cocaine – blocks reuptake transporters for dopamine, norepinephrine, and serotonin, increasing their levels in the synaptic cleft.
• Amphetamines – increase release of dopamine and norepinephrine and can reverse their transporters, flooding synapses with monoamines.

Medical Use of Amphetamines

Several drugs in the amphetamine family (or functionally similar stimulants) are prescribed for attention-deficit/hyperactivity disorder (ADHD) and certain sleep disorders (e.g., narcolepsy). Examples include:

• Amphetamine/dextroamphetamine combinations (e.g., formulations similar to Adderall).
• Methylphenidate-based drugs (e.g., formulations similar to Ritalin).
• Dexmethylphenidate and related compounds.

These medications, when used under medical supervision, can improve attention and impulse control by modulating catecholamine signaling in prefrontal and striatal circuits.

However, they are also frequently used without prescription for “academic performance” or recreational purposes, which increases the risk of cardiovascular side effects, dependence, and other harms.

Recreational Amphetamines: Risks

Short-term effects of amphetamines may include:

• Increased alertness and wakefulness
• Euphoria and a sense of confidence
• Increased stamina and reduced fatigue

Long-term or high-dose use, however, can be severely damaging:

• Sleeplessness and profound sleep disruption
• Weight loss and poor nutrition
• Cardiovascular strain (elevated heart rate and blood pressure)
• Psychiatric symptoms – prolonged use can lead to compulsive, agitated behavior and paranoia that can resemble paranoid schizophrenia.

Chronic methamphetamine use is notoriously associated with marked physical and psychological deterioration—a vivid reminder of how powerful and destructive monoamine dysregulation can be.

Hallucinogens / Psychedelics

Hallucinogens, often called psychedelics, are drugs that profoundly alter perception, emotion, and sometimes the sense of self. They can produce:

• Visual distortions and complex imagery
• Altered auditory and somatosensory experiences
• Changes in the perception of time and space
• Intense emotional or “spiritual” experiences

They act on multiple systems, but a major theme is modulation of serotonin (5-HT) receptors (especially 5-HT_2A) in cortex. Others affect glutamate, acetylcholine, and norepinephrine as well.

Many hallucinogens are abused (used non-medically or illicitly), but most are not strongly addictive in the sense of causing compulsive daily use with severe withdrawal. Their risks arise more from acute psychological distress, unsafe behavior, and (for some agents) potential neurotoxicity.

LSD and Classic Psychedelics

Lysergic acid diethylamide (LSD) is a semi-synthetic compound originally derived from ergot (a fungus that infects grains). A key figure in its discovery and early exploration is often called the “father of LSD.”

LSD acts primarily as an agonist (or partial agonist) at several serotonin receptors, especially 5-HT_2A, which are dense in visual cortex and higher-order association areas. It also has actions at other monoamine receptors.

Subjective effects frequently include:

• Intense and vivid colors, geometric patterns
• Novel visual objects and illusions (and, at higher doses, true hallucinations)
• Altered sense of time (minutes feel longer or shorter)
• Emotional lability, from euphoria to anxiety

These experiences are strongly shaped by set (mindset, expectations) and setting (environment and social context).

Psychedelics and Possible Clinical Applications

Recent research has revisited classic and “newer” psychedelics as potential treatments for certain psychiatric conditions, always in carefully controlled clinical settings with psychological support. Some of the leading candidates include:

Important: these potential clinical uses involve carefully controlled doses, medical screening, and structured psychotherapy. This is very different from unsupervised recreational use, which can be dangerous.

Bringing It Together

Across opioids, stimulants, and hallucinogens, the same core principles reappear:

• Drugs act as agonists, antagonists, or modulators at specific receptors and transporters.
• Their effects are constrained by dose–response relationships and therapeutic index.
• Repeated use drives tolerance, dependence, and sometimes profound neuroadaptations.
• The same molecular mechanisms that give a drug therapeutic power can also create risk for addiction and toxicity.

Neuropharmacology, then, is not just about how drugs change the brain; it is also about how the brain changes in response to drugs—and how we can harness these changes safely and ethically in the service of treating disease.

Neuropharmacology III: Clinical Drugs, Cannabinoids & Addiction

In the previous section, we explored major classes of psychoactive drugs—opiates, stimulants, and hallucinogens—and began to connect their subjective effects to their molecular actions on neurotransmitter systems. We also saw that some of these compounds, especially psychedelics, may have carefully controlled clinical uses despite their history as recreational substances.

In this final section on neuropharmacology, we will:

• Revisit hallucinogens with an emphasis on their clinical applications.
• Survey key clinical drug classes (antipsychotics, antidepressants, anesthetics, depressants).
• Introduce cannabinoids and the brain’s endocannabinoid system.
• Develop a framework for understanding addiction / substance use disorders (SUDs), their neural basis, and approaches to treatment.

Psychedelics and Their Clinical Potential (Recap)

Hallucinogens, or psychedelics, are drugs that create profound perceptual distortions—visual, auditory, and somatosensory—and shifts in cognition and emotion. As noted earlier:

• They often act as agonists or partial agonists at 5-HT_2A and other monoamine receptors.
• They do not typically produce classic physical dependence, but can still be abused (non-medical or illicit use).

Key examples include:

• LSD – a 5-HT_2A receptor agonist derived from ergotamine (a natural product from the ergot fungus). Produces vivid visual changes, complex patterns, altered sense of time and self.
• Psilocybin – the active component of certain mushrooms; partial agonist at 5-HT receptors, especially 5-HT_2A, strongly affecting visual cortex and frontal networks.
• Ketamine – a dissociative anesthetic; NMDA receptor antagonist with additional actions on opioid and cholinergic systems.
• MDMA – increases release of serotonin, dopamine, norepinephrine, and oxytocin, producing intense prosocial and empathogenic effects.

Recent research suggests that, when used in a structured therapeutic context (screened patients, controlled dosing, psychotherapy support), these compounds may:

• Rapidly relieve symptoms of treatment-resistant depression, anxiety, and certain obsessive–compulsive symptoms.
• Reduce the burden of cluster headaches in some patients.
• Assist in treating PTSD (especially MDMA-assisted psychotherapy).
• Support recovery from alcohol use disorder and other addictions (e.g., LSD/psilocybin in trials).

Important: this promising work does not mean unsupervised use is safe. The clinical setting is tightly controlled, unlike recreational contexts.

Major Clinical Neuropsychiatric Drugs

Beyond recreational substances, many psychoactive drugs are prescribed daily for psychiatric and neurological conditions. Here we consider four broad categories:

1. Antipsychotics
2. Antidepressants
3. Anesthetics
4. Depressants (anxiolytics, sedatives, hypnotics)

Antipsychotics

Antipsychotic drugs are among the most frequently prescribed classes of medications in psychiatry. They are primarily used to treat psychotic disorders such as schizophrenia and schizoaffective disorder, and sometimes bipolar disorder with psychotic features.

Two broad groups are often distinguished:

• Typical (first-generation) antipsychotics
  • Primarily D₂ dopamine receptor antagonists.
  • Reduce positive symptoms of psychosis: paranoia, delusions, hallucinations (e.g., “voices”).
  • Side effects often include motor symptoms (Parkinsonian-like effects, tardive dyskinesia) due to DA blockade in motor pathways.
• Atypical (second-generation) antipsychotics
  • Act on DA receptors and other transmitters (often serotonin, e.g., 5-HT_2A antagonism).
  • Better at addressing some negative symptoms (social withdrawal, blunted affect) and cognitive deficits.
  • Generally less motor side effects, but can cause metabolic problems (weight gain, diabetes risk).

Antidepressants

Antidepressants are widely prescribed for major depressive disorder, anxiety disorders, and related conditions. They primarily modulate monoamine neurotransmission (5-HT, NE, DA).

Major classes include:

• SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin–norepinephrine reuptake inhibitors)
  • Block reuptake of 5-HT (SSRIs) or both 5-HT and NE (SNRIs).
  • Increase monoamine levels in the synaptic cleft, enhancing receptor activation.
• Tricyclic antidepressants (TCAs)
  • Older drugs that block reuptake of 5-HT, NE, and often DA.
  • Effective but can have significant side effects (anticholinergic, cardiotoxic at high doses).
• MAOIs (monoamine oxidase inhibitors)
  • Inhibit monoamine oxidase, the enzyme that degrades monoamine neurotransmitters.
  • Increase levels of 5-HT, NE, and DA.
  • Less commonly used now due to potential dangerous interactions (e.g., with certain foods and medications) and risk of severe side effects.

Anesthetics

Anesthetics are drugs that produce unconsciousness (general anesthesia) or localized loss of sensation (local anesthesia).

Local anesthetics:

• Block voltage-gated Na⁺ channels (VGNaCs) in peripheral nerves.
• Prevent action potentials from propagating along sensory fibers → loss of sensation in the targeted region.

General anesthetics:

• Often enhance GABA_A receptor function (e.g., many IV and inhaled agents, propofol) → increased inhibition → loss of consciousness.
• Some inhibit specific glutamate receptors (e.g., ketamine and xenon as NMDA antagonists), leading to dissociative states or anesthesia.
• Multiple molecular targets are usually involved; the precise mechanisms are complex.

Depressants (Anxiolytics, Sedatives, Hypnotics)

Depressants are drugs that depress action potential firing and neural activity (the term “depressant” refers to neural activity, not necessarily mood). They are often used as:

• Anxiolytics – reduce anxiety.
• Sedatives – calm and reduce arousal.
• Hypnotics – promote sleep.

Most act as agonists (or positive allosteric modulators) at inhibitory receptors:

• GABA_A receptors – primary target of benzodiazepines, barbiturates, and ethanol (alcohol).
• Glycine receptors – additional inhibitory targets in spinal cord and brainstem.

Examples include:

• Benzodiazepines – enhance GABA_A receptor activity; used for anxiety, insomnia, seizures.
• Barbiturates – older sedative–hypnotics; powerful but with high overdose risk.
• Alcohol (ethanol) – complex actions; prominently increases GABAergic inhibition and alters glutamate signaling.

Cannabinoids and the Endocannabinoid System

Marijuana is derived from Cannabis sativa. Its best-known psychoactive component is Δ⁹-tetrahydrocannabinol (THC), but the plant contains many other biologically active compounds, including cannabinol (CBN), cannabidiol (CBD), and tetrahydrocannabivarin.

Physiological Effects of Cannabis

Cannabis produces a mixture of effects:

• Some excitatory or stimulating effects (e.g., mild euphoria, altered perception).
• Sometimes sedative, calming effects (but typically without the risk of respiratory failure seen with opioids).
• Mild analgesia – relief of certain types of pain.
• Antiemetic effects and appetite stimulation (“the munchies”).
• At high doses, can produce perceptual changes or hallucinations in some users.

Endocannabinoids: Natural Cannabinoid-like Transmitters

The brain produces its own cannabis-like molecules, called endocannabinoids.

• The first identified was anandamide (from Sanskrit for “bliss”).
• Another abundant endocannabinoid is 2-arachidonoylglycerol (2-AG).

Endocannabinoids are:

• Lipid-like (fatty) molecules, synthesized on demand in the postsynaptic neuron.
• Often released retrogradely (from postsynaptic cell back to presynaptic terminal), where they modulate neurotransmitter release.

Cannabinoid Receptors

There are two major cannabinoid receptor types, both G protein–coupled (metabotropic):

• CB1 receptors
  • Abundant in the CNS (cortex, hippocampus, basal ganglia, cerebellum).
  • Mediate many of the psychoactive and rewarding properties of cannabinoids, including THC.
• CB2 receptors
  • Prominent in the immune system and peripheral tissues.
  • Involved in inflammation and immune responses; may play a role in pain and immune modulation.

Medical Uses of Cannabis and Cannabinoids

Clinically, cannabinoids (plant-derived or synthetic) may be used for:

• Anxiolysis – reduction of anxiety in some patients.
• Analgesia – relief of certain chronic pain conditions.
• Anti-emetic and appetite stimulation – THC-based medications are approved for chemotherapy-induced nausea and appetite loss.
• Anticonvulsant – CBD-based medications are approved for specific seizure disorders.
• Lowering intraocular pressure – historically, for glaucoma (now less commonly first-line).
• Cardiovascular effects – can lower blood pressure in some contexts, though this may not always be desirable.

As with all psychoactive drugs, benefits must be weighed against risks (e.g., cognitive effects, dependence in some individuals, and possible interactions with other conditions or medications).

Addiction and Substance Use Disorders (SUDs)

Not all psychoactive drugs are equally addictive. A critical organizing idea is:

Examples with high addiction liability:

• Alcohol
• Benzodiazepines and other depressants
• Nicotine
• Opiates/opioids
• Cocaine

Neural Development

We have focused till this point on the adult nervous system—how neurons are built, how they communicate, and how drugs modulate their activity. But those mature circuits do not simply appear fully formed. They are the end result of a long, tightly orchestrated sequence of developmental events that begin with a single cell.

Neural development asks:

From Fertilized Egg to Germ Layers

Development begins at the moment of fertilization:

• Fertilized egg (zygote) – a single totipotent cell.
  • Definition. A totipotent cell can divide and give rise to all cell types in the body, including extra-embryonic tissues (e.g., placenta).
• As the zygote divides, it gives rise to pluripotent cells.
  • Definition. Pluripotent cells have begun to specialize, but can still generate many different tissues of the embryo proper.

Early in development, a key process called gastrulation reorganizes the embryo and establishes three primary lineages known as the germ layers:

• Endoderm – gives rise to the lining of the gut and associated organs (e.g., liver, lungs).
• Mesoderm – forms muscle, bone, blood, and connective tissue.
• Ectoderm – forms skin and the entire nervous system.

Neural Tissue from Ectoderm

It may feel surprising that the brain—buried inside the skull—is derived from the outermost germ layer, the ectoderm. Most ectodermal cells become “outside” structures such as skin. Neural tissue arises because part of this ectodermal sheet folds inward into the interior of the embryo.

The sequence looks like this (simplified):

1. The dorsal ectoderm thickens to form the neural plate.
2. The neural plate invaginates (folds in) to form the neural groove.
3. The sides of the groove elevate and fold toward each other.
4. When the folds meet and fuse, they form the neural tube.

The neural tube ultimately gives rise to the central nervous system (CNS)— brain and spinal cord. The cells at the crest of the folding ectoderm, the neural crest cells, migrate out and form much of the peripheral nervous system (PNS), including:

• sensory ganglia,
• autonomic ganglia,
• and some non-neural structures (e.g., parts of the face and skull).

Early Patterning: Spinal Cord to Forebrain

Development is polar: as the neural tube forms, it becomes spatially organized along its length. Different regions along the rostrocaudal (head-to-tail) axis will form major divisions of the CNS:

• Spinal cord – caudal (tail) end of the tube.
• Rhombencephalon (hindbrain) – will give rise to medulla, pons, cerebellum.
• Mesencephalon (midbrain).
• Diencephalon and telencephalon (forebrain):
  • Diencephalon – thalamus, hypothalamus.
  • Telencephalon – cerebral hemispheres (cortex, basal ganglia, etc.).

Signals along the neural tube (from adjacent tissues and internal patterning molecules) help establish where spinal cord, hindbrain, midbrain, and forebrain territories will form. This “rough map” is in place very early; the rest of development refines, populates, and connects these regions.

The Six Stages of Neural Development

We can conceptually break neural development into six major stages. In reality, many of these overlap in time, but it is useful to treat them separately:

1. Neurogenesis – birth of neurons and glia from precursor cells.
2. Cell migration – movement of cells to their appropriate locations.
3. Cell differentiation – cells become specific neuron or glial types.
4. Synaptogenesis – growth of axons/dendrites and formation of synapses.
5. Neuronal cell death – selective elimination of many neurons.
6. Synapse rearrangement – pruning and refinement of synaptic connections.

Stage 1 – Neurogenesis

Definition. Neurogenesis is the production of new nerve cells (neurons) from dividing precursor cells.

Inside the neural tube is a region called the ventricular zone (VZ). Here:

• Non-neural precursor cells undergo mitosis.
• These dividing precursors give rise to neural progenitor cells.
• Progenitors can then become either neurons or glial cells (astrocytes, oligodendrocytes).

Early in development, neurogenesis is extremely active; later, much of it slows or stops, and the brain relies more on refining existing circuits than adding entirely new neurons (with some regional exceptions).

Stage 2 – Cell Migration

Once neurons are born, they rarely stay where they were generated. In cell migration, neurons move away from the ventricular zone to form distinct layers and nuclei.

Key features:

• Cells closest to the ventricles are established first.
• Later-born neurons must often crawl past older neurons to form more superficial layers.
• Radial glial cells act as scaffolding or “glial spokes” along which neurons migrate outward.
• Cell adhesion molecules (CAMs) help cells stick to appropriate pathways and neighbors.

In the cerebral cortex, this results in an “inside-out” layering: older neurons form deeper layers; younger neurons migrate further to form more superficial layers.

Stage 3 – Cell Differentiation

After migration, neurons must acquire their mature identity.

• Cells differentiate into specific neuronal types (e.g., pyramidal cells, interneurons) or glial types (astrocytes, oligodendrocytes).
• Differentiation depends on:
  • Intrinsic factors – gene expression programs already active in the cell.
  • Extrinsic cues – signals from neighboring cells, local environment, and afferent inputs.

Location matters: the physical position of a cell within the nervous system exposes it to specific cues, which help determine what that cell will become. Once differentiated, neurons must then form functional connections—enter synaptogenesis.

Stage 4 – Synaptogenesis

Synaptogenesis is the process by which neurons extend processes and form synapses with their appropriate targets.

Two related processes occur:

• Process outgrowth – growth of axons and dendrites.
• Synapse formation – making specific, functional contacts with target cells.

At the tips of growing axons and dendrites are specialized structures called growth cones.

• Growth cones have thin, finger-like protrusions called filopodia.
• Filopodia “sample” the environment—probing for chemical and physical cues.
• Growth cones steer toward attractive cues and away from repulsive ones.

Target cells and intermediate guideposts release:

• Chemoattractants – diffusible or surface-bound chemical cues that attract certain growth cones.
• Chemorepellents – cues that repel certain growth cones.

The general strategy is:

Stage 5 – Neuronal Cell Death (Apoptosis)

One of the striking features of neural development is that many more neurons are produced than will survive. A significant fraction of neurons undergo programmed cell death.

Definition. Apoptosis is an active, regulated form of cell death—sometimes called “cellular suicide.” It is not an accident; it is part of the normal developmental program.

Why kill off neurons? Because the nervous system adopts a “make more than you need, then keep the best” strategy:

• Neurons compete for trophic factors (“nourishing” factors) produced by their target cells.
• Correct synaptic connections allow neurons to receive the right amount of trophic support.
• Neurons that fail to make appropriate, functional connections receive inadequate trophic support and activate apoptotic pathways.

A simplified model:

• Target cells secrete specific neurotrophic factors (e.g., NGF, BDNF).
• Neurons that successfully innervate those targets take up the “right” trophic factor.
• Trophic factor uptake triggers pro-survival gene expression.
• Neurons that fail to receive sufficient trophic support undergo apoptosis.

Apoptosis proceeds through characteristic stages:

• Chromatin condensation – DNA condenses and becomes fragmented.
• Nuclear fragmentation.
• Blebbing – cell membrane forms bulges.
• Cell fragmentation into small vesicles.
• Cell remnants are cleared by phagocytic cells (e.g., microglia).

Far from being purely destructive, this “sculpting by cell death” helps match the number of neurons to the size and needs of their target tissues.

Stage 6 – Synapse Rearrangement (Pruning and Refinement)

Even after neuronal cell death, the nervous system is still over-connected. Many synapses are present that will not be maintained into adulthood. In synapse rearrangement, connections are refined:

• Some synapses are strengthened and stabilized.
• Others are weakened and eventually eliminated (pruned).

This process is heavily influenced by neural activity and experience:

• “Active” synapses that contribute to useful circuits tend to be preserved and strengthened.
• “Inactive” or mismatched synapses are more likely to be pruned away.

Pruning helps:

• Sharpen topographic maps (e.g., in sensory cortices).
• Refine motor coordination.
• Optimize efficiency and reduce redundancy in neural circuits.

Thus, development follows a general blueprint:

1. Generate lots of cells and processes.
2. Let them explore and form many candidate connections.
3. Use trophic factors and activity-dependent rules to keep the best matches.
4. Eliminate the rest through apoptosis and synaptic pruning.

Putting It All Together

Neural development is not a rigid assembly line but a dynamic conversation between genes, cells, and environment:

• Spatial cues and timing help define who becomes spinal cord, hindbrain, midbrain, or forebrain.
• Migration and differentiation generate the right cell types in the right places.
• Synaptogenesis, cell death, and synapse rearrangement refine those early circuits based on trophic support and activity patterns.

The end result is a brain whose structure reflects both a genetic plan and a history of experience. This developmental framework sets the stage for all of the physiology and neuropharmacology we have discussed—and for the remarkable capacity of the nervous system to adapt, learn, and change across the lifespan.

Circadian Rhythms

Just as neural development shapes wherehow circuits are wired, circadian systems shape when those circuits are most active. The Earth rotates once every 24 hours, producing a regular light–dark cycle. Life evolved in this rhythmic environment, and many organisms—from bacteria to humans—have internal timing systems that anticipate these daily changes rather than merely reacting to them.

The field that studies these daily timing processes is chronobiology, and its core concept is the circadian rhythm.

What Is a Circadian Rhythm?

The term circadian comes from Latin:

• circa – “about” or “approximately”
• dia – “day”

Definition. A circadian rhythm is any biological process that shows a roughly 24-hour cycle in the absence of external timing cues. These rhythms can be:

• Behavioral – sleep–wake cycles, activity vs. rest, feeding patterns.
• Physiological – body temperature, hormone secretion (e.g., cortisol, melatonin), heart rate.
• Biochemical – gene expression, enzyme activity, receptor sensitivity.

Humans show clear circadian rhythms: we tend to sleep at night, have peak alertness during the day, and daily oscillations in temperature and hormone levels—even when external cues are reduced.

Measuring Circadian Rhythms: Actograms

In the lab, circadian rhythms are often visualized using an actogram.

Definition. An actogram is a plot of activity (e.g., wheel running) over time, typically:

• Each horizontal line = one day of recording.
• Activity (e.g., wheel revolutions) is marked as dark bars.
• Days are stacked vertically so patterns across days can be seen.

When animals are kept on a normal 12 h light–12 h dark schedule (LD 12:12), actograms show activity aligned to the light–dark cycle (e.g., nocturnal rodents run mostly during the dark phase). When these external cues are removed (constant darkness, DD), rhythms often “drift,” revealing the properties of the internal clock.

Endogenous Clocks, Free-Running Rhythms, and Entrainment

Circadian rhythms are not simply driven by the environment—they are generated by an internal endogenous clock.

Definition. A free-running rhythm is the rhythm expressed by an organism when it is isolated from time cues (e.g., kept in constant darkness). Under these conditions:

• Animals still show regular activity cycles.
• However, the period is often not exactly 24 h (e.g., 23.5 h or 24.5 h).

This shows that the internal clock runs “about” a day—circa dia—but needs the environment to stay perfectly aligned.

External cues that synchronize the internal clock to the outside world are called zeitgebers (“time-givers”). Common zeitgebers include:

• Light–dark cycles (the most powerful for many species).
• Feeding schedules.
• Social cues or temperature cycles.

Definition. Entrainment is the process by which the internal circadian clock is reset each day to match environmental zeitgebers. When the timing of the zeitgeber changes, the rhythm gradually shifts to realign.

A phase shift is the change in the timing of a circadian rhythm in response to a synchronizing cue (for example, when the onset of darkness is moved earlier or later).

Effect of Changing Zeitgebers

When the light–dark schedule is abruptly shifted:

• The animal’s activity rhythm gradually shifts to match the new cycle—this is a phase shift.
• In constant darkness, with no zeitgebers, the animal shows its intrinsic free-running period (~24 h but not exactly).

This is analogous to human experiences of jet lag or shift work: our internal clock must gradually re-entrain to a new light–dark schedule.

The Suprachiasmatic Nucleus: The Master Clock

In mammals, the central circadian clock resides in the suprachiasmatic nucleus (SCN), a small bilateral structure in the hypothalamus, located just above the optic chiasm.

Key evidence:

• Lesions of the SCN disrupt circadian rhythms.
  • Animals first entrained to a light–dark cycle show clear rhythms.
  • After SCN lesions, rhythms become disorganized, especially in constant darkness.
• Isolated SCN neurons in culture maintain rhythmic electrical activity that reflects the previous light–dark cycle—indicating that rhythm generation is intrinsic to SCN cells.

Strikingly, transplant experiments demonstrate that the SCN not only generates rhythms but also determines their period.

SCN Transplant Experiments

Classic experiments in hamsters:

1. Lesion the SCN → abolish the animal’s circadian rhythm.
2. Transplant fetal SCN tissue from a donor with a known circadian mutation—e.g., the tau mutation, which produces a ~20 h period.
3. The recipient’s circadian rhythm is restored, but now with the shorter period of the donor SCN.

This shows that the SCN contains an intrinsic, transplantable clock that sets the period of the organism’s circadian rhythms.

Light as a Zeitgeber: The Retinohypothalamic Pathway

How does light reset the clock in mammals? Light does not act only through rods and cones for vision; there is a dedicated pathway:

Definition. The retinohypothalamic pathway carries light information from the eye directly to the SCN.

• It consists of a special set of retinal ganglion cells whose axons project to the SCN.
• These ganglion cells:
  • Do not rely on rods and cones for their light sensitivity.
  • Contain melanopsin, a unique photopigment.
  • Are especially sensitive to blue light (short wavelengths).

In other vertebrates:

• In amphibians and birds, the pineal gland is directly light-sensitive and participates in circadian photoreception.
• In mammals, the pineal gland primarily secretes melatonin, but light detection for entrainment is mediated by retina → SCN.

Components of a Circadian System

We can think of a circadian system as having three major components:

• Input – pathways that convey zeitgeber information (e.g., retinohypothalamic pathway for light).
• Clock – the core oscillator (SCN in mammals) that generates ~24 h cycles.
• Output – neural and hormonal routes through which the SCN influences behavior and physiology (e.g., sleep–wake, hormone release, body temperature).

Molecular Basis of the Circadian Clock

At the cellular level, the circadian clock in SCN neurons is built from a transcription–translation feedback loop involving specific clock genes and proteins.

In mammals, SCN cells produce at least two key proteins:

• Clock
• Bmal1 (the mammalian homolog of the Drosophila protein Cycle)

These proteins bind to each other to form a Clock/Bmal dimer. This dimer acts as a transcription factor to promote expression of other clock genes, including:

• Period (Per)
• Cryptochrome (Cry)

The Negative Feedback Loop

The Per and Cry proteins, once synthesized:

• Bind to each other in the cytoplasm to form a Per/Cry complex.
• The Per/Cry complex translocates back into the nucleus.
• Inside the nucleus, it inhibits the activity of the Clock/Bmal dimer, reducing transcription of the Per and Cry genes.

As a result:

• Per and Cry protein levels gradually decline as existing proteins degrade.
• Once they drop sufficiently, inhibition is lifted, Clock/Bmal activity resumes, and a new cycle of Per/Cry production begins.

This feedback loop takes about 24 hours to complete, generating a molecular oscillation that underlies the circadian rhythm.

How Light Resets the Molecular Clock

Light can reset the phase of this molecular clock:

• In flies, light reaches the brain directly and can degrade Cry protein, resetting the feedback loop.
• In mammals:
  • Light is detected by melanopsin-containing retinal ganglion cells.
  • These cells send signals via the retinohypothalamic pathway to the SCN.
  • At the SCN, they release glutamate onto clock neurons.
  • Glutamate-triggered signaling leads to increased Per expression, shifting the phase of the Per/Cry cycle and, consequently, the animal’s behavior.

Sleeping and Waking: A Behavioral Output of the Clock

One of the most obvious circadian outputs in humans is the sleep–wake cycle.

• Sleep tends to be synchronized to outside events, especially light–dark cycles.
• Additional cues—jobs, mealtimes, alarm clocks—act as zeitgebers that shape when we are awake or asleep.

When external cues are removed, humans show a free-running period of about 25 hours on average (with some individual variation and age dependence). This highlights the importance of daily entrainment by light and social schedules.

Sleep Across the Life Span

Human sleep patterns change dramatically with age.

Infancy. Newborns and infants:

• Sleep much more overall than adults.
• Have shorter sleep cycles (e.g., 50–60 minutes rather than 90 minutes).
• Spend a larger fraction of sleep in REM sleep (rapid eye movement sleep)—around 50% in early life.

REM sleep is characterized by:

• Rapid eye movements.
• Low muscle tone (near paralysis).
• Vivid dreaming.

The high amount of REM sleep in infancy may provide essential internal stimulation for the developing nervous system (when external sensory experience is limited).

Some infants are slow to entrain their sleep to the day–night cycle, leading to highly irregular sleep for the baby—and for the caregiver. Classic case studies highlight just how variable early circadian development can be.

Adulthood and aging. As we age:

• Total sleep time generally decreases.
• Proportion of REM sleep declines compared to infancy.
• Sleep may become more fragmented in older adulthood.

Developmental Changes in Circadian Rhythms

During puberty, many individuals experience a noticeable shift in their circadian rhythms:

• They naturally prefer to fall asleep later and wake up later.
• This is not just “laziness”—it reflects a biologically driven phase delay in the circadian system.

Unfortunately, many high schools require very early start times, forcing adolescents to wake up long before their internal clock says “morning.” This mismatch:

• Reduces total sleep time.
• Increases daytime sleepiness and in-class sleeping.
• Is associated with worse mood and greater risk of depression.

Studies of districts that have delayed school start times show:

• Improved attendance and enrollment.
• Less daytime sleepiness.
• Better mood and academic outcomes.

Extreme Variants: Sleep Phase Syndromes

Some individuals show extreme deviations from typical sleep timing that have a genetic basis.

• Familial advanced sleep phase syndrome (FASPS)
  • People become sleepy very early in the evening and wake up very early in the morning.
  • Often linked to mutations in core clock genes (e.g., Per genes).
• Delayed sleep phase syndrome (DSPS)
  • Sleep onset is greatly delayed; individuals naturally fall asleep and wake much later than typical.
  • Can cause significant social and occupational impairment when schedules conflict with the internal clock.

These syndromes illustrate that our preferred sleep–wake timing is not purely a matter of “willpower”—underlying clock mechanisms and genetics play a major role.

Summary

Circadian rhythms demonstrate how deeply time is embedded in neurobiology:

• Endogenous clocks generate ~24 h rhythms.
• External zeitgebers, especially light, entrain these clocks to the environment.
• The SCN and its molecular clockwork coordinate timing across the brain and body.
• Sleep–wake cycles, hormone secretion, and even cognitive performance all bear the imprint of circadian control.

Understanding circadian rhythms is therefore essential not only for basic neuroscience, but also for practical issues like shift work, jet lag, school schedules, and the treatment of sleep and mood disorders.

Sensory Processing I

We have covered how neurons are built, how they communicate, and how their activity is timed across the day. The next question is: how does all of this circuitry allow us to sense the world? Sensory systems are the brain’s interfaces with the external (and internal) environment—they convert physical events into neural signals that the CNS can interpret and act upon.

In this section we will:

• Introduce general principles of sensory processing.
• Explain the idea of labeled lines and range fractionation.
• Use the skin as a concrete example of a complex sensory organ.

What Is Sensation?

The body has specialized organs and receptor cells that detect particular kinds of stimuli. These stimuli can be:

• Substances – e.g., molecules that carry the scent of vanilla, or chemicals that activate taste receptors.
• Forms of energy – e.g., a photon of light, mechanical pressure on the skin, heat, or sound waves.

Definition. Sensation is the detection of a stimulus by specialized receptor cells and its conversion into an electrical signal that the nervous system can use.

These receptor cells carry out sensory transduction—they translate physical events into graded electrical changes, and ultimately into action potentials in sensory neurons. The brain then integrates information across multiple sensory modalities (vision, touch, hearing, etc.) to construct a coherent representation of the world.

What Kinds of Stimuli Can We Detect?

Sensory systems can be organized by the type of stimulus energy they detect. Examples include:

• Mechanical – touch, pressure, stretch, vibration, sound (mechanical movement of air), proprioception.
• Visual – photons of light in a particular wavelength range.
• Thermal – warmth and cold, via temperature-sensitive receptors.
• Chemical – taste, smell, internal chemical composition (e.g., CO₂, pH, hormones).
• Electrical and magnetic – important in many non-human species (e.g., electroreception in fish, magnetoreception in migratory animals).

Regardless of the stimulus category, the brain faces the same problem:

Themes of Sensory Processing

There are several recurring principles across sensory systems:

• Specialization of receptor cells. Different sensory neurons are specialized to translate specific kinds of stimuli into electrical signals (e.g., photoreceptors for light, mechanoreceptors for touch).
• Preservation of spatial information. The anatomical organization of the CNS often mirrors the spatial layout of receptors (e.g., maps of the body surface, visual space, or auditory space).
• Difference detection. The nervous system emphasizes changes and contrasts:
  • New or changing stimuli are highlighted.
  • Edges and boundaries are exaggerated (e.g., where light or touch changes abruptly).
• Bottom-up and top-down influences. Sensory signals are shaped both by incoming information (“bottom-up”) and by expectations, goals, and attention from higher brain centers (“top-down”).

Labeled Lines: How Does the Brain Know What Type of Stimulus It Was?

All sensory systems ultimately use the same basic currency—action potentials. An AP on a given axon looks essentially like an AP on any other axon. So how does the brain distinguish heat from a pinprick, or sound from light?

The answer lies in specialization of receptor neurons and their wiring.

• Individual sensory neurons are tuned to one particular modality (or a narrow range of modalities):
  • Some respond only to mechanical stretch.
  • Others respond only to temperature changes.
  • Others respond only to photons in a certain wavelength range, etc.
• The axons of these neurons project along specific pathways to defined regions of the CNS.

This leads to a “labeled lines” organization:

Definition. In labeled line coding, each sensory neuron and its pathway carry information about one type of stimulus. The brain can infer the stimulus type simply from which line is active, even though the action potentials themselves look the same.

For example, if a particular set of touch receptors is active, the brain interprets the signal as “vibration on the fingertip,” not “flash of light,” because those axons originate in skin receptors and terminate in somatosensory pathways.

Skin as a Sensory Organ: Sensory Transduction and Receptor Potentials

The skin is a rich example of a complex sensory organ. It contains multiple receptor types, each tuned to a particular form of mechanical or thermal stimulus (light touch, deep pressure, stretch, vibration, pain, temperature).

Sensory transduction begins when a stimulus causes a change in membrane potential in the receptor cell. In many somatosensory neurons, the receptor is a specialized ending of the neuron itself.

When a stimulus is applied:

• Ion channels in the receptor ending open or close.
• This produces a receptor potential (also called a generator potential)—a local, graded change in membrane potential.
• If the receptor potential is large enough to reach threshold at the trigger zone (often near the first node of Ranvier), the sensory neuron generates action potentials.

Compare this to synaptic potentials:

• Previously, we discussed: neurotransmitter → postsynaptic potential → threshold → action potential.
• For sensory neurons, the sequence is: sensory stimulus → receptor potential → threshold → action potential.

The logic is similar—small, graded potentials are integrated, and if they are large enough, an “all-or-none” action potential is produced. The difference lies in the source of the graded potential: synaptic input vs. sensory receptor activation.

Example: Detecting Vibration with the Pacinian Corpuscle

The Pacinian corpuscle (or lamellated corpuscle) is a mechanoreceptor in the skin specialized for detecting vibration and rapid changes in pressure.

• It consists of a nerve ending wrapped in concentric layers of connective tissue (like an onion).
• When the skin is vibrated or rapidly deformed, these layers are distorted, and the nerve ending is mechanically stretched.

At the molecular level:

• The nerve ending contains stretch-sensitive cation channels.
• Deformation of the membrane opens these channels.
• Positive ions (e.g., Na⁺, Ca²⁺) enter, depolarizing the membrane—this is the receptor potential.

If the receptor potential is large enough, it triggers action potentials in the associated sensory axon. Stronger vibration produces larger receptor potentials and thus higher frequencies of action potentials.

Encoding Stimulus Intensity

Action potentials are binary events—each one either occurs or it does not. So how does the nervous system encode the intensity of a stimulus (e.g., light brush vs. firm pressure)?

There are two main strategies:

1. Frequency coding (within a single neuron).
   • As stimulus intensity increases, the frequency of action potentials increases.
   • A stronger stimulus → larger receptor potential → more rapid AP firing (up to a physiological limit).
2. Population coding and range fractionation (across multiple neurons).
   • Different sensory neurons of the same modality (e.g., stretch-sensitive neurons) can have different thresholds for firing.
   • “High-sensitivity” neurons respond to weak stimuli; “low-sensitivity” neurons fire only when the stimulus is strong.

Definition. Range fractionation is the strategy in which different cells in a sensory system have different thresholds, allowing the system as a whole to encode a wide range of stimulus intensities.

By reading out:

• Which neurons are active (low-threshold vs. high-threshold), and
• How fast they are firing,

the CNS can infer both the quality and the intensity of the stimulus.

Difference Detection and Sensory Adaptation

Sensory systems are particularly good at detecting changes rather than steady-state conditions. When a new stimulus appears:

• Sensory neurons often fire a burst of high-frequency action potentials.
• If the stimulus continues without change, the firing rate typically declines over time.

This decline in responsiveness during a constant stimulus is called sensory adaptation.

Definition. Sensory adaptation is the progressive decrease in receptor response (and thus firing rate) during a sustained stimulus.

Adaptation helps the nervous system:

• Filter out unchanging background stimulation.
• Direct attention to novel or changing stimuli—things that may be more behaviorally relevant.

Phasic vs. Tonic Receptors

Not all sensory neurons adapt to the same degree.

• Phasic receptors show strong adaptation:
  • They respond vigorously when a stimulus is first applied.
  • Their firing rate drops quickly if the stimulus is maintained.
  • They are excellent at signaling changes or stimulus onset/offset.
• Tonic receptors show little or no adaptation:
  • They continue to fire as long as the stimulus is present.
  • They encode the ongoing level of a stimulus (e.g., sustained pain, steady pressure).

Adaptation is one mechanism by which the nervous system implicitly says, “this stimulus is no longer new—shift attention elsewhere.”

Other Ways to Control Sensory Input

In addition to adaptation, the nervous system can regulate sensory input by:

• Accessory structures – physical structures that limit or modulate stimulation:
  • Eyelids that close or narrow the opening,
  • Pupil constriction or dilation,
  • Middle-ear muscles that dampen loud sounds.
• Top-down processing – higher brain centers can:
  • Suppress some sensory inputs (e.g., ignoring background noise), or
  • Amplify others (e.g., focusing attention on a faint sound).

Somatosensory Receptive Fields

To know where a stimulus came from, the brain relies on the concept of receptive fields.

Definition. The receptive field of a somatosensory neuron is the specific region of the body surface in which a stimulus will alter the firing of that neuron.

Important consequences:

• The location of an active neuron tells the brain which body region is stimulated.
• The size of the receptive field limits spatial resolution.

The Two-Point Discrimination Test

A simple demonstration of receptive fields is the two-point discrimination test.

• Two points (e.g., toothpicks) are pressed simultaneously against the skin.
• The distance between the points is varied.
• The subject reports whether they feel one point or two.

If the two points fall within the same neuron’s receptive field, they are perceived as one stimulus. If they fall in separate receptive fields, they are perceived as two.

Results:

• On the fingertip, two points as close as 2–3 mm can be distinguished.
• On the back, the threshold distance is around 40 mm.

This difference reflects:

• Much smaller receptive fields on the fingertips, and
• Higher density of sensory neurons in regions where fine touch discrimination is behaviorally important.

Somatosensory Maps in Cortex

The somatosensory system detects body sensations, including touch, temperature, proprioception, and pain. Information from the body surface ultimately reaches the primary somatosensory cortex (S1).

• The body surface is mapped onto S1 in an orderly, somatotopic fashion.
• Each part of the body corresponds to a specific cortical region.
• Sensory information is organized largely in a contralateral manner (left body → right cortex, and vice versa).
• The amount of cortical area devoted to a body part is proportional to its sensory importance and receptor density (e.g., large areas for hands and face, smaller for trunk and legs).

This cortical “map” (often illustrated as a sensory homunculus) reflects how central the skin and body senses are for guiding our behavior and interaction with the world.

Together, concepts like labeled lines, receptor potentials, adaptation, range fractionation, and receptive fields form the foundation for understanding sensory processing. In subsequent sections we will delve more deeply into specific sensory modalities and how their detailed circuitry supports perception.

Sensory Processing II & Pain

In the previous section we focused on how sensory receptors in the skin translate physical stimuli into receptor potentials and action potentials, and how concepts like labeled lines, range fractionation, and receptive fields allow the nervous system to encode what and how strong a stimulus is. We now follow these signals into the central nervous system and examine one of the most complex and important sensory experiences: pain.

Organization of the Somatosensory System

The somatosensory system detects body sensations, including touch, proprioception, temperature, and pain. Several organizing principles carry over from the periphery into the brain:

• Stimulus type and location.
  • Stimulus type is encoded by which receptor class is activated (mechanoreceptors, thermoreceptors, nociceptors, etc.).
  • Stimulus location is inferred from the position of the activated receptors on the body surface.
• Contralateral processing. Information from one side of the body is largely processed in the opposite (contralateral) hemisphere.
• Somatotopic mapping. The body surface is systematically mapped onto the primary somatosensory cortex (S1). Neighboring points on the skin project to neighboring regions in S1.
• Cortical magnification. The amount of cortex devoted to a body part is proportional to its sensory acuity, not to its physical size (large representation of hands and lips; small of back and trunk).
• Thalamic relay. Somatosensory information typically passes through the thalamus before reaching S1. The thalamus acts as a relay and processing hub for sensory signals.

Primary vs. Secondary Somatosensory Areas

Within cortex, we can distinguish between:

• Primary somatosensory cortex (S1).
  • The first cortical area to receive somatosensory input from the thalamus.
  • Contains a detailed somatotopic map.
  • Encodes basic features such as location, intensity, and type of somatic stimulus.
• Secondary somatosensory cortex (SII) and higher areas.
  • Receive input from S1 and other regions.
  • Integrate somatosensory signals with information from other modalities and with memory.
  • Contribute to learning, recognition of objects by touch (stereognosis), and more abstract representations of the body.

Thus, somatosensory processing progresses from basic detection in S1 to higher-order interpretation and integration in SII and beyond.

Pain: An Unpleasant but Adaptive Experience

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Despite its negative quality, pain is profoundly adaptive:

• It motivates us to withdraw from harmful stimuli.
• It encourages rest and recuperation when tissue is damaged.
• It serves as a social signal to others, recruiting help and modifying social behavior.

There are large individual differences in sensitivity to pain. At one extreme, complete inability to sense pain is possible—but dangerously so.

Congenital Insensitivity to Pain (CIP)

Congenital insensitivity to pain is a rare inherited disorder in which individuals cannot feel pain.

• Often caused by mutations in specific voltage-gated sodium channels expressed in nociceptive neurons.
• Because these channels do not function normally, affected sensory neurons cannot generate action potentials in response to painful stimuli.
• Children with CIP frequently present with:
  • Severe oral injuries from biting tongue or lips.
  • Untreated fractures or burns.
  • Advanced infections due to unnoticed injuries.

Paradoxically, the absence of pain is not a blessing—it removes a critical protective system.

Paroxysmal Extreme Pain Disorder (PEPD)

Another rare inherited condition involving the same sodium channel gene produces the opposite problem: paroxysmal extreme pain disorder.

• Characterized by sudden, intense bouts of pain, often in specific body regions (e.g., jaw, rectal area, eyes).
• Here the sodium channel is over-active, making nociceptive neurons hyperexcitable.

Together, CIP and PEPD illustrate how small genetic changes in ion channels can drastically alter pain perception.

Phantom Limb Pain

Phantom limb pain is a form of neuropathic pain that occurs after amputation.

• Individuals feel pain seemingly coming from a limb that is no longer present.
• The phantom limb is often perceived as “clenched” or “twisted,” and attempts to “move” it may change the pain.
• Neurons in the CNS that formerly received input from the missing limb can develop aberrant activity patterns in the absence of normal input.
• Cortical maps can reorganize (plasticity), and inputs from neighboring body regions may invade territory formerly devoted to the missing limb.

Treatments such as mirror therapy (creating the visual appearance of a controllable limb) can sometimes reduce phantom pain by re-establishing a more coherent link between intended movement and sensory feedback.

Measuring Human Pain: The McGill Pain Questionnaire

Pain is not simply a single sensation; it has multiple components. The McGill Pain Questionnaire distinguishes three major dimensions:

• Sensory–discriminative – the quality and intensity of the pain:
  • e.g., throbbing, stabbing, burning, aching; mild vs. intense.
• Motivational–affective – the emotional quality:
  • e.g., tiring, sickening, fearful, punishing.
• Cognitive–evaluative – how the pain is interpreted and appraised:
  • e.g., “no pain,” “annoying,” “unbearable,” “excruciating.”

These dimensions help explain why two people with similar injuries can report very different pain experiences, and why psychological factors (attention, expectation, mood) strongly shape pain perception.

Nociceptors: Peripheral Pain Receptors

Nociception is the neural process of encoding and processing noxious (potentially tissue-damaging) stimuli. The receptors that initiate nociception are called nociceptors.

• Nociceptors are specialized free nerve endings in the dermis and deeper tissues.
• They express receptor proteins that can be activated by:
  • Extreme temperatures (hot or cold).
  • Mechanical damage (pinch, cut, strong pressure).
  • Chemicals released during tissue injury or inflammation (e.g., prostaglandins, bradykinin, H⁺, ATP).

Examples: Heat, Cold, and Chemical Activation

Some nociceptors express transient receptor potential (TRP) channels that act as molecular thermometers and chemoreceptors.

• TRPV1 (transient receptor potential vanilloid type 1)
  • Activated by painful heat (around > 43 °C).
  • Also activated by the chemical capsaicin—the compound that makes chili peppers feel “hot.”
  • Expressed on C fibers: thin, unmyelinated axons that conduct action potentials slowly.
  • Responsible for slow, dull, burning pain that lingers.
• TRP2
  • Activated by even higher temperatures (more intense heat).
  • Does not respond to capsaicin.
  • Expressed on Aδ fibers (A-delta): larger, myelinated axons that conduct more rapidly.
  • Associated with fast, sharp, well-localized pain.
• CMR1 (cool–menthol receptor 1)
  • Activated by cool temperatures.
  • Also activated by menthol, which is why menthol feels cool.
  • Typically found on C fibers, contributing to slow, cool sensations.

By combining information from different fiber types (Aδ vs. C) and different receptors (TRPV1, TRP2, CMR1, etc.), the CNS can distinguish sharp vs. dull pain and hot vs. cold stimuli.

C Fibers vs. Aδ Fibers

Two major classes of nociceptive fibers carry pain information:

• Aδ fibers
  • Lightly myelinated, relatively fast conduction.
  • Convey the initial, sharp, pricking pain (“first pain”).
• C fibers
  • Unmyelinated, slow conduction.
  • Convey delayed, diffuse, dull, or burning pain (“second pain”).

The Spinothalamic (Anterolateral) Pathway: Pain to the Brain

Pain and temperature information ascends to the brain via the anterolateral (or spinothalamic) system.

1. Peripheral transduction. Nociceptors in the skin or deeper tissues transduce noxious stimuli and generate action potentials.
2. Entry into spinal cord. Nociceptive fibers enter the spinal cord through the dorsal root and synapse on neurons in the dorsal horn.
3. Crossing the midline. Second-order neurons in the dorsal horn send axons that cross to the contralateral side of the spinal cord.
4. Ascending to thalamus. These axons ascend in the anterolateral white matter to reach the thalamus.
5. Cortical targets. From the thalamus, projections go to:
   • Primary and secondary somatosensory cortices (encoding location and intensity).
   • Limbic regions (e.g., anterior cingulate cortex, insula) that contribute to the emotional aspects of pain.

This dual projection pattern—toward both motor/sensory regions and limbic structures—helps explain why pain simultaneously triggers reflexive movement away from the stimulus and a strong emotional reaction.

Two Responses, Two Brain Regions

• Motor response. Pain-related projections to motor areas and spinal circuits produce withdrawal reflexes and more complex avoidance behaviors.
• Affective response. Projections to the limbic system, especially the anterior cingulate cortex (ACC), help generate the unpleasant, aversive component of pain.

Analgesia: Reducing Pain

Analgesia is relief from pain, whereas anesthesia refers to a broader loss of sensation or consciousness. Pain can be modulated at multiple levels:

• Peripheral mechanisms.
• Spinal cord mechanisms.
• Central (brain) mechanisms, including top-down control.

Peripheral Sites of Analgesic Action

Some analgesics act at or near the site of injury:

• Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen:
  • Block enzymes (cyclooxygenases) involved in synthesis of prostaglandins.
  • Prostaglandins sensitize nociceptors; blocking them reduces pain and inflammation.
• Acetaminophen (paracetamol):
  • Also reduces pain and fever, though its exact mechanism is somewhat distinct and centrally acting.
• Local anesthetics (e.g., lidocaine):
  • Block voltage-gated sodium channels in peripheral nerves.
  • Prevent action potentials, temporarily eliminating sensation (including pain) from a region.

Spinal Cord as a Site of Analgesic Action

Analgesic or anesthetic agents can be delivered near the spinal cord:

• Epidural anesthesia:
  • Injection of drug into the epidural space (outside the dura mater) surrounding the spinal cord.
  • Blocks action potential conduction in spinal nerves, reducing or eliminating sensation from lower body regions.

Top-Down Analgesia: Pain Control from the Brain

The brain can actively modulate pain signals descending to the spinal cord. This involves endogenous opioids and a set of descending control pathways.

• Endogenous opioid peptides (e.g., endorphins, enkephalins, dynorphins) are neurotransmitters that bind to opioid receptors in the brain and spinal cord.
• Opiate drugs (e.g., morphine) are effective analgesics because they mimic these endogenous opioids.

Descending Pain Pathways

A key structure in descending pain modulation is the periaqueductal gray (PAG) in the midbrain:

• Activation of the PAG produces potent analgesia.
• The PAG is rich in opioid receptors and receives input from higher brain areas.
• From the PAG, signals descend to the raphe nuclei in the brainstem.

Raphe neurons release serotonin (5-HT) onto neurons in the spinal dorsal horn:

• 5-HT release activates opioid-containing interneurons in the spinal cord.
• These interneurons release endogenous opioids, which inhibit ascending nociceptive pathways at the level of the spinal cord.

Thus, top-down signals can “turn down the volume” on pain before it reaches higher centers.

Types of Pain Relief

There are multiple classes of pain-relieving strategies, which can be loosely grouped as:

• Psychogenic mechanisms – psychological and cognitive factors:
  • Placebo – expectation of relief can activate endogenous opioid systems.
  • Hypnosis – alters perception of pain.
  • Stress-induced analgesia – intense stress can trigger endorphin release.
  • Cognitive and coping strategies – reappraisal, distraction, and learning can modify pain.
• Pharmacological mechanisms:
  • Opiates – bind opioid receptors in PAG and spinal cord.
  • Local or spinal blocks – block conduction of pain signals.
  • Anti-inflammatory drugs – block inflammatory mediators.
  • Cannabinoids – act on CB receptors in nociceptors, spinal cord, and brain.
• Stimulation-based mechanisms:
  • TENS (transcutaneous electrical nerve stimulation) or mechanical stimulation – activation of large non-nociceptive fibers can reduce pain signals (gate control theory).
  • Acupuncture – may activate endogenous opioids and modulate peripheral pathways.
  • Electrical stimulation of PAG or related structures – engages endorphin-mediated pain control systems.

Overall, pain is not a simple “input” but a complex, multidimensional experience shaped by peripheral receptors, spinal processing, ascending pathways, cortical and limbic networks, and powerful descending control systems. Understanding these layers is essential both for basic neuroscience and for developing effective strategies to treat pain.

Visual Processing I

As of late, we have focused on how sensory receptors convert physical stimuli into electrical signals and how the somatosensory system, including pain pathways, carries that information into the brain. Vision follows the same basic logic—receptors detect a stimulus, convert it into action potentials, and send those signals centrally—but with its own elaborate anatomy and specializations.

In this section we will:

• Describe the overall organization of the visual system.
• Explain how light is focused onto the retina.
• Examine the cellular organization of the retina.
• Contrast rod-based (scotopic) and cone-based (photopic) vision, especially at the fovea.
• Introduce phototransduction in rods and cones and mechanisms for handling an enormous range of light intensities.
• Show how the retina begins to compute edges and contrast via center–surround receptive fields and lateral inhibition.

Overall Organization of the Visual System

The visual system is organized as a series of stages, each transforming the representation of the visual world:

• Light enters the eye and is focused onto the retina.
• Photoreceptors (rods and cones) in the retina transduce light into electrical signals.
• These signals are processed by local retinal circuits and converge onto retinal ganglion cells.
• Ganglion cell axons form the optic nerve, which exits the eye and partially crosses at the optic chiasm.
• Beyond the chiasm, axons form the optic tracts, projecting mainly to the lateral geniculate nucleus (LGN) of the thalamus.
• From the LGN, visual information is relayed to primary visual cortex (V1) and then to higher-order visual areas.

Binocular Vision and Visual Fields

Each eye sees part of the world, and their views overlap in the middle. The system is organized by visual field, not by individual eye:

• Light from the right visual field strikes the nasal (inner) retina of the right eye and the temporal (outer) retina of the left eye.
• At the optic chiasm:
  • Axons from nasal retinae cross to the opposite side.
  • Axons from temporal retinae remain on the same side.
• As a result:
  • Information from the right visual field travels in the left optic tract and is processed by the left hemisphere.
  • Information from the left visual field travels in the right optic tract and is processed by the right hemisphere.

This arrangement supports binocular vision, allowing the brain to combine slightly different views from both eyes to compute depth and spatial relationships.

Focusing Light onto the Retina

For vision to be sharp, light rays from a point in the world must be brought to a focus on the retina.

Several structures contribute:

• Cornea – provides most of the eye’s refractive power; its curvature bends incoming light.
• Lens – fine-tunes focus; its shape can be adjusted to bring near or far objects into sharp focus.
• Iris – the colored ring of muscle that controls the size of the pupil.
• Pupil – the opening in the iris that regulates how much light enters the eye.

Definition. Accommodation is the process by which the lens changes shape to focus light from objects at different distances onto the retina.

• For near objects, the ciliary muscles contract, allowing the lens to become rounder and more powerful.
• For distant objects, the ciliary muscles relax, making the lens thinner and less powerful.

Simultaneously, the pupil adjusts its size:

• In bright light, the pupil constricts, reducing light entry and improving depth of field.
• In dim light, the pupil dilates, allowing more photons to reach the retina.

Organization of the Retina

The retina is a thin, layered sheet of neural tissue lining the back of the eye. Interestingly, its organization is inverted:

• Light passes through several layers of neurons and glial cells before reaching the photoreceptors at the back.
• Processed signals then move from photoreceptors forward through the retinal circuitry to the ganglion cells.

The retina contains several major cell types arranged in distinct layers:

• Photoreceptor cells – rods and cones; transduce light into receptor potentials.
• Bipolar cells – receive input from photoreceptors and relay it to ganglion cells.
• Retinal ganglion cells – receive input from bipolar cells; their axons form the optic nerve.
• Horizontal cells – interneurons that make lateral connections among photoreceptors and bipolar cells.
• Amacrine cells – interneurons that make lateral connections among bipolar and ganglion cells.

Horizontal and amacrine cells are particularly important for lateral inhibition and other computations that shape receptive fields and emphasize contrast.

Rods and Cones: Scotopic vs Photopic Vision

Rods and cones serve overlapping but distinct roles in vision.

• Rods – the basis of the scotopic system:
  • Extremely sensitive to light; operate well in dim conditions.
  • Do not support color vision; essentially black-and-white detectors.
  • Provide poor spatial resolution compared to cones.
  • Numerous in the periphery of the retina; completely absent from the fovea.
• Cones – the basis of the photopic system:
  • Require more light; best in daylight or bright conditions.
  • Support color vision and high acuity.
  • Densest at the fovea—the central region of the retina where visual acuity is highest.

The Fovea: High-Acuity, Cone-Only Vision

The fovea is the point on the retina where light from the center of gaze is focused. It has several specializations:

• Contains only cones; no rods.
• Outer layers of cells are displaced to the side, allowing light more direct access to photoreceptors.
• Photoreceptors are densely packed, providing high spatial resolution.

Because of this, the fovea supports:

• Fine detail discrimination (e.g., reading small print).
• Color vision (due to the presence of multiple cone types).

Furthermore, a disproportionately large portion of visual cortex is devoted to processing input from the fovea:

Note. This cortical magnification means that the central visual field has far more “brain real estate” than the periphery, reflecting its importance for fine visual tasks.

Rod-Dominated Periphery

Rods are almost absent from the fovea but become increasingly dense toward the peripheral retina. This arrangement:

• Makes peripheral vision especially sensitive to dim light.
• Explains why faint stars are often easier to see when you look slightly to the side rather than directly at them.

Phototransduction: Rhodopsin and Signal Amplification

Photoreceptors are extraordinarily sensitive to light. One reason for this is the amplification built into the phototransduction cascade.

In rods, the key photopigment is rhodopsin.

• Rhodopsin consists of:
  • RETINAL (a form of vitamin A derivative, retinaldehyde), the light-sensitive chromophore.
  • OPSIN, a seven-transmembrane G protein–coupled receptor (GPCR).

When a photon is absorbed:

• RETINAL changes shape (isomerizes) from 11-cis to all-trans.
• This conformational change activates opsin.
• Activated opsin triggers a G protein cascade in the photoreceptor, leading to closure of cGMP-gated ion channels.

The cascade allows one photon to influence many ion channels, producing a detectable change in membrane potential. This GPCR-based amplification is a crucial reason why the visual system can operate over extremely low light levels.

Range of Sensitivity and Adaptation

The visual system must cope with an enormous range of light intensities—from starlight to bright sunlight. It uses several strategies:

• GPCR amplification – increases sensitivity at low light levels.
• Pupil adjustments – the pupil constricts in bright light and dilates in dim light, regulating how many photons enter the eye.
• Range fractionation across receptors – different receptors (e.g., rods vs cones, and cone subtypes) have different operating ranges and thresholds.
• Photoreceptor adaptation – photoreceptors themselves reduce their response during sustained, strong stimulation.

As a result, the visual system maintains useful responsiveness across many orders of magnitude of illumination, while still preserving contrast information.

The Visual System as a Difference Detector

Like other sensory systems, the visual system is especially tuned to differences and edges rather than absolute illumination levels.

This emphasis begins in the retina itself, where circuits create center–surround receptive fields and employ lateral inhibition to enhance contrast.

Retinal Processing and Center–Surround Receptive Fields

The output neurons of the retina are the ganglion cells. Each ganglion cell receives input from a specific set of photoreceptors via bipolar and horizontal cells. The part of visual space that influences a ganglion cell’s firing is its receptive field.

Retinal ganglion cell receptive fields typically have a center–surround organization:

• A central region (the center) where light has one effect on firing.
• A surrounding region (the surround) where light has the opposite effect.

On-Center vs Off-Center Ganglion Cells

There are two main types:

• On-center, off-surround cells
  • Light in the center of the receptive field increases firing (excitation).
  • Light in the surround decreases firing below baseline (inhibition).
• Off-center, on-surround cells
  • Light in the center decreases firing.
  • Light in the surround increases firing.

These receptive fields are created by the pattern of connections from photoreceptors to bipolar cells and the modulatory influences of horizontal cells in the outer retina.

On-center and off-center ganglion cells are not simply “light detectors”; they are tuned to contrast—they respond most strongly when there is a difference between the illumination in center and surround.

Lateral Inhibition and Edge Enhancement

Lateral inhibition is a circuit motif in which active cells inhibit their neighbors, sharpening boundaries and enhancing differences.

• In the retina, horizontal cells receive input from arrays of photoreceptors and feed back inhibitory signals onto those photoreceptors and bipolar cells.
• When a region of the retina is strongly illuminated, the photoreceptors there inhibit neighboring regions via horizontal cells.

The result is that at edges, where illumination changes abruptly, ganglion cell responses are enhanced. This leads to perceptual phenomena such as the Mach band illusion, where uniform gradients appear to have exaggerated brightness differences at edges.

Center–surround receptive fields and lateral inhibition thus help the visual system act as a difference detector, prioritizing edges and changes over uniform areas.

Color Vision and Color-Opponent Processing

Color vision arises because different classes of cones are tuned to different portions of the visible spectrum. The visual system compares activity across these cone types rather than reading any single cone in isolation. This comparison, together with center–surround receptive fields, allows us to detect both hue and color contrast.

Recall. Cones form the basis of the photopic system—they operate in bright light, support high acuity, and allow color vision. Rods dominate scotopic (dim-light) vision and do not provide color information.

In humans there are three main functional cone types:

• S-cones (“short” wavelength) – most sensitive to blue light.
• M-cones (“medium” wavelength) – most sensitive to green light.
• L-cones (“long” wavelength) – most sensitive to red light.

Any given wavelength of light will stimulate all three cone types to different degrees. The brain interprets the pattern of activity across S, M, and L cones as a particular color. This “trichromatic” coding is only the first step. Retinal circuits then reorganize this information into color-opponent channels.

Definition. Color-opponent ganglion cells are retinal ganglion cells whose receptive fields are built from cones of different spectral sensitivities, arranged in a center–surround organization. Typical examples include:

• Red–green opponent cells
  • Center might receive input primarily from L-cones (red) and surround from M-cones (green), or vice versa.
  • Excited when “red” part of the receptive field is more active than “green,” inhibited when the opposite is true.
• Blue–yellow opponent cells
  • Center might be driven by S-cones (blue) and surround by a combination of M+L cones (yellowish), or the reverse.
  • Enhance contrast between “blue-ish” and “yellow-ish” regions in the image.

Just as luminance-sensitive ganglion cells emphasize edges in brightness, color-opponent cells emphasize edges in chromatic content. This organization:

• Improves our ability to discriminate fine differences in color.
• Contributes to color constancy across changes in lighting.

Note. Genetic defects that eliminate or alter one cone type disrupt these comparisons, resulting in color blindness (e.g., red–green dichromacy). The brain’s color circuitry is intact, but it has insufficiently distinct cone signals to compute certain color differences.

From Retina to Cortex: LGN and Orientation Selectivity

Signals from retinal ganglion cells travel along the optic nerve, pass through the optic chiasm, and continue as the optic tracts to the lateral geniculate nucleus (LGN) of the thalamus. The LGN is the main relay station from eye to cortex.

Several key principles are preserved in the LGN:

• Retinotopic mapping. Neighboring points on the retina project to neighboring neurons in the LGN, preserving the spatial layout of the visual scene.
• Eye-specific layers. Inputs from each eye are kept largely separate in distinct LGN layers, setting up the substrate for later binocular processing.
• Center–surround receptive fields. LGN neurons maintain a similar center–surround organization to retinal ganglion cells (ON-center/OFF-surround and OFF-center/ON-surround).

From the LGN, axons project via the optic radiations to primary visual cortex (V1) in the occipital lobe. In V1, receptive fields become more complex.

Simple and Complex Cells in V1

In V1, neurons can be categorized (classically) as simple or complex cells, based on their receptive field properties:

• Simple cells
  • Respond best to bars or edges of a particular orientation (e.g., vertical, horizontal).
  • Have fairly well-defined excitatory and inhibitory subregions within their receptive field.
  • Can be constructed conceptually by summing inputs from multiple LGN cells with aligned center–surround fields.
• Complex cells
  • Also selective for orientation, but receptive fields are larger and less clearly divided into excitatory/inhibitory zones.
  • Often respond best to oriented bars that are moving in a particular direction.

Thus, the cortex builds orientation-selective receptive fields by combining input from many LGN neurons, each with center–surround receptive fields. This is a classic example of hierarchical processing:

• Retina and LGN encode points and contrast.
• V1 combines these to detect edges and bars at specific orientations and positions.
• Higher visual areas then combine oriented elements into contours, shapes, and objects.

Dorsal (“Where”) and Ventral (“What”) Streams

Beyond primary visual cortex, information is sent to multiple higher-order areas that specialize in different aspects of visual perception. A prominent organizational scheme distinguishes two major processing streams:

• Ventral stream (“what” pathway)
  • Projects from occipital cortex into the inferior temporal lobe.
  • Specialized for object recognition, including shapes, categories, and faces.
  • Neurons in this stream respond to increasingly complex and abstract features (e.g., a particular object or face).
• Dorsal stream (“where” or “how” pathway)
  • Projects from occipital cortex into the parietal lobe.
  • Specialized for spatial processing, motion, and visually guided action (reaching, grasping).
  • Helps answer “Where is it?” and “How do I interact with it?”

Lesions and Visual Deficits

Damage to different parts of these streams leads to characteristic deficits that highlight their functions.

Ventral stream lesions: agnosias

• Visual agnosia
  • Difficulty recognizing objects despite normal basic vision (intact acuity, normal pupillary responses, etc.).
  • A patient may copy a drawing accurately but be unable to say what the object is.
• Prosopagnosia (“face blindness”)
  • Specific inability to recognize faces, even of close friends or family members.
  • Associated with damage to the fusiform face area in the ventral temporal cortex.
  • Patients often rely on non-facial cues (voice, clothing, posture) to identify people.

Dorsal stream lesions: spatial and action deficits

• Optic ataxia
  • Difficulty using vision to guide movements (e.g., reaching incorrectly for objects).
  • Patients may see and verbally identify an object but cannot accurately reach toward it.
• Hemispatial neglect (often involving parietal damage)
  • Failure to attend to or acknowledge stimuli on one side of space (typically the side opposite the lesion).
  • Patients may ignore half of drawings, shave only one side of the face, or deny that anything is missing.

Altogether, the ventral and dorsal pathways illustrate how visual processing is divided into specialized streams: one concerned primarily with what things are, and the other with where they are and how to act upon them. Disruptions in these circuits reveal the remarkable complexity underlying what feels like effortless visual perception.

Auditory System and Language

Thus far, we have examined how sensory systems such as touch and vision detect physical stimuli and transform them into patterned neural activity. Hearing and language follow the same basic principles—specialized receptors convert mechanical vibrations of air into electrical signals, which are then interpreted by higher brain areas as sound and, in humans, as speech and language.

Physical Dimensions of Sound

Sound is a mechanical wave—repeating changes in air pressure over time. Two key physical properties of sound relate directly to how we perceive it:

• Amplitude (intensity) – the size of the pressure changes; we perceive this as loudness.
  • Larger amplitude → louder sound.
  • Measured in decibels (dB) on a logarithmic scale.
• Frequency – the number of cycles of vibration per second, measured in Hertz (Hz); we perceive this as pitch.
  • Low frequency (e.g., 100 Hz) → low-pitched sounds (bass).
  • High frequency (e.g., 4000 Hz) → high-pitched sounds (treble).

Our auditory system can detect an impressive range of both amplitude and frequency, from faint whispers to loud concerts, and from low rumbles to high chirps.

From Air to Fluid: The Outer and Middle Ear

Before sound can be transduced into neural activity, it must be collected and mechanically transformed by the ear.

The External (Outer) Ear

• Pinna – the visible “ear” on the side of the head. Its complex folds:
  • Help collect and funnel sound into the ear canal.
  • Shape the spectrum of incoming sounds, providing cues about the vertical location of sound sources.
• Ear canal – guides sound waves toward the tympanic membrane (eardrum).

The Middle Ear: Impedance Matching

The middle ear converts large, low-pressure vibrations in air into smaller, higher-pressure vibrations in fluid. This is necessary because fluid is harder to move than air.

• Tympanic membrane (eardrum) – vibrates in response to incoming sound waves.
• Ossicles – three tiny bones that form a lever system:
  • Malleus (hammer)
  • Incus (anvil)
  • Stapes (stirrup)
  These bones transmit vibrations from the tympanic membrane to the oval window of the inner ear.

Note. By focusing the force from the large area of the eardrum onto the much smaller oval window, the ossicles concentrate sound energy and improve transfer of vibrations into the fluid-filled cochlea.

The Inner Ear and the Cochlea

The inner ear houses the machinery that converts mechanical energy into neural signals. The core auditory structure is the cochlea.

• The cochlea is a spiral-shaped, fluid-filled tube with a base (near the oval window) and an apex (the tip of the spiral).
• Within the cochlea lies the organ of Corti, which contains the sensory receptors for hearing: hair cells.

The Organ of Corti

The organ of Corti sits on the basilar membrane and contains three key components:

• Hair cells – specialized sensory cells that convert movement into neurotransmitter release.
  • Their “hairs” are stereocilia, small, rigid projections organized in bundles.
• Basilar membrane – vibrates up and down in response to sound-induced pressure waves in the cochlear fluid.
• Supporting cells and neighboring membranes (including the tectorial membrane) that help translate basilar membrane motion into stereocilia deflection.

Tonotopic Mapping in the Cochlea

Different sound frequencies cause different regions of the basilar membrane to vibrate most strongly:

• High-frequency sounds (e.g., 8–20 kHz) maximally displace the narrow, stiff base of the basilar membrane.
• Low-frequency sounds (e.g., 100–500 Hz) maximally displace the wider, more flexible apex.

This systematic mapping of frequency onto position along the basilar membrane is called tonotopy. It is the auditory analog of retinotopy in vision and is preserved all the way up into the auditory cortex.

Hair Cell Transduction: From Motion to Current

When the basilar membrane vibrates, it causes the hair cell stereocilia to bend. This bending is the key to turning mechanical energy into a receptor potential.

• Tip links – fine protein filaments that connect the tips of shorter stereocilia to mechanically gated ion channels on their taller neighbors.
• When stereocilia are deflected in the preferred direction:
  • Tip links stretch and mechanically open ion channels.
  • Positively charged ions (especially K⁺ from the high-potassium endolymph) flow into the hair cell.
  • The hair cell depolarizes, opening voltage-gated Ca²⁺ channels at its base.
  • Ca²⁺ entry triggers neurotransmitter release (primarily glutamate) onto auditory nerve fibers.

Deflection in the opposite direction slackens the tip links, closes ion channels, and hyperpolarizes the cell, reducing transmitter release. In this way, hair cells encode sound vibrations as graded changes in membrane potential and transmitter output.

Note. Inner hair cells provide most of the auditory information to the brain, while outer hair cells act as a cochlear amplifier, actively fine-tuning and amplifying basilar membrane motion.

Auditory Pathways: From Cochlea to Cortex

The electrical signals generated by hair cells are carried into the brain along the auditory nerve, part of cranial nerve VIII, the vestibulocochlear nerve.

• Auditory nerve fibers – receive glutamatergic input from inner hair cells and encode sound frequency (via tonotopy) and intensity (via firing rate).
• These fibers project to the cochlear nuclei in the brainstem.
• From the cochlear nuclei, information is relayed to the superior olivary nuclei, where binaural (two-ear) comparisons are first made.
• Signals then ascend to the inferior colliculi in the midbrain.
• From there, they project to the medial geniculate nucleus (MGN) of the thalamus.
• Finally, MGN neurons send projections to primary auditory cortex (A1) in the temporal lobe.

At each stage, tonotopic organization is preserved: neighboring neurons respond to neighboring sound frequencies.

Binaural Cues and Sound Localization

How do we determine where a sound is coming from? The brain uses binaural cues, based on information from both ears. The key computations occur in the superior olivary nucleus.

• Intensity differences (interaural level differences):
  • For high-frequency sounds, the head casts an “acoustic shadow.”
  • The ear closer to the sound receives a slightly louder signal.
• Latency (time) differences (interaural time differences):
  • A sound reaching the right ear slightly before the left indicates a source to the right, and vice versa.
  • Especially important for low-frequency sounds, where intensity differences are smaller.

By comparing inputs from both ears, neurons in the superior olive can compute the horizontal location of a sound source.

Tonotopic Maps in the Auditory Cortex

Primary auditory cortex (A1) in the temporal lobe maintains a tonotopic map of sound frequency, similar to how the primary visual cortex maintains a retinotopic map.

• Neighboring cortical neurons prefer similar sound frequencies.
• Frequency preferences shift systematically across the cortical surface.

Beyond A1, secondary auditory areas process more complex features such as combinations of frequencies, temporal patterns, and, in humans, the acoustic structure of speech and music.

Higher-Order Auditory Processing Streams

The brain organizes auditory information into partially distinct processing streams, analogous to the dorsal (“where”) and ventral (“what”) streams in vision.

• Dorsal auditory stream – projects into parietal regions.
  • Specialized for spatial location of sounds (“where”).
  • Helps orient toward or away from sound sources.
• Ventral auditory stream – remains largely within temporal regions.
  • Analyzes the identity and components of complex sounds (“what”).
  • Critical for recognizing speech, voices, and environmental sounds.

Human language processing relies heavily on these temporal lobe structures, especially in the left hemisphere.

Lateralization of Language and Auditory Functions

Unlike basic hearing, which is relatively symmetric, language is strongly lateralized.

Definition. Lateralization refers to the specialization of the two cerebral hemispheres for different functions.

• For most people, the left hemisphere is dominant for core language functions, including speech production and comprehension.
• The right hemisphere contributes more to:
  • Perception of music.
  • Processing of prosody (emotional tone, intonation) in speech.

Evidence from the Wada Test and Split-Brain Patients

The Wada test temporarily anesthetizes one hemisphere at a time (using sodium amytal) to determine which side supports language.

• When the left hemisphere is anesthetized in a left-language-dominant person, speech and comprehension are severely disrupted.
• Anesthetizing the right hemisphere typically has less dramatic effects on language but can affect spatial and musical abilities.

Split-brain patients—individuals whose corpus callosum has been surgically severed or is absent—provide further evidence:

• Visual or auditory stimuli presented exclusively to the right hemisphere (e.g., via the left visual field) may not be verbally reported, illustrating the left hemisphere’s dominance for speech.
• However, the right hemisphere can still show evidence of understanding via nonverbal responses (e.g., pointing), revealing its partial language capacity.

What is Language?

Language is a highly specialized form of communication uniquely elaborated in humans.

Definition. Language is the system in which arbitrary symbols (sounds, signs, written marks) are combined according to rules (grammar) to convey an essentially unlimited range of meanings—objects, actions, abstractions, and relationships.

Key features:

• Phonology – basic sound units.
• Syntax and grammar – rules for combining words into meaningful sentences.
• Semantics – meaning associated with words and sentences.

Overview of the Language Network

Language is processed primarily in the left hemisphere, but involves a distributed network of regions in temporal, frontal, and parietal lobes.

• Posterior temporal cortex – important for speech perception and comprehension.
• Inferior frontal cortex – important for speech production and planning of articulation.
• Parietal regions – contribute to reading, writing, and integration of auditory and visual language information.

Damage to these regions results in characteristic language deficits known as aphasias.

Aphasia: When Language Breaks Down

Definition. Aphasia is an acquired impairment of language production and/or comprehension, typically following brain injury such as stroke.

Common signs include:

• Paraphasia – substituting an incorrect sound or word (e.g., “tephelone” for “telephone”).
• Neologism – producing a novel, meaningless word.
• Nonfluent speech – effortful, halting speech with short phrases and reduced melodic intonation.

Broca’s (Nonfluent) Aphasia

• Associated with damage to the inferior frontal gyrus in the left hemisphere (Broca’s area).
• Patients have:
  • Great difficulty producing fluent speech.
  • Relatively preserved comprehension (especially for simple sentences).
  • Telegraphic speech—mostly content words, few function words.
• Classic case: patient “Tan,” who could say little more than that single syllable despite understanding much of what was said to him.

Wernicke’s (Fluent) Aphasia

• Associated with damage to the posterior superior temporal gyrus and adjacent parietal cortex (Wernicke’s area).
• Patients:
  • Produce fluent, well-articulated speech that is often semantically empty and filled with paraphasias and neologisms.
  • Have marked difficulty understanding spoken and written language.
• Speech may sound “normal” in rhythm and prosody but is often unintelligible in content.

Global Aphasia

• Results from large left-hemisphere lesions involving multiple language areas.
• Patients show severe impairments in both production and comprehension of language.
• Spontaneous speech is limited or absent; comprehension is also severely reduced.

Dyslexia: Difficulties with Reading

Dyslexia refers to difficulty in learning to read or in processing written language, despite adequate intelligence and educational opportunity.

Acquired Dyslexias

• Deep dyslexia – acquired after brain injury; written words may be read as semantically related but incorrect words (e.g., “cow” read as “horse”).
• Surface dyslexia – difficulty reading words with irregular spelling-to-sound rules (e.g., “though,” “cough”), relying heavily on letter-by-letter pronunciation.

Developmental Dyslexia

• Begins in childhood and can persist into adulthood.
• Occurs across languages, although specific reading challenges depend on the writing system (orthography).
• Genetic factors contribute; variants in genes such as DYX1C1, ROBO1, and DCDC2 are associated with increased risk.
• Neuroanatomical studies reveal:
  • Ectopic cell clusters (neurons in abnormal locations).
  • Micropolygyria (excessively folded small regions) in language-related cortical areas.

Animal Models of Vocal Learning and “Language-Like” Behavior

Although true human language is unique, animal models help us study components of language such as vocal learning and symbolic communication.

Songbirds

• Male songbirds learn a species-typical song by listening to adult tutors and their own vocal output.
• There is a critical period during which song must be learned; after this period, the song becomes “crystallized” and relatively fixed.
• Song learning is guided by auditory feedback: birds compare what they produce to a stored template and adjust via trial-and-error.
• This provides a powerful experimental model for studying the neural basis of vocal learning.

Nonhuman Primates and Other Animals

• Nonhuman primates (e.g., chimpanzees, gorillas):
  • Have been taught vocabulary using sign language or symbol systems.
  • Show some ability to combine signs and use them communicatively.
  • Debate remains about whether this constitutes true language, as grammar and generativity are limited.
• Alex the parrot (African Grey parrot):
  • Learned over 100 words and could use them appropriately in many contexts.
  • Demonstrated impressive cognitive abilities (e.g., labeling colors, shapes, counting small numbers).
  • His training illustrates how limited “language-like” systems can be used to probe animal cognition, without claiming full human-like language.

All together, studies of auditory processing, language networks, and animal models highlight how the brain transforms simple vibrations into rich perceptual experiences and complex symbolic communication.

The Auditory System and Language

Up to now, we have examined how sensory systems such as touch and vision detect physical stimuli and transform them into patterned neural activity. Hearing and language follow the same basic principles—specialized receptors convert mechanical vibrations of air into electrical signals, which are then interpreted by higher brain areas as sound and, in humans, as speech and language.

Physical Dimensions of Sound

Sound is a mechanical wave—repeating changes in air pressure over time. Two key physical properties of sound relate directly to how we perceive it:

• Amplitude (intensity) – the size of the pressure changes; we perceive this as loudness.
  • Larger amplitude → louder sound.
  • Measured in decibels (dB) on a logarithmic scale.
• Frequency – the number of cycles of vibration per second, measured in Hertz (Hz); we perceive this as pitch.
  • Low frequency (e.g., 100 Hz) → low-pitched sounds (bass).
  • High frequency (e.g., 4000 Hz) → high-pitched sounds (treble).

Our auditory system can detect an impressive range of both amplitude and frequency, from faint whispers to loud concerts, and from low rumbles to high chirps.

From Air to Fluid: The Outer and Middle Ear

Before sound can be transduced into neural activity, it must be collected and mechanically transformed by the ear.

The External (Outer) Ear

• Pinna – the visible “ear” on the side of the head. Its complex folds:
  • Help collect and funnel sound into the ear canal.
  • Shape the spectrum of incoming sounds, providing cues about the vertical location of sound sources.
• Ear canal – guides sound waves toward the tympanic membrane (eardrum).

The Middle Ear: Impedance Matching

The middle ear converts large, low-pressure vibrations in air into smaller, higher-pressure vibrations in fluid. This is necessary because fluid is harder to move than air.

• Tympanic membrane (eardrum) – vibrates in response to incoming sound waves.
• Ossicles – three tiny bones that form a lever system:
  • Malleus (hammer)
  • Incus (anvil)
  • Stapes (stirrup)
  These bones transmit vibrations from the tympanic membrane to the oval window of the inner ear.

Note. By focusing the force from the large area of the eardrum onto the much smaller oval window, the ossicles concentrate sound energy and improve transfer of vibrations into the fluid-filled cochlea.

The Inner Ear and the Cochlea

The inner ear houses the machinery that converts mechanical energy into neural signals. The core auditory structure is the cochlea.

• The cochlea is a spiral-shaped, fluid-filled tube with a base (near the oval window) and an apex (the tip of the spiral).
• Within the cochlea lies the organ of Corti, which contains the sensory receptors for hearing: hair cells.

The Organ of Corti

The organ of Corti sits on the basilar membrane and contains three key components:

• Hair cells – specialized sensory cells that convert movement into neurotransmitter release.
  • Their “hairs” are stereocilia, small, rigid projections organized in bundles.
• Basilar membrane – vibrates up and down in response to sound-induced pressure waves in the cochlear fluid.
• Supporting cells and neighboring membranes (including the tectorial membrane) that help translate basilar membrane motion into stereocilia deflection.

Tonotopic Mapping in the Cochlea

Different sound frequencies cause different regions of the basilar membrane to vibrate most strongly:

• High-frequency sounds (e.g., 8–20 kHz) maximally displace the narrow, stiff base of the basilar membrane.
• Low-frequency sounds (e.g., 100–500 Hz) maximally displace the wider, more flexible apex.

This systematic mapping of frequency onto position along the basilar membrane is called tonotopy. It is the auditory analog of retinotopy in vision and is preserved all the way up into the auditory cortex.

Hair Cell Transduction: From Motion to Current

When the basilar membrane vibrates, it causes the hair cell stereocilia to bend. This bending is the key to turning mechanical energy into a receptor potential.

• Tip links – fine protein filaments that connect the tips of shorter stereocilia to mechanically gated ion channels on their taller neighbors.
• When stereocilia are deflected in the preferred direction:
  • Tip links stretch and mechanically open ion channels.
  • Positively charged ions (especially K⁺ from the high-potassium endolymph) flow into the hair cell.
  • The hair cell depolarizes, opening voltage-gated Ca²⁺ channels at its base.
  • Ca²⁺ entry triggers neurotransmitter release (primarily glutamate) onto auditory nerve fibers.

Deflection in the opposite direction slackens the tip links, closes ion channels, and hyperpolarizes the cell, reducing transmitter release. In this way, hair cells encode sound vibrations as graded changes in membrane potential and transmitter output.

Note. Inner hair cells provide most of the auditory information to the brain, while outer hair cells act as a cochlear amplifier, actively fine-tuning and amplifying basilar membrane motion.

Auditory Pathways: From Cochlea to Cortex

The electrical signals generated by hair cells are carried into the brain along the auditory nerve, part of cranial nerve VIII, the vestibulocochlear nerve.

• Auditory nerve fibers – receive glutamatergic input from inner hair cells and encode sound frequency (via tonotopy) and intensity (via firing rate).
• These fibers project to the cochlear nuclei in the brainstem.
• From the cochlear nuclei, information is relayed to the superior olivary nuclei, where binaural (two-ear) comparisons are first made.
• Signals then ascend to the inferior colliculi in the midbrain.
• From there, they project to the medial geniculate nucleus (MGN) of the thalamus.
• Finally, MGN neurons send projections to primary auditory cortex (A1) in the temporal lobe.

At each stage, tonotopic organization is preserved: neighboring neurons respond to neighboring sound frequencies.

Binaural Cues and Sound Localization

How do we determine where a sound is coming from? The brain uses binaural cues, based on information from both ears. The key computations occur in the superior olivary nucleus.

• Intensity differences (interaural level differences):
  • For high-frequency sounds, the head casts an “acoustic shadow.”
  • The ear closer to the sound receives a slightly louder signal.
• Latency (time) differences (interaural time differences):
  • A sound reaching the right ear slightly before the left indicates a source to the right, and vice versa.
  • Especially important for low-frequency sounds, where intensity differences are smaller.

By comparing inputs from both ears, neurons in the superior olive can compute the horizontal location of a sound source.

Tonotopic Maps in the Auditory Cortex

Primary auditory cortex (A1) in the temporal lobe maintains a tonotopic map of sound frequency, similar to how the primary visual cortex maintains a retinotopic map.

• Neighboring cortical neurons prefer similar sound frequencies.
• Frequency preferences shift systematically across the cortical surface.

Beyond A1, secondary auditory areas process more complex features such as combinations of frequencies, temporal patterns, and, in humans, the acoustic structure of speech and music.

Higher-Order Auditory Processing Streams

The brain organizes auditory information into partially distinct processing streams, analogous to the dorsal (“where”) and ventral (“what”) streams in vision.

• Dorsal auditory stream – projects into parietal regions.
  • Specialized for spatial location of sounds (“where”).
  • Helps orient toward or away from sound sources.
• Ventral auditory stream – remains largely within temporal regions.
  • Analyzes the identity and components of complex sounds (“what”).
  • Critical for recognizing speech, voices, and environmental sounds.

Human language processing relies heavily on these temporal lobe structures, especially in the left hemisphere.

Lateralization of Language and Auditory Functions

Unlike basic hearing, which is relatively symmetric, language is strongly lateralized.

Definition. Lateralization refers to the specialization of the two cerebral hemispheres for different functions.

• For most people, the left hemisphere is dominant for core language functions, including speech production and comprehension.
• The right hemisphere contributes more to:
  • Perception of music.
  • Processing of prosody (emotional tone, intonation) in speech.

Evidence from the Wada Test and Split-Brain Patients

The Wada test temporarily anesthetizes one hemisphere at a time (using sodium amytal) to determine which side supports language.

• When the left hemisphere is anesthetized in a left-language-dominant person, speech and comprehension are severely disrupted.
• Anesthetizing the right hemisphere typically has less dramatic effects on language but can affect spatial and musical abilities.

Split-brain patients—individuals whose corpus callosum has been surgically severed or is absent—provide further evidence:

• Visual or auditory stimuli presented exclusively to the right hemisphere (e.g., via the left visual field) may not be verbally reported, illustrating the left hemisphere’s dominance for speech.
• However, the right hemisphere can still show evidence of understanding via nonverbal responses (e.g., pointing), revealing its partial language capacity.

What is Language?

Language is a highly specialized form of communication uniquely elaborated in humans.

Definition. Language is the system in which arbitrary symbols (sounds, signs, written marks) are combined according to rules (grammar) to convey an essentially unlimited range of meanings—objects, actions, abstractions, and relationships.

Remark. This is different to the definition of a language derivable mathematically.

Key features:

• Phonology – basic sound units.
• Syntax and grammar – rules for combining words into meaningful sentences.
• Semantics – meaning associated with words and sentences.

Overview of the Language Network

Language is processed primarily in the left hemisphere, but involves a distributed network of regions in temporal, frontal, and parietal lobes.

• Posterior temporal cortex – important for speech perception and comprehension.
• Inferior frontal cortex – important for speech production and planning of articulation.
• Parietal regions – contribute to reading, writing, and integration of auditory and visual language information.

Damage to these regions results in characteristic language deficits known as aphasias.

Aphasia: When Language Breaks Down

Definition. Aphasia is an acquired impairment of language production and/or comprehension, typically following brain injury such as stroke.

Common signs include:

• Paraphasia – substituting an incorrect sound or word (e.g., “tephelone” for “telephone”).
• Neologism – producing a novel, meaningless word.
• Nonfluent speech – effortful, halting speech with short phrases and reduced melodic intonation.

Broca’s (Nonfluent) Aphasia

• Associated with damage to the inferior frontal gyrus in the left hemisphere (Broca’s area).
• Patients have:
  • Great difficulty producing fluent speech.
  • Relatively preserved comprehension (especially for simple sentences).
  • Telegraphic speech—mostly content words, few function words.
• Classic case: patient “Tan,” who could say little more than that single syllable despite understanding much of what was said to him.

Wernicke’s (Fluent) Aphasia

• Associated with damage to the posterior superior temporal gyrus and adjacent parietal cortex (Wernicke’s area).
• Patients:
  • Produce fluent, well-articulated speech that is often semantically empty and filled with paraphasias and neologisms.
  • Have marked difficulty understanding spoken and written language.
• Speech may sound “normal” in rhythm and prosody but is often unintelligible in content.

Global Aphasia

• Results from large left-hemisphere lesions involving multiple language areas.
• Patients show severe impairments in both production and comprehension of language.
• Spontaneous speech is limited or absent; comprehension is also severely reduced.

Dyslexia: Difficulties with Reading

Dyslexia refers to difficulty in learning to read or in processing written language, despite adequate intelligence and educational opportunity.

Acquired Dyslexias

• Deep dyslexia – acquired after brain injury; written words may be read as semantically related but incorrect words (e.g., “cow” read as “horse”).
• Surface dyslexia – difficulty reading words with irregular spelling-to-sound rules (e.g., “though,” “cough”), relying heavily on letter-by-letter pronunciation.

Developmental Dyslexia

• Begins in childhood and can persist into adulthood.
• Occurs across languages, although specific reading challenges depend on the writing system (orthography).
• Genetic factors contribute; variants in genes such as DYX1C1, ROBO1, and DCDC2 are associated with increased risk.
• Neuroanatomical studies reveal:
  • Ectopic cell clusters (neurons in abnormal locations).
  • Micropolygyria (excessively folded small regions) in language-related cortical areas.

Animal Models of Vocal Learning and “Language-Like” Behavior

Although true human language is unique, animal models help us study components of language such as vocal learning and symbolic communication.

Songbirds

• Male songbirds learn a species-typical song by listening to adult tutors and their own vocal output.
• There is a critical period during which song must be learned; after this period, the song becomes “crystallized” and relatively fixed.
• Song learning is guided by auditory feedback: birds compare what they produce to a stored template and adjust via trial-and-error.
• This provides a powerful experimental model for studying the neural basis of vocal learning.

Nonhuman Primates and Other Animals

• Nonhuman primates (e.g., chimpanzees, gorillas):
  • Have been taught vocabulary using sign language or symbol systems.
  • Show some ability to combine signs and use them communicatively.
  • Debate remains about whether this constitutes true language, as grammar and generativity are limited.
• Alex the parrot (African Grey parrot):
  • Learned over 100 words and could use them appropriately in many contexts.
  • Demonstrated impressive cognitive abilities (e.g., labeling colors, shapes, counting small numbers).
  • His training illustrates how limited “language-like” systems can be used to probe animal cognition, without claiming full human-like language.

In short, studies of auditory processing, language networks, and animal models highlight how the brain transforms simple vibrations into rich perceptual experiences and complex symbolic communication.

Motor Control

So far, we have treated the nervous system primarily as a sensing and signaling device: detecting stimuli, processing them, and transmitting information across synapses. But much of the brain’s purpose is ultimately to act on the world—to move the eyes, shift posture, speak, grasp, walk, or play an instrument.

Motor control links motoneurons, muscles, spinal circuits, and multiple brain regions in a hierarchical system. At the periphery, the neuromuscular junction produces reliable contractions; centrally, the spinal cord, cortex, cerebellum, and basal ganglia work together to initiate, refine, and adapt movement.

The Neuromuscular Junction (NMJ)

The final common pathway from the nervous system to skeletal muscle is the neuromuscular junction.

Definition. The neuromuscular junction (NMJ) is the chemical synapse where the terminal of a motor neuron contacts a skeletal muscle fiber and controls its contraction.

• The NMJ is an extremely effective synapse: a single action potential in the motor neuron almost always produces a muscle action potential and a contraction.
• A single spinal motor neuron can branch extensively and form NMJs on many muscle fibers.

Definition. A motor unit is a single motor neuron and all of the muscle fibers it innervates. Motor units are the fundamental units of control in the skeletal muscle system.

• Small motor units (few fibers) → allow fine control (e.g., fingers, extraocular muscles).
• Large motor units (many fibers) → generate large forces but coarse control (e.g., postural muscles).

Acetylcholine at the NMJ

The neurotransmitter at the skeletal NMJ is acetylcholine (ACh).

• An action potential in the motor neuron arrives at the NMJ and opens voltage-gated Ca²⁺ channels.
• Ca²⁺ influx triggers vesicle fusion and ACh release into the synaptic cleft.
• ACh binds to nicotinic ACh receptors on the muscle fiber membrane (the motor endplate).
• These ionotropic receptors open and allow cations (mainly Na⁺) to enter the muscle, depolarizing it.
• If the endplate potential reaches threshold, a muscle action potential is generated and triggers contraction.

Disorder Spotlight: Myasthenia Gravis

Myasthenia gravis is a classic example of how altering ACh signaling at the NMJ disrupts movement.

• It is an autoimmune disease in which antibodies target and destroy nicotinic ACh receptors at the NMJ.
• Fewer functional receptors → less effective neuromuscular transmission.
• Clinically, it presents as muscle weakness that worsens with use (e.g., drooping eyelids, difficulty chewing or speaking as the day goes on).
• Treatment often includes drugs that inhibit acetylcholinesterase (AChE), the enzyme that breaks down ACh, thereby increasing ACh levels at the NMJ and partially compensating for receptor loss.

How Skeletal Muscle Produces Movement

Skeletal muscles attach to bones via tendons and can only pull (contract) or relax—they cannot push.

• Movements are produced by coordinated activation of different muscle groups.
• Antagonistic muscle pairs (e.g., biceps and triceps) act around joints to allow flexion and extension.
• The shape of the joint (hinge, ball-and-socket, etc.) constrains the possible range of motion.

By selectively activating different sets of motor units in multiple muscles, the nervous system can generate a vast repertoire of movements.

Proprioception: Knowing Where We Are

To control movement, the brain must continuously monitor the body’s position and tension.

Definition. Proprioception is the sense of the body’s own movements and positions, mediated by specialized sensory receptors in muscles and tendons.

• Muscle spindles – stretch-sensitive receptors embedded within the muscle:
  • Detect muscle length and rate of change of length.
  • Provide feedback about how much and how quickly a muscle is being stretched.
• Golgi tendon organs – located in tendons:
  • Monitor muscle tension (force of contraction).
  • Help prevent damage by signaling when tension is dangerously high.

Together, these proprioceptors give the nervous system a continuous “internal map” of limb position and muscle load, allowing for smooth, coordinated adjustments during movement.

Spinal Reflexes: Fast, Stereotyped Movements

Not all movements require deliberation or cortical involvement. Some are mediated by spinal circuits alone.

Definition. A reflex is a simple, unvarying, and unlearned response to a specific sensory stimulus. Reflexes are mediated by small neural circuits within the spinal cord and brainstem.

• Spinal connections between dorsal roots (sensory input) and ventral roots (motor output) form the basis of reflex arcs.
• Reflexes provide rapid protective responses (e.g., withdrawal from pain, maintaining posture).

The Knee-Jerk (Stretch) Reflex

The classic knee-jerk response illustrates a simple monosynaptic reflex arc:

1. Tap the patellar tendon → stretches the quadriceps muscle.
2. Muscle spindles detect this rapid stretch and fire action potentials.
3. These sensory afferents enter the spinal cord via the dorsal root and synapse directly on the motor neurons to the same muscle.
4. Motor neurons fire and cause the quadriceps to contract, producing leg extension.

This circuit provides an automatic, very rapid response that helps maintain posture and muscle tone.

A Hierarchy of Motor Control Systems

Voluntary movement arises from a hierarchical organization of control systems.

• Spinal cord – contains circuits for reflexes and central pattern generators (basic rhythmic movements).
• Primary motor cortex (M1) – initiates voluntary commands for action.
• Nonprimary motor cortex – helps plan and sequence movements.
• Cerebellum and basal ganglia – modulate and refine motor commands via loops through the thalamus and back to cortex.

Brain vs. Spinal Control

• Most skeletal muscles are innervated by spinal motor neurons; commands descend from the brain to the spinal cord and then out to muscles.
• Some muscles—especially those of the head and neck (e.g., facial expression, tongue, jaw)—are controlled directly by:
  • Cranial motor nuclei in the brainstem, whose axons form various cranial nerves.

Descending Motor Pathways: Pyramidal and Extrapyramidal Systems

Commands from the brain reach spinal motor neurons via two major pathways.

The Pyramidal (Corticospinal) System

Definition. The pyramidal system consists of axons that originate primarily in the primary motor cortex (M1) and descend through the brainstem to the spinal cord, forming the pyramidal tract.

• Many of these fibers originate from neurons in the precentral gyrus (M1).
• They pass through the internal capsule and form visible “pyramids” on the ventral surface of the medulla.
• Most fibers decussate (cross) in the medulla, so the left hemisphere controls the right side of the body and vice versa.
• The pyramidal system is especially important for fine, voluntary movements, such as finger control.

The Motor Homunculus

As with somatosensory cortex, M1 contains a somatotopic map of the body, sometimes depicted as a motor homunculus.

• Body parts requiring fine motor control (e.g., hands, face, tongue) occupy disproportionately large areas of M1.
• Less dexterous regions (e.g., trunk) occupy relatively smaller areas.

The Extrapyramidal System

The extrapyramidal system includes several subcortical structures, chiefly the basal ganglia and cerebellum, that modulate motor commands.

• These structures do not directly innervate motor neurons; instead, they:
  • Form loops with cortex via the thalamus.
  • Adjust the timing, scaling, and initiation of movements.

Nonprimary Motor Cortex: Planning and Sequencing

Nonprimary motor areas lie anterior to M1 and contribute to the planning and organization of movements.

• Supplementary Motor Area (SMA):
  • Important for internally generated sequences of movement (e.g., playing a memorized piano piece).
  • Activated during mental rehearsal of complex movement sequences, even without overt movement.
  • Receives strong input from the basal ganglia.
• Premotor Cortex:
  • Involved in movements that are guided by external cues (e.g., visually guided reaching).
  • Participates in learning arbitrary associations between stimuli and motor responses.
  • Includes Broca’s area (on the left), a region critical for motor aspects of speech production.

Mirror Neurons

Within the ventral premotor cortex, some neurons exhibit a remarkable property.

Definition. Mirror neurons are neurons that fire both when an individual executes a particular movement and when they observe someone else performing the same movement.

• Thought to contribute to understanding the actions of others.
• May be important for imitation learning and possibly for aspects of social cognition.

Disorders of the Pyramidal System: ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects the pyramidal system.

• Both upper motor neurons (in M1) and lower motor neurons (in spinal cord and cranial motor nuclei) degenerate.
• As motor neurons die, muscles receive less or no stimulation and atrophy.
• Patients gradually lose voluntary control of muscles, including those for speech and breathing.

The Basal Ganglia: GO and STOP Circuits

The basal ganglia are a group of interconnected subcortical nuclei that play a crucial role in the control of movement.

• Striatum – composed of:
  • Caudate nucleus
  • Putamen
• Globus pallidus
• Associated structures:
  • Substantia nigra
  • Subthalamic nucleus

The basal ganglia help determine:

• The amplitude and direction of movement.
• Whether a planned movement is initiated or suppressed.

They are especially important for movements that are influenced by past experience and learning (habitual or practiced actions). Conceptually, the basal ganglia contain:

• A “GO” pathway that facilitates voluntary movement.
• A “STOP” pathway that inhibits competing or inappropriate movements.

Huntington’s Disease: Too Much Movement

Huntington’s disease (HD) is a hereditary neurodegenerative disorder that prominently affects the basal ganglia.

• Characterized by cell loss in the striatum and cortex.
• Motor symptoms include chorea—involuntary, writhing movements and grimacing, reflecting inadequate inhibition of motion.
• Non-motor symptoms:
  • Cognitive impairment
  • Depression and other mood changes
  • Personality changes

HD is also a classic genetic disease:

• Caused by an expanded CAG trinucleotide repeat in the gene huntingtin.
• Normal alleles: ~10–34 CAG repeats; HD alleles: >36 repeats.
• The more repeats, the earlier the onset of symptoms.
• HD and similar disorders are sometimes referred to as “CAG repeat” or “poly-Q” diseases.

The Cerebellum: Coordination and Precision

The cerebellum (literally “little brain”) is another major component of the extrapyramidal system, essential for smooth, coordinated movement.

• The cerebellar cortex is organized around Purkinje cells, which send powerful inhibitory outputs to deep cerebellar nuclei.
• Through this inhibitory output, the cerebellum fine-tunes motor commands and adjusts ongoing movement.
• Across vertebrates, cerebellar size correlates with the range and complexity of movements the animal can perform.

Ataxia and Cerebellar Disorders

Ataxia refers to uncoordinated movements resulting from cerebellar damage.

• Symptoms can include stumbling, difficulty with gait, jerky or imprecise limb movements, and tremors.
• Spinocerebellar ataxias (SCAs) are a family of neurodegenerative disorders in which the cerebellum is primarily affected.

Summary: Brain Areas Involved in Movement

Many brain regions participate in the selection, planning, execution, and refinement of movement. Their roles can be summarized as follows:

Together, these systems transform neural plans into fluid, adaptive actions—from a simple reflexive knee-jerk to the coordinated motor patterns of speech, music, and skilled movement.