Neurons, Neurotransmission, and Cortical Organization

Brain landmarks and major lobes

• Three major fissures as prominent brain landmarks: central (Rolandic) fissure, Sylvian (lateral) fissure, and the longitudinal fissure.

  • Central (Rolandic) fissure: separates each hemisphere in an anterior–posterior direction; in front of it tends to be motor processing, behind tends to be sensory processing.

  • Sylvian (lateral) fissure: separates in a dorsal–ventral dimension; below this fissure is the temporal lobe, key for memory, emotion, and auditory processing.

  • Longitudinal fissure: separates the right and left hemispheres; each hemisphere has some specialization in cognitive and emotional functioning.

• These fissures divide each hemisphere into four major regions, or lobes:

  • Frontal lobe: in front of the central fissure.

  • Temporal lobe: area below the Sylvian fissure.

  • Parietal lobe: region directly behind the central fissure but above the Sylvian fissure.

  • Occipital lobe: the remaining region behind the parieto-occipital sulcus.

• Note: The book will return to the four major lobes after examining neurons in more detail.

A closer look at neurons: electrochemical signaling

• Neurons transfer information via electrical and chemical processes; two broad principles:

  • Information is relayed within a neuron by an electrical signal.

  • One neuron influences another via a chemical signal.

• Resting potential: $V_{ ext{rest}} \approx -70\,\mathrm{mV}$

  • The cell membrane acts as a barrier that separates ions inside and outside the neuron.

• Ion channels: ions (e.g., Na⁺, K⁺) traverse the membrane only through ion channels, which can open or close to allow or block flow.

• Threshold and firing:

  • When the cell is stimulated enough to reduce the membrane potential to about $V_{ ext{threshold}} \approx -55\,\mathrm{mV}$, the neuron fires.

  • The action potential sequence: from threshold to peak and back to resting potential.

Action potential: phases and properties

• Action potential phases (simplified):

  • (1) Threshold reached; Na⁺ begins to enter the cell, depolarizing the membrane.

  • (2) Voltage rises to a peak; Na⁺ entry ceases as Na⁺ channels inactivate and K⁺ begins to exit.

  • (3) Peak reached; the membrane potential is about $+40\,\mathrm{mV}$ (depolarization).

  • (4) Repolarization: K⁺ efflux returns the membrane toward baseline; afterhyperpolarization occurs as the membrane potential briefly undershoots resting.

  • (5) Return to resting potential.

• Key properties of the action potential:

  • Self-propagating: once set in motion, it continues without further input.

  • Non-dissipative with distance: the peak remains around $+40\,\mathrm{mV}$ along the axon.

  • All-or-nothing: either the cell fires or it does not.

• Basic neuron layout in relation to signaling:

  • Action potential originates at the axon hillock.

  • Propagates along the axon to the terminal bouton (end of the axon).

  • Terminal bouton contains synaptic vesicles filled with neurotransmitter.

  • Action potential triggers vesicle fusion and neurotransmitter release into the synaptic cleft.

  • Neurotransmitters diffuse to the neighboring neuron’s postsynaptic region; the synapse is the contact region between presynaptic bouton, synaptic cleft, and postsynaptic membrane.

Transmission within a neuron and the synapse

• At the presynaptic side: synaptic vesicles release neurotransmitter into the synaptic cleft when an action potential arrives.

• In the postsynaptic neuron: receptors in the postsynaptic membrane bind neurotransmitters at binding sites, changing receptor configuration and altering ionic flow, producing local postsynaptic potential.

• Binding converts chemical signal back into an electrical change in the postsynaptic neuron.

• Dendritic tree and soma: excitatory synapses are typically on dendrites; inhibitory synapses are often near the soma or axon hillock to maximize influence.

• Neurotransmitter clearance and fate: neurotransmitters do not stay bound forever; they are cleared via several mechanisms (see below).

Postsynaptic potentials and summation

• Postsynaptic potentials (PSPs) come in two main types:

  • Excitatory postsynaptic potential (EPSP): makes the postsynaptic neuron more positive (toward threshold); brings the cell closer to the firing threshold.

  • Inhibitory postsynaptic potential (IPSP): makes the postsynaptic cell more negative (away from threshold); moves cell away from firing threshold.

• Magnitude and duration:

  • PSPs are graded: their strength decreases with distance and time from the synapse.

  • Typical PSP magnitude: $| ext{EPSP/IPSP}| \approx 0.5\text{ to }5\,\mathrm{mV}$.

