Nervous System

The nervous system is central to maintaining homeostasis in the body [in conjunction with the endocrine system]. The following critical organs comprise the nervous system: the brain, spinal cord, nerves, and ganglia. The nervous system affects all aspects of one’s health, like mental activity, mobility, heart and respiration rates, sleep, among many others. Its general functions can be thought of as three-fold: sensory, integrative, and motor. 

Embryonic Development of the Nervous System

Introduction

The general embryonic development can be described in 2 ways

Trimesters (3x 3-month periods) 

• First → foundations of major organs
• Second → development of organs 
• Third → rapid growth & fully functional organs 

Anatomical stages

• Pre-embryonic period (0-2 weeks) 
  • Fertilization 
  • Blastocyst formation & explanation 
  • Gastrulation 
• Embryonic period (3-8 weeks) 
  • Development and differentiation of 3 germ layers into foundations of organs 
• Fetal period (9 weeks to birth) 
  • Period of growth, not differentiation 

Some useful terminology

rostral	head
caudal	tail
dorsal	back
ventral	front
ganglia	groups of nerve cell bodies
gyrus	elevations (crests) of the folds on the cerebral cortex
sulcus	grooves (furrows) between gyri on the cerebral cortex

Embryonic development of the nervous system 

Blastocyst (pre-embryonic period) 

• A fertilized egg reaches the Morula stage (Day 3), differentiates into a Blastocyst (Day 7) and then implants in the endometrium
• The implanted Blastocyst consists of an ‘inner-cell mass’ surrounded by Trophoblasts
• This ‘inner-cell mass’ differentiates to form the Bilaminar Disc (2 layers of cells)
  • Epiblast layer: The top layer of columnar cells
  • Hypoblast layer: The bottom layer of cuboidal cells

Gastrulation (Embryonic Period, week 3+)

• Gastrulation is the process that establishes the 3 primary germ layers in the embryo
• Begins with formation of the primitive streak (a shallow midline groove) along the caudal/tail half of bilaminar disc
• At the cephalic/head end of the primitive streak is the primitive node which surrounds the small primitive pit. Cells of the epiblast proliferate & migrate through the primitive pit into the gap between the epiblast & the hypoblast. This is known as invagination
• The epiblast then becomes the ectoderm, the invaginated cells become the mesoderm and the hypoblast becomes the endoderm

Neurulation 

• Neurulation is the process wherein the ectoderm around the midline thickens to form an elevated neural plate
• This neural plate invaginates to form a neural groove down the midline, flanked by two neural folds
• The notochord, a flexible rod of mesoderm-derived cells, defines the primitive axis of the embryo
• The outer edges of the two neural folds continue folding towards the midline where they fuse together to form the neural tube
  • Initially this happens around the center of the embryo, leaving open neural grooves at both the cephalic & caudal ends
  • These neural grooves (aka neuropores), close off by around week 6 of development
  • Failure of a neuropore to close can result in neural tube defects such as spina bifida
• The hollow part inside the neural tube is called the neurocoele
• The neural tube then separates from the ectoderm and sinks down to the level of the mesoderm
  • The mesoderm that flanks the sunken neural tube develops into the somites, which eventually become the skin, skeletal muscle, and vertebrae & skull
• Next, some cells on the top of the neural tube differentiate and separate to form the neural crest
  • Cells of the neural crest eventually migrate & give rise to peripheral sensory neurons, autonomic neurons, and sensory ganglia of the spinal nerves

Somites

• Somites are the mesoderm tissue directly adjacent to neural tube
• Somites grow in association with the developing nervous system → establish early connections
• Somites differentiate into 3 regions:
  • Sclerotome becomes the vertebral column & skull
  • Myotome becomes skeletal muscle
  • Dermatome becomes skin
• Hence, the somites determine the distribution of nervous supply to all mesoderm-derived tissue

Development of the neural tube into the spinal cord

Once the neural tube closes, the cells differentiate into neuroblasts

• These neuroblasts give rise to 2 concentric layers, the mantle layer (inner) and the marginal layer (outer)
  • Mantle layer: later forms the gray-matter of the spinal cord (ventral & dorsal ‘horns’)
  • Marginal layer: later forms the white-matter of the spinal cord
• The dorsal & ventral regions of the mantle layer thicken forming 2 basal plates, and 2 alar plates
  • Basal plates: (motor plates) develop into motor neurons innervating skeletal muscles
    • Become the ventral horns
  • Alar plates: (sensory plates) develop into sensory neurons
    • Become the dorsal horns

Note: the lateral horns in the thoracic & lumbar regions of the spinal cord are autonomic motor neurons and their axons exit via the ventral roots.

Development of the neural crest cells into the sensory (‘dorsal-root’) ganglia of PNS 

• Neural crest cells also differentiate into neuroblasts which become the sensory (‘dorsal-root’) ganglia
• The neuroblasts of the dorsal-root ganglia develop 2 processes:
  • Penetrates into the alar plate of the neural tube and/or into the marginal layer & up to brain
  • Grows distally (outwards) and integrates with the ventral motor root, forming the trunk of the spinal nerve (these neurons eventually terminate in the sensory receptors in skin/muscle/tendons)

Note: these dorsal-root ganglia processes form the ‘sensory pseudounipolar’ nerve-type.

By week 7, we have a near functional nervous system very similar in organization to adult anatomy.

Development of the head & brain

Neural tube enlargement (cephalic end) 

• At around 3-4 weeks, the cephalic portion of the neural tube enlarges to form 3 regions, the primary brain vesicles:
  • Prosencephalon (forebrain)
  • Mesencephalon (midbrain)
  • Rhombencephalon (hindbrain)

Note: the cephalic flexure between the prosencephalon & mesencephalon – important in humans for bipedalism (brain at 90 degrees to spinal cord)

• By around 4-5 weeks, the primary brain vesicles develop further:
  • Prosencephalon (forebrain) develops into:
    • Telencephalon (future cerebral hemispheres)
    • Diencephalon (future thalamus & hypothalamus)

Mesencephalon (midbrain)

• Rhombencephalon (hindbrain) develops into:
  • Metencephalon (future pons & cerebellum)
  • Myelencephalon (future medulla)

Brain formation 

• At around 11-13 weeks, there is massive proliferation of neuroblasts in cephalic neural tube, causing folding due to lack of space within the cranium

Pharyngeal arches & cranial nerves

• Pharyngeal arches are similar to the somites in lower parts of the embryo
• Each pharyngeal arch consists of:
  • Ectoderm tissue → cranial nerves & skin of face
  • Mesenchyme (mesoderm) tissue → musculature of face & neck
  • Endoderm tissue → pharyngeal epithelium
• Note: essentially, this results in segmental development of the head & neck, similar to somites.

Formation of ventricles 

• The neurocoele of the neural tube becomes the ventricles of the adult brain
  • Lateral ventricles (ventricles 1 & 2)
    • Sits in the cerebral hemispheres (telencephalon)
    • Are shaped due to folding of brain during development
    • Each consists of:
      • A frontal (anterior) horn
      • A ‘body’
      • An occipital (posterior) horn
      • A temporal (inferior) horn
  • Third ventricle
    • Sits in the diencephalon
    • Lateral walls formed by thalamus & hypothalamus
    • Connects with the 4th ventricle via the cerebral aqueduct
  • Fourth ventricle
    • Sits in the brainstem
    • Is continuous with the spinal canal (central canal)

Overview & Organization of the Nervous System

Overview 

Macrostructures 

• Brain 
• Spinal cord
• Peripheral nerves
• Sense organs
  • Eyes
  • Ears
  • Tongue
  • Olfactory bulbs
  • Skin

Functions

• Detection of stimuli (external/internal)
• Response to stimuli 
• Coordinates activity of other organs & systems

Organization of the nervous system 

Central nervous system (the “CPU” and “motherboard”)

• Brain
• Spinal cord

Peripheral nervous system (the “cables) 

• Cranial nerves and spinal nerves
• Communication between CNS and rest of the body 

The neuron: structural features 

• Receptive field: dendrites
  • Stimulated by inputs
• Cell body: soma
  • Responds to graded inputs
• Efferent projection: axon (and axon hillock)
  • Conducts nerve impulses to target
  • Myelinated and unmyelinated
• Efferent projection: myelin sheath
• Efferent projection: “nodes of Ranvier”
• Output: synaptic terminals (axon terminals)

Supporting cells: neuroglia (glia) 

• Smaller support cells of NS
• Outnumber neurons 10:1
• Structural & mechanical support
• Roles in maintaining homeostasis & myelination 
• Immune responses via phagocytosis

Neuroglia of the central nervous system (CNS) 

Astrocytes

• Nutrient bridge between neuron & capillaries
• Guide migrating young neurons
• Synapse formation
• Mop up excess K⁺ ions & neurotransmitters

Microglia

• Long thorny processes
• Monitors neuron health
• Senses damaged neurons 
• Migrates to damaged neuron 
• Phagocytoses microbes and debris (immune cells are denied access to CNS) 

Oligodendrocytes

• Myelin formation in CNS

Ependymal cells

• Lines central cavities of brain and spinal cord
• Blood-brain barrier
• Beating cilia circulates cerebrospinal fluid (CSF) 

Neuroglia of the peripheral nervous system (PNS) 

Schwann cells

• Myelin formation → wrap around axon
• Regeneration of damaged neurons 

Satellite cells

• Surround neuron bodies 
• Structure, nutritional support, protection 

Connective tissue sheaths on peripheral nerves

Endoneurium 

• Delicate connective tissue layer 
• Surrounds each axon 

Perineurium 

• Coarser connective tissue layer 
• Bundles groups of fibers into fascicles

Epineurium 

• Tight, fibrous sheath 
• Bundles fascicles into a single nerve 
• Houses blood vessels 

Gray matter and white matter

Gray matter

• Made up of neuron bodies (soma) 
• Imbedded in neuroglial cells 
• Examples
  • Cortex of brain 
  • Center of spinal cord
  • Ganglia/nuclei 

White matter 

• Neuron fibers (axons & dendrites) 
• White due to myelin
• Examples
  • Peripheral nerves & plexuses 
  • Central fiber tracts 

Ganglia 

• Collections of neuron cell bodies in the PNS
  • Afferent spinal nerves
    • Cell bodies of sensory neurons
    • ‘Dorsal root ganglion’
  • Efferent spinal nerves
    • Cell bodies of autonomic nerve fibers
    • ‘Sympathetic trunk ganglion’ 
  • In central nervous system
    • Called: basal nuclei/nuclei
  • Important for both motor & autonomic nervous systems

Spinal nerves

Dermatomes

A portion of the mesoderm (skin, sensory receptors, sebaceous glands, blood vessels) innervated by the cutaneous branches of a single spinal nerve 

Surface Anatomy of the Brain

Surface anatomy

Dorsal landmarks

Fissures

• Longitudinal fissure separates left & right hemispheres
• Transverse cerebral fissure separates occipital lobe from cerebellum

Sulci 

• Central sulcus separates the frontal & parietal lobes
• Lateral sulcus separates the temporal lobe from the other lobes
• Parieto-occipital sulcus separates parietal lobe & occipital lobe

Lobes

• Occipital lobe is the most caudal lobe (visual cortex) 
• Temporal lobe is the most lateral lobe
• Frontal lobe is the most anterior lobe

Ventral landmarks

• Olfactory bulbs are responsible for sense of smell
• Optic chiasm (“optic crossing”) is an ‘X’-shaped crossing-over of optic nerves
• Infundibulum is the connection between pituitary & hypothalamus
• Hypothalamus is responsible for many autonomic homeostatic functions
• Pituitary is an important neuroendocrine organ
• Mamillary bodies form part of the limbic system & are important for recollective memory
• Pyramids (pyramidal tracts) carry motor fibers from the cerebral cortex to the spinal cord

Medial landmarks (i.e., on sagittal section) 

• Cingulate gyrus is part of the limbic system and is involved in emotion and behavior regulation
• Corpus callosum is a thick bundle of connecting nerve fibers connecting left and right hemispheres
• Lateral ventricle holds cerebrospinal fluid
• Pineal body is involved in circadian rhythm (night/day body clock)
• Thalamus has multiple physiological roles including sensory, motor, & consciousness regulation
• Hypothalamus regulates hunger, thirst, temperature control, memory, & stress responses
• Pituitary gland controls metabolism, growth, sexual function, blood pressure, and others
• Colliculi are nestled in between the cerebrum & cerebellum
  • 2x superior → controls eye movements
  • 2x inferior → part of auditory pathway
• Cerebellum is important for coordination, precision, & timing of movements
• Pons are critical for respiratory rhythm & breathing
• Medulla oblongata relays messages between the brain and spinal cord; also regulates cardiorespiratory functions
• Fourth ventricle contains CSF

Coronal section landmarks

• Cortex (gray matter) has key roles in attention, perception, awareness, thought, memory, language, sensation, and motor functions
• White matter is mostly axons & myelin; relays action potentials to their destinations
• Lateral ventricle contains CSF
• Caudate nucleus is important in planning & executing movement; also has learning, memory, reward, motivation & emotional functions
• Corpus striatum is the reinforcement circuit of the brain
• Thalamus has multiple physiological roles including sensory, motor, and consciousness regulation
• Massa intermedia is the bridge between the left & right thalamus
• Hippocampus plays major role in learning and memory

Blood Supply of the Brain

Why does the brain need blood? 

• Consumes 15-20% of the body’s total energy needs and receives 15% of cardiac output, despite being only 2% of total body mass
• Neurons require high ATP to
  • Maintain ion gradients across plasma membrane
  • Regulate neurotransmitter synthesis/re-uptake
• Neurons have no anaerobic capacity → therefore the brain absolutely depends on oxygenated blood
  • Hence, any deficit in blood supply is detrimental (≈30+ seconds of a lack of blood/O₂ to brain → unconscious)

Blood supply to the brain is an anastomosis

• Anastomosis is where multiple arteries supply the same region of tissue (i.e., a dual blood supply) 
• The advantage → if one of the arteries becomes blocked/damaged, the other will compensate for it 

Arterial supply of the brain 

• Brain is supplied by 2 arterial systems
  • 2x vertebral arteries → 1x basilar artery → Circle of Willis
  • 2x internal carotid arteries → Circle of Willis
• Circle of Willis, the anastomosis of the brain
  • The ‘roundabout’ of arteries on the underside of the brain with multiple ‘roads’ coming off it
  • Encircles the optic chiasm, the pituitary gland & the mammillary bodies
  • The ‘roads’: (anterior → posterior)
    • 2x anterior cerebral arteries
    • 1x anterior communicating artery
    • 2x internal carotid arteries
    • 2x middle cerebral arteries
    • 2x posterior communicating arteries
    • 2x posterior cerebral arteries
    • 1x basilar artery

Note: Communicating arteries are always patent, but generally not functional (no blood flow) when blood flow from both carotids & basilar arteries is normal. However, if blood flow from one of the major arteries is impeded, blood is shunted through the communicating arteries to compensate.

Distribution of cerebral arteries

Anterior cerebral arteries

• Travels up and over the corpus callosum, sprouting branches outwards towards the cortex 
• Medial portion of frontal lobe (including cortex) 
• Medial portion of parietal lobe (including cortex) 
• Corpus callosum

Middle cerebral arteries

• Travels through lateral fissure/sulcus and emerges onto the lateral surface of the brain 
• Lateral portion of frontal lobe (including cortex) 
• Lateral portion of parietal lobe (including cortex) 
• Entire temporal lobe (including cortex) 

Posterior cerebral arteries 

• Travels along the inferior brain surface between the cortex and the cerebellum 
• Inferior portion of temporal lobe (including cortex) 
• Posterior-medial portion of parietal lobe (including cortex) 
• Entire occipital lobe (including cortex) 

The blood-brain barrier

• Isolates the brain from blood to provide a stable environment, necessary for control & function of CNS neurons 
• How?
  • The endothelial cells of the CNS capillaries are seamlessly joined by tight junctions
    • This prevents diffusion of most materials except dissolved gasses & lipid-soluble compounds
    • Therefore, any required water-soluble compound must be transported across the BBB
  • Thick basement membrane of capillary

• Note: In the 2 choroid plexuses, the BBB is formed by tight junctions between glial (ependymal) cells as the capillaries in this region are fenestrated and highly leaky
• The BBB exists everywhere, except:
  • Hypothalamus → monitors chemical composition of blood (i.e., hormone levels, water balance, etc.) 
  • Vomiting center → monitors poisonous substances in blood

Venous drainage of the brain (via dural sinuses) 

• Venous drainage begins with venous blood collecting in small venous channels known as dural sinuses 
• Sinuses sit within the dura mater
  • The dura mater is the thickest and outermost of the 3 meninges of the brain 
  • Extends deep into the brain in 2 locations, the falx cerebri and tentorium cerebelli

Falx cerebri 

• The dura mater folds deep into the longitudinal fissure (falx cerebri) of the brain,

where it forms 2 sinuses

• A triangular superior sagittal sinus at the top of the dural fold
• A lower inferior sagittal sinus at the bottom of the dural fold

Tentorium cerebelli 

• The dura mater folds deep into the transverse cerebral fissure (tentorium cerebelli) of the brain, where it forms a pair of sinuses
  • The right and left transverse sinuses 
• All the blood from the superior & inferior sagittal sinuses and the straight sinus empties into these transverse sinuses 

• The left and right transverse sinuses become the left and right sigmoid sinuses, respectively
  • These sigmoid sinuses turn inferiorly and become the internal jugular veins 

Regulation of blood flow to the brain 

Blood flow to the brain is autoregulated 

• i.e., blood pressure in the brain is kept constant, despite systemic blood pressure fluctuations 
• It also means different areas of the brain control their blood flow depending on metabolic activity 

The myogenic autoregulation of blood flow to the brain 

• When mean arterial pressure rises, the SNS constricts the larger arteries of the brain to prevent damaging high pressures in smaller, more delicate vessels (important for preventing stroke) 

The 3 metabolic autoregulatory factors affect blood flow to the brain 

Blood 

• ↑[CO2] → Vasodilation (to ↑ Blood Flow)
• ↓[CO2] → Vasoconstriction (to ↓ Blood Flow)

Blood/CSF pH

•  ↑[CO2] → ↑[H+] via carbonic anhydrase → ↓pH → Vasodilation  (to ↑ Blood Flow) 
• ↓[CO2] → ↓[H+] via carbonic anhydrase → ↑pH → Vasoconstriction (to ↓ Blood Flow)

Blood/CSF [O₂]

• ↓[O2] → Vasodilation (to ↑ Blood Flow)
• ↑[O2] → Vasoconstriction (to ↓ Blood Flow)

Intracranial pressure 

What is it? 

Pressure within the cranium created by CSF, and exerted on the brain tissue and brain’s blood circulation vessels 

Determinants 

• CSF production/resorption (e.g., ↑Production + ↓Resorption)
• Brain tissue (e.g., tumor/inflammation) 
• Blood (e.g., hemorrhage) 

High intracranial pressure

• Compresses cerebral arteries → decreased blood supply → brain drainage
• Can also displace the brain 

Symptoms of high intracranial pressure 

• Altered consciousness
• Changes in BP & HR
• Changes in eye responses 
• Changes in motor function 

Cerebral blood flow and intracranial pressure 

• Cerebral blood flow is carefully regulated under normal conditions
• Cerebral blood flow
  • What percentage of cardiac output goes to the cerebral circulation at rest?
    • 750 mL/min (15% of CO) 
  • Relationship between cerebral blood flow & arterial pressure 

• Kelly-Monroe Doctrine 
  • States that the cranial compartment is incompressible, and the volume is fixed
  • The cranial constituents (blood, CSF, and brain matter) create a state of volume equilibrium:
    • Any increase in volume of one of the constituents must be compensated by a decrease in volume of another
  • Volume buffers
    • Both CSF and, to a lesser extent, blood volume
    • e.g. an extradural hematoma → CSF & venous blood volumes are decreased
    • → maintain normal ICP
    • Buffer capacity ≈ 100-120 mL

Flow & production of CSF 

Reabsorption of CSF into the dural sinuses 

• Note: CSF is constantly being produced, and therefore must also be constantly drained to prevent a rise in intracranial pressure
• Therefore, CSF is reabsorbed into the venous system via diffusion through arachnoid villi (arachnoid granulation)
  • Arachnoid villi are invaginations of arachnoid mater through the dura mater and into the superior sagittal sinus

Cerebral edema

What is it? 

An excess accumulation of water in the intracellular and/or extracellular spaces of the brain 

Types of cerebral edema

Vasogenic 

• Extracellular edema 
• Due to a breakdown of tight endothelial junctions which form the BBB
• e.g., hydrostatic cerebral oedema – where acutely high cerebral capillary pressure results in fluid moving from capillary → ECF

Cytotoxic 

• Intracellular edema 
• Due to a defect in cellular metabolism → inadequate functioning of the Na/K-ATPase in the cell membrane → cellular retention of H₂O

Osmotic 

• Extracellular edema
• Where a drop in plasma osmolality (compared to CSF osmolality) causes water to flow from the venous sinuses back into the subarachnoid space

Migraines 

What are they? 

Incapacitating neurovascular disorder characterized by unilateral, throbbing headaches, photophobia, phonophobia, nausea, & vomiting 

What causes them? 

Decrease in serotonin levels → ↑sensitivity to migraine triggers + cerebral vasoconstriction → ↓cerebral blood flow → raphe nuclei in brainstem release serotonin → cerebral vasodilation + release of proinflammatory mediators from trigeminal nerve & spinal nerves → perivascular cerebral inflammation → pain

Classic vs. common 

Classic 

Associated with ‘aura’ (a visual symptom, such as an arc of sparkling/scintillating zig-zag lines or blotting out of vision, or both) 

Common 

Migraine without ‘aura’ (only 20% of sufferers experience aura; most bypass aura phase) 

Migraine as a risk factor 

• ↑ Risk of silent posterior cerebral infarcts
• ↑ Risk of stroke & CVD (women)
• ↑ Risk of MI (men)

Cranial Nerves

Similarities between spinal nerves & cranial nerves 

Cranial nerves develop similar to spinal nerves, and hence have a similar structural organization

Sensory cranial nerves 

Similar to afferent spinal nerves – sensory cranial nerves’ dendrites are associated with peripheral sensory receptors & their cell bodies are located in a sensory ganglia (similar to the dorsal root ganglion in the spinal cord). Their axons then terminate in the sensory nuclei of the brainstem (similar to dorsal horn of spinal cord), and synapse with one of the ascending pathways (depending on the type of stimulus):

• Touch → posterior pathway
• Pain → spinothalamic
• Proprioception → spinocerebellar

Somatic motor cranial nerves 

Similar to efferent spinal nerves – motor cranial nerves (both somatic & branchial) have

their cell bodies in gray-matter motor nuclei in the brainstem (similar to ventral horn of

spinal cord). Their axons leave the brainstem & directly innervate the skeletal muscles.

Visceral motor cranial nerves

Similar to autonomic spinal nerves – visceral-motor cranial nerves have their cell bodies in the gray-matter visceral nuclei in the brainstem (similar to lateral horn of spinal cord). Their axons then synapse with a second-order neuron in an autonomic ganglion, where the second neuron innervates the smooth muscle

e.g., just as spinal nerves grow in association with their somites, some cranial nerves grow in association with the 6 pharyngeal arches 

The pharyngeal (branchial) arches 

• Note: There are 6 pharyngeal arches, but the 5th only exists transiently during embryonic growth
• No structures result from the 5th arch
• Appear ≈4-5 weeks of development

Pharyngeal arch	Nerve	Muscular contributions
1st – Mandibular	Trigeminal (CN V)	Muscles of mastication Anterior digastricMylohyoidTensor tympani Tensor veli palatini
2nd – Hyoid	Facial (CN VII)	Muscles of facial expression Posterior digastricStylohyoidBuccinator
3rd	Glossopharyngeal (CN IX)	Stylopharyngeus
4th	Vagus (CN X)	Cricothyroid muscleSoft palate muscles
6th	Vagus (CN X)	Intrinsic laryngeal muscles

The 12 cranial nerves: basic overview 

1. Olfactory

smell 

2. Optic

vision (visual acuity) 

3. Oculomotor (‘eye-mover’)

controllers 4 of the 6 eye muscles 

4. Trochlear (pulley) 

controls 1 of the extrinsic eye muscles (pulley-shaped) 

5. Trigeminal 

3-branched (ophthalmic, maxillary, mandibular) sensory fibers to the face & cornea + mastication 

6. Abducens (‘abduct) 

controls extrinsic eye muscle that abducts the eyeball (lateral rotation) 

7. Facial 

facial expression (i.e., furrow brow, shut eyes, smile, etc.) 

8. Vestibulocochlear 

hearing and balance (formerly the ‘auditory nerve’)

9. Glossopharyngeal (‘tongue & pharynx’) 

sensory tongue & pharynx (gag reflex) 

10. Vagus (‘the wanderer’)

mouth motor + parasympathetic effects in the thorax & abdomen 

11. Accessory 

neck & shoulder muscles 

12. Hypoglossal (‘under-tongue’)

tongue movement – poke tongue out 

Functional components of cranial nerves

Cranial nerves carry one/more of the following 5 functional components 

Voluntary (somatic) motor Somatic motor: “general somatic efferents” (GSE)  – Innervate striated skeletal muscle derived from embryonic somites, not pharyngeal arches  – Including ocular muscles, tongue, external neck muscles (sternocleidomastoid & trapezius)  Branchial motor: “special visceral efferents” (SVE)  – Innervate striated skeletal muscle derived from embryonic pharyngeal arches  – Including muscles of the face, palate, pharynx, larynx, mastication	Oculomotor Trochlear  Trigeminal  Abducens Facial  Glossopharyngeal  Vagus Accessory  Hypoglossal
Involuntary (visceral) motor: “general visceral efferents” (GVE)  – Innervate smooth muscle in vessels/glands/etc. via a 2-neuron approach Presynaptic fibers emerge from the brain as cranial nerves, which then synapse in a parasympathetic ganglion  Postsynaptic neurons then innervate the smooth muscles & glands, etc.  – Constitute the cranial outflow of the parasympathetic nervous system	Oculomotor Facial  Glossopharyngeal  Vagus
Visceral sensation: “general visceral afferents” (GVA) Blood pressure, blood O2/CO2 from carotid sinus and body, plus visceral sensation from pharynx, larynx, trachea, bronchi, lungs, heart, GI tract	Oculomotor Trigeminal  Facial  Glossopharyngeal  Vagus
Special sensation: “special somatic/visceral afferents” (SSA/SVA) Vision, taste, smell, hearing, balance	Olfactory Optic Facial Vestibulocochlear Vagus

Nerve	Functional components	Location of nerve cell bodies	Cranial exit point	Major functions
CN I	Special sensory	Olfactory epithelium	Cribriform plate of the ethmoid bone	Smell
CN II	Special sensory	Retinal ganglion	Optic canal	Vision and associated reflexes
CN III	Somatic motor	Midbrain	Superior orbital fissure	Movements of eyes (superiorly, inferiorly, medially)
CN III	Visceral motor (parasympathetic)	Presynaptic – midbrain, postsynaptic – ciliary ganglion	Superior orbital fissure	Pupillary constriction and lens accommodation (parasympathetic)
CN IV	Somatic motor	Midbrain	Superior orbital fissure	Movements of eyes (inferolaterally)
CN V1	General sensory	Trigeminal ganglion	Superior orbital fissure	Sensation from cornea, V1 dermatome
CN V2	General sensory	Pons	Foramen rotundum	Sensation from maxillary teeth, nasal mucosa, maxillary sinuses, palate, V2 dermatome
CN V3	General sensory	Pons	Foramen ovale	Sensation from mandibular teeth, mucosa of mouth, tongue, V3 dermatome
CN V3	Branchial motor	Pons	Foramen ovale	Muscles of mastication, swallowing
CN VI	Somatic motor	Pons	Superior orbital fissure	Lateral rectus muscle – abduction (lateral rotation) of the eye
CN VII	Branchial motor	Pons	Internal acoustic meatus; facial canal; stylomastoid foramen	Facial muscles, some muscles of mastication
CN VII	Special sensory	Geniculate ganglion	Internal acoustic meatus; facial canal; stylomastoid foramen	Taste (anterior ⅔ of tongue)
CN VII	Visceral motor (parasympathetic)	Presynaptic – pons, postsynaptic – pterygopalatine ganglion, submandibular ganglion	Internal acoustic meatus; facial canal; stylomastoid foramen	Stimulation of submandibular & sublingual salivary glands, lacrimal glands
CN VIII – Vestibular	Special sensory	Vestibular ganglion	Internal acoustic meatus	Position of head, balance (body’s gyro)
CN VIII – Cochlear	Special sensory	Spiral ganglion	Internal acoustic meatus	Hearing (via spiral organ)
CN IX	Branchial motor	Medulla	Jugular foramen	Stylopharyngeus muscle (assists with swallowing)
CN IX	Visceral motor	Presynaptic – medulla, postsynaptic – otic ganglion	Jugular foramen	Stimulate parotid salivary gland
CN IX	Visceral sensory	Superior ganglion	Jugular foramen	Visceral sensation from parotid gland, carotid sinus, pharynx, middle ear
CN IX	Special sensory	Inferior ganglion	Jugular foramen	Taste (posterior ⅓ of tongue)
CN IX	General sensory	Inferior ganglion	Jugular foramen	Cutaneous sensation of external ear
CN X	Branchial motor	Medulla	Jugular foramen	Constrictor muscles of pharynx, muscles of larynx, palate, upper ⅔ esophagus
CN X	Visceral motor	Presynaptic – medulla, postsynaptic – viscera	Jugular foramen	Maintains smooth muscle, tone in trachea & bronchi, peristalsis in git & ↓HR
CN X	Visceral sensory	Superior ganglion	Jugular foramen	Visceral sensation from base of tongue, pharynx, larynx, trachea, bronchi, heart, esophagus, stomach & intestine → L-colic flexure
CN X	Special sensory	Inferior ganglion	Jugular foramen	Taste (epiglottis & palate)
CN X	General sensory	Superior ganglion	Jugular foramen	Sensation from external ear
CN XI	Somatic motor	Spinal cord	Jugular foramen	Sternocleidomastoid, trapezius muscles
CN XII	Somatic motor	Medulla	Hypoglossal canal	Intrinsic & extrinsic muscles of the tongue

Cranial nerve nuclei

• Location
  • CN I & II – both extensions of the forebrain 
  • CN III to XII – originate from nuclei located in brainstem 
• Organization
  • Nuclei of similar functional components are generally aligned into functional columns in the brainstem 

Sensory ganglia of cranial nerves 

Cranial nerve	Receptor types	Sensory ganglia
Olfactory	Olfactory	Olfactory epithelium
Optic	Retinal	Retina of the eye
Trigeminal	Somatosensory	Trigeminal ganglion
Facial	Somatosensory	Geniculate ganglion
Vestibulocochlear	Equilibrium and hearing	Vestibular ganglion, spiral ganglion
Glossopharyngeal	Somatosensory, visceral, taste	Inferior ganglion
Vagus	Somatosensory, visceral, taste	Superior and inferior ganglia

Parasympathetic ganglia of cranial nerves 

Cranial nerves in more detail 

Olfactory 

• Function
  • Purely special sensory
  • Carry afferent impulses of smell 
• Origin and course
  • Olfactory nerves arise from olfactory receptors in the olfactory epithelium 
  • They pass up through the cribriform palate of the ethmoid bone, synapse with olfactory bulb
  • Olfactory bulb neurons run posteriorly as the olfactory tract, terminates in primary olfactory cortex 

Optic 

• Function
  • Purely sensory 
  • Carry afferent impulses of vision
• Origin and course
  • Fibers arise from the retina, form the optic nerve
  • Optic nerve passes through the optic canal of the orbit
  • Optic nerves converge to form the optic chiasma where half of each nerve’s fibers cross over and continue on as optic tracts
  • Optic tracts synapse in the thalamus, and thalamic fibers extend to the visual cortex 

Oculomotor

• Function
  • Somatic motor
    • voluntary movement of 4 of the 6 of the extrinsic eye muscles
      • Inf. oblique, sup. rectus, inf. rectus, med. rectus & upper-eyelid muscle
    • Note: proprioceptive afferents exist for each muscle.
  • Visceral motor
    • Parasympathetic control of pupillary sphincter (constriction) & ciliary muscle (lens accommodation)
• Origin and course
  • Fibers arise from the midbrain and pass through the superior orbital fissure to the eye

Trochlear 

• Function
  • Purely somatic motor
    • voluntary movement of 1 of the 6 extrinsic eye muscles (the superior oblique)
• Origin and course
  • Fibers arise from the midbrain, pass through superior orbital fissure to the eye 

Trigeminal

Note: Has 3 divisions (ophthalmic, maxillary, mandibular), each with different specific functions and courses through the skull 

• Function
  • Mostly somatosensory (From face) 
  • Some branchial motor 
• Origin and course
  • Ophthalmic – fibers run from face → superior orbital fissure → pons
  • Maxillary – fibers from from face → foramen rotundum → pons
  • Mandibular – fibers pass through foramen ovale 

	Ophthalmic (V1)	Maxillary (V2)	Mandibular (V3)
Origin & course	Fibers from face to pons via orbital fissure	Fibers run from face to pons via foramen rotundum	Fibers pass through skull via foramen ovale
Function	Conveys sensory impulses from skin of anterior scalp, upper eyelid, and nose; from nasal cavity mucosa, cornea, lacrimal gland	Conveys sensory impulses from nasal cavity mucosa, palate, upper teeth, skin of cheek, upper lip, lower eyelid	Conveys sensory impulses from anterior tongue (ex. taste buds), lower teeth, skin of chin, temporal region of scalp; supplies motor fibers to, and carries proprioceptor fibers from muscles of mastication

Spinal Cord 

General information 

• Extends from foramen magnum
• Resides in the vertebral canal
• Bathed in cerebrospinal fluid
• Terminates at the ‘conus medullaris’ (cone of medulla) – approx l1 in adults.
• Transmits motor information distally from the brain
• Transmits sensory information back up to the brain
• Emits spinal nerves at the level of each vertebrae.
• Cauda equina
  • Nerve rootlets of lower-lumbar & sacral regions extend further down vertebral canal
• Filum terminale
  • Connective tissue anchors cauda equina to the base of vertebral canal

https://www.msdmanuals.com/home/brain,-spinal-cord,-and-nerve-disorders/biology-of-the-nervous-system/spinal-cord

https://commons.wikimedia.org/wiki/File:Spinal_Cord_Sectional_Anatomy.png

Internal structure 

• Grey matter
  • All neuronal cell bodies
  • 2 dorsal horns
    • Nerve cells that receive sensory information from body via the dorsal root fibers
  • 2 ventral horns
    • Contain motor nerve cells
    • Cell axons leave through ventral root fibers
  • Lateral horns
    • Present in thoracic & upper lumbar regions
    • Autonomic motor nerves from sympathetic nervous system
    • Exit spinal cord through the ventral roots
• White matter
  • Ascending and descending fiber tracts

External structure 

• Spinal nerves
  • Merging of dorsal & ventral root fibers
  • Carry mixed sensory and motor info to relevant body area 
• Branches of spinal nerves
  • Ventral rami – ventral branch 
  • Dorsal rami – dorsal branch 
• Sympathetic chain 
• Sympathetic ganglia 

Information pathways: central → peripheral 

Somatic 

Afferent (sensory information) 

• Receptor cells in periphery
• Info conveyed along peripheral axon → Soma (in dorsal root ganglion)
• Info conveyed along proximal axon → spinal cord (CNS)
• Info → ascending fibers (white matter) → brain for processing

Efferent (skeletal muscle) 

• Neuronal cell bodies in ventral horn of grey matter
• Cell axon leaves spinal