• Summation at the axon hillock:

  • The final decision to fire depends on the sum of EPSPs and IPSPs from many inputs converging on the axon hillock.

  • Spatial summation: inputs near the same region of the dendritic tree can have a larger effect than distant inputs.

  • Temporal summation: close-timeEPSPs add up more effectively than those separated in time.

• Practical implication:

  • A single PSP is unlikely to trigger an action potential; the neuron typically requires coordinated EPSPs and IPSPs from many inputs.

Coding the strength of a stimulus: firing rate

• Neurons code stimulus intensity with the rate of firing rather than the amplitude of an action potential.

  • Weak stimulus: fewer spikes per unit time.

  • Strong stimulus: higher firing rate (more spikes per unit time).

• Illustration reference: firing rate increases with stimulus strength (conceptual Figure 1.17).

Modulating neurotransmission: presynaptic, cleft, and postsynaptic mechanisms

• Three broad modulation domains:

  • Presynaptic mechanisms: influence neurotransmitter production and release.

  • Neurotransmitter amount in the synaptic cleft: reuptake, enzymatic breakdown, glial uptake, autoreceptors, and diffusion.

  • Postsynaptic mechanisms: receptor binding and receptor dynamics.

• Presynaptic modulation examples:

  • Production: increasing choline intake promotes acetylcholine (ACh) production (e.g., cauliflower, milk).

  • Release: some toxins (e.g., black widow venom) promote excessive ACh release, causing paralysis due to persistent ACh at receptors.

  • Autoreceptors: presynaptic autoreceptors bind the same neurotransmitter released by the neuron to dampen activity (negative feedback).

• Mechanisms modulating cleft neurotransmitter levels:

  • Reuptake: transporter-mediated reabsorption into presynaptic neuron.

  • Enzymatic breakdown: enzymes degrade transmitter in the cleft.

  • Glial uptake: astrocytes take up transmitter.

  • Autoreceptors: as above, modulate release.

  • Diffusion: transmitter simply diffuses away from the synapse.

• Postsynaptic mechanisms:

  • Binding site interactions: agonists mimic transmitter by binding to receptors and activating ion channels (e.g., nicotine as an ACh agonist).

  • Antagonists block binding or prevent channel opening (e.g., curare blocks ACh receptors without opening the channel).

  • Duration of binding: reuptake, astrocyte uptake, enzymatic deactivation, or diffusion remove transmitter to free receptors for another signal.

• Neurotransmitters come in two broad classes:

  • Amino acids: main excitatory and inhibitory transmitters in the CNS.

  • Neurotransmitter systems: diffuse-projecting systems including cholinergic, serotonergic, noradrenergic, and dopaminergic.

• Agonists versus antagonists:

  • Agonist: chemical that mimics or facilitates the effect of a neurotransmitter.

  • Antagonist: chemical that diminishes or blocks the effect of a neurotransmitter.

Amino acids: glutamate and GABA

• Glutamate: main excitatory transmitter in the CNS; active at ~15–20% of CNS synapses.

• GABA (gamma-aminobutyric acid): main inhibitory transmitter; about 40% of CNS receptors are GABAergic.

• Why both present? Inhibitory inputs dampen excitatory activity to prevent runaway excitation.

• Glutamate-related disorders:

  • Overactivity linked to epilepsy and excitotoxicity (excessive receptor activation can kill neurons).

  • Ischemia (reduced oxygen) can cause excitotoxic damage due to glutamate.

• GABA-related relevance:

  • Important for dampening oscillatory activity; helps prevent seizures; linked to anxiety, insomnia, and schizophrenia.

• Substances influencing GABA receptors:

  • Barbiturates: reduce seizure activity; sedative effects.

  • Benzodiazepines (e.g., Valium): anxiolytic, antiseizure, muscle relaxation.

  • Alcohol: affects GABA receptors leading to sedative effects.

Neurotransmitter systems and their core components

• Systemic transmitters vs. amino acids:

  • Systems are produced by subcortical neuron populations with diffuse cortical projections.

  • Four major systems discussed: cholinergic, serotonergic, noradrenergic, and dopaminergic.

• Common theme: these systems influence a broad set of behaviors but show some degree of functional specificity.

Cholinergic system (ACh)

• Primary transmitter: Acetylcholine (ACh).

• Cell bodies (origins) and projections:

  • Basal forebrain nuclei project diffusely to most cortical regions.

  • Septal nuclei project to the hippocampus.

• Roles:

  • Maintains cortical excitability; ACh levels rise with convulsants and fall with anesthesia.

  • Linked to REM sleep and dreaming.

  • Important for attention and arousal; enhances focus on prominent stimulus features.

• Nicotine: ACh agonist; can improve sustained attention and filtering of irrelevant information.

• Memory association: Historically linked to memory processing, with Alzheimer’s disease showing reduced ACh; newer views emphasize attention-mediated encoding as a key factor for memory.

• Key references in discussion: Sarter et al. (2005); Klinkenberg & Blokland (2010); Bartus (2000).

Serotonergic system (5-HT)

• Primary transmitter: Serotonin (5-HT).

• Cell bodies: located in raphe nuclei of midbrain, pons, and medulla; projections to hypothalamus, hippocampus, amygdala, limbic system, striatum, cortex, and thalamus.

• Functional domains:

  • Sleep, mood, sexual behavior, eating, and memory.

  • Sleep regulation and REM sleep association with dreaming.

  • Mood regulation; linked to depression; SSRIs elevate synaptic serotonin by blocking presynaptic reuptake.

• Pharmacology:

  • SSRIs (e.g., fluoxetine/Prozac) alter serotonin levels but have broad side effects due to widespread serotonin signaling.

• Cognitive role:

  • Serotonin is linked to memory processes, especially the formation of new long-term memories; tryptophan depletion impairs new memory formation.

• Clinical notes:

  • Ecstasy (MDMA) toxicity to serotonergic neurons is associated with long-term memory deficits.

Noradrenergic system (norepinephrine)

• Primary transmitter: Noradrenaline (norepinephrine).

• Origin and projections:

  • Locus coeruleus (brainstem) as the main source; projects to thalamus, hypothalamus, and cortex (notably prefrontal cortex).

• Main cognitive effects:

  • Enhances arousal and attention; regulates overall wakefulness and vigilance; modulates sleep (thalamic activity can induce sleep-like states; REM sleep involves reduced norepinephrine).

• Pharmacology and cognitive performance:

  • Low-dose clonidine reduces noradrenaline release; impairs sustained attention and alerting tasks.

  • Noradrenergic function implicated in ADHD.

• Memory modulation:

  • α-receptors: linked to short-term memory improvements with noradrenergic activation.

  • β-receptors: linked to long-term emotional memory; propranolol (β-adrenergic antagonist) can reduce emotional memory enhancement.

• Interactions: overlaps with cholinergic involvement in attention and memory.

Dopaminergic system

• Primary neurotransmitter: Dopamine.

• Three subsystems:

  • Nigrostriatal: substantia nigra to dorsal striatum (caudate and putamen); mainly involved in motor control and action selection; affected in Parkinson’s disease.

  • Mesolimbic: ventral tegmental area (VTA) to limbic structures (nucleus accumbens, ventral striatum, amygdala, hippocampus); linked to reward processing.

  • Mesocortical: VTA to prefrontal cortex; contributes to working memory, planning, and executive function.

• Receptors and behavior:

  • Receptors come in D1-like (D1, D5) and D2-like (D2, D3, D4) families.

  • D2 receptors: common targets of antipsychotic drugs (e.g., chlorpromazine); reduce positive symptoms of schizophrenia but may not alleviate cognitive deficits.

  • D1 receptors: related to working memory and cognitive control; evidence shows altered D1 versus D2 balance may contribute to schizophrenia symptoms.

• Subsystems and functions:

  • Nigrostriatal: motor regulation and initiation/cessation of motor actions.

  • Mesolimbic: reward-related behavior; response to natural rewards and drugs of abuse; money as an abstract reward can also engage this pathway.

  • Mesocortical: supports working memory and planning; dopamine depletion in dorsolateral prefrontal cortex leads to cognitive deficits.

Interactions among neurotransmitter systems

• Neurotransmitter systems are highly interrelated and not truly independent:

  • Dopamine and noradrenaline both play roles in attention and are tyrosine-derived.

  • Serotonergic and cholinergic systems influence sleep and memory and project diffusely across the brain.

  • Cholinergic and noradrenergic systems both influence attention and memory, among other overlaps.

• Current research emphasizes how these systems interact to produce complex cognitive and behavioral outcomes.

In focus: herbs and memory, attention, and mood (ethnobotany box)

• Historical and cross-cultural interest in herbal aids for cognition and mood.

• Example herbs and proposed mechanisms:

  • Rosemary, lemon balm, sage: used for memory problems; sage inhibits acetylcholinesterase and binds muscarinic receptors; sage may act as a GABA receptor antagonist in some contexts.

  • Ginkgo biloba: GB extracts (EGb 761) shown to slow mental decline in Alzheimer's in some meta-analyses; typical effective doses around ~240 mg; effects may approach those of acetylcholinesterase inhibitors in some cases; mixed evidence in healthy older adults for cognitive enhancement.

  • St. John’s wort: widely used for mild-to-moderate depression; SSRI-like mechanism via serotonin and noradrenaline uptake inhibition; interactions with many drugs due to liver enzyme pathways; meta-analytic support for efficacy vs. placebo in mild-to-moderate depression; long-term effects less clear.

  • Kava: reduces anxiety and induces calm.

  • Ginseng: may facilitate acetylcholine release and muscarinic receptor binding.

  • Saffron: thought to inhibit acetylcholinesterase; potential antidepressant effects.

  • Indian ginseng and concussion on receptor specificity: some herbs show targeted receptor action (e.g., Indian ginseng with cholinergic specificity; ginkgo showing broader cholinergic effects).

• Ethnobotany drug discovery example:

  • Caucasian Snowdrop (Galanthus caucasicus) extract led to galantamine, an acetylcholinesterase inhibitor used in Alzheimer's treatment; illustrates ethnobotany-driven drug discovery.

• Cautions and caveats:

  • Regulatory status varies; dosages and purity often unregulated in some regions.

  • Herb-drug interactions can be substantial; e.g., St. John’s wort affecting blood pressure, anesthetic interactions, sun sensitivity, and liver metabolism interactions; ginkgo nut overdose linked to seizures in one case.

  • Some true benefits exist (galantamine, some ginkgo effects), but results are mixed and context-dependent.

• Bottom line: herbs may modulate cholinergic, serotonergic, noradrenergic systems or vascular oxygen delivery, but dosage, interactions, and individual differences matter; not a substitute for evidence-based pharmaceutical treatments.

Myelination and long-distance signaling

• Myelin and conduction velocity:

  • Myelin sheath increases the speed of electrical conduction along axons.

  • Unmyelinated axons conduct at about $v_{ ext{unmyel}} \approx 0.5\,\frac{\text{mm}}{\text{ms}}$.

  • Myelinated axons conduct much faster, about $v_{ ext{myel}} \approx 50\,\frac{\text{mm}}{\text{ms}}$.

• Consequences for signaling:

  • Without myelin, a long-distance signal (e.g., to motor neurons in the spinal cord) would take roughly 2000 ms for a 1 m distance (assuming 0.5 mm/ms):

  • $t \approx \frac{1\,\mathrm{m}}{0.5\,\frac{\mathrm{mm}}{\mathrm{ms}}} = 2000\,\mathrm{ms}$.

  • With myelin, conduction time drops dramatically to roughly 20 ms for the same distance in an idealized calculation:

  • $t \approx \frac{1\,\mathrm{m}}{50\,\frac{\mathrm{mm}}{\mathrm{ms}}} = 20\,\mathrm{ms}$.

  • The text notes a figure of about 200 ms, highlighting a potential discrepancy between the numerical example and the prose; the key idea remains: myelin dramatically speeds signaling.

• Structural basis:

  • Myelin is produced by glial cells called oligodendrocytes in the brain.

  • The wrapping of myelin around axons creates discrete myelinated segments; spaces between segments are nodes of Ranvier, enabling saltatory conduction.

  • White matter consists largely of myelinated axons; gray matter consists largely of cell bodies and non-myelinated regions.

• Large fiber tracts and development:

  • When many axons converge, they form fiber tracts (often myelinated) to traverse long distances.

  • The corpus callosum is a major long-distance, myelinated tract connecting the two hemispheres.

  • Myelination develops across childhood and adolescence; sensory and motor regions myelinate earlier, while long-range corticocortical connections may finish myelinating by the mid-twenties, increasing functional connectivity during adolescence (Simmonds et al., 2014; Stevens, 2016).

• Disease relevance:

  • Multiple sclerosis involves patchy demyelination, disrupting motor and cognitive function; greater demyelination correlates with poorer quality of life (Mowry et al., 2009).

The cerebral cortex: cytoarchitectonics and Brodmann areas

• Cortical organization:

  • All cortical areas have five or six layers (laminae), but the relative thickness and cell types vary by region.

  • Areas with similar laminar structure and cell types are grouped into cytoarchitectonic regions.

• Brodmann map:

  • The map divides the cortex into distinct areas based on cellular architecture (laminar patterns).

  • The borders on the Brodmann map are not absolute and may be fuzzy, with smoother transitions in some regions.

  • Although the Brodmann map is anatomically defined, some regions have clear functional specializations while others show weak structure-function correspondence.

• Use in cognitive neuroscience:

  • Brodmann areas are a popular reference for talking about specific brain tissue regions in cognitive neuroscience.

• Note on figures:

  • The inside back cover of the book contains Figures A and B illustrating Brodmann map areas; inner references to cytoarchitectonics guide cortical localization in research.

• Link to broader topics:

  • Brodmann areas provide a framework for linking anatomical organization to functional questions as brain imaging methods advance ( Chapter 3 to discuss imaging techniques ).

Summary of key numerical and definitional references

• Resting potential: $V_{ ext{rest}} \approx -70\,\mathrm{mV}$

• Threshold: $V_{ ext{threshold}} \approx -55\,\mathrm{mV}$

• Action potential peak: $V_{ ext{peak}} \approx +40\,\mathrm{mV}$

• EPSP magnitude: $\text{EPSP} \approx 0.5\text{ to }5\,\mathrm{mV}$

• Unmyelinated conduction speed: $v_{ ext{unmyel}} \approx 0.5\,\frac{\mathrm{mm}}{\mathrm{ms}}$

• Myelinated conduction speed: $v_{ ext{myel}} \approx 50\,\frac{\mathrm{mm}}{\mathrm{ms}}$

• Distance to spinal cord example: about $1\,\mathrm{m}$

• Time estimates (note discrepancy in text):

  • Unmyelinated travel time for 1 m: $t \approx \frac{1\,\mathrm{m}}{0.5\,\frac{\mathrm{mm}}{\mathrm{ms}}} = 2000\,\mathrm{ms}$

  • Myelinated travel time for 1 m: $t \approx \frac{1\,\mathrm{m}}{50\,\frac{\mathrm{mm}}{\mathrm{ms}}} = 20\,\mathrm{ms}$

  • Text cites ~200 ms for myelinated travel, illustrating a possible inconsistency between numbers and narrative while preserving the conceptual point.

• Memory and neurotransmitter interactions:

  • ACh involvement in attention and memory; nicotine can enhance attention; memory effects may be mediated via attention (Sarter et al., 2005; Klinkenberg & Blokland, 2010).

  • SSRIs increase serotonin in synaptic cleft (e.g., fluoxetine/Prozac) and affect sleep, appetite, and sexual function as side effects; memory effects linked to long-term memory formation.

• Myelination development timeline:

  • Sensory and motor regions myelinate early; higher cortical regions and integration connections show prolonged myelination into the mid-20s; adolescence involves increased functional connectivity.

• Disease associations:

  • MS: demyelination affects motor and cognitive functions; worse QoL with greater demyelination.

• Ethnobotany examples:

  • Galantamine (anti-cholinesterase) derived from Caucasian Snowdrop; used for Alzheimer's disease.

  • Ginkgo, St. John’s wort, sage, rosemary, saffron, and ginseng have various proposed CNS effects through multiple neurotransmitter systems; interactions and side effects require cautious use.

Connections to broader concepts and real-world relevance

• Structure–function relationships:

  • Fissures and lobes provide the anatomical basis for functional localization and integration in cognition and sensorimotor processing.

  • Cortical cytoarchitectonics (Brodmann areas) provide a framework for relating cellular architecture to function and to interpreting neuroimaging data.

• Neural signaling mechanics:

  • The electrical signal within a neuron and the chemical signal between neurons together enable fast, selective, and modulatable information processing in the CNS.

  • The balance of excitatory and inhibitory inputs (EPSPs vs IPSPs) and their spatial-temporal summation underlie the brain’s complex dynamics and behaviour.

• Neurotransmitter systems and behavior:

  • Dopamine, serotonin, noradrenaline, and acetylcholine interact to regulate attention, memory, arousal, mood, reward, and executive function, with implications for disorders such as ADHD, depression, schizophrenia, and Alzheimer’s disease.

• Pharmacology and therapeutics:

  • Agonists and antagonists reveal how specific receptor subtypes contribute to behavior and cognition.

  • Understanding transporter and enzyme actions helps explain how drugs like cocaine, SSRIs, and acetylcholinesterase inhibitors exert their effects.

• Practical considerations:

  • Herbals and supplements can modulate CNS function but require careful consideration of dosage, interactions, and regulatory status.

  • Demyelinating diseases highlight the importance of myelin for efficient neural communication and the potential for cognitive as well as motor symptoms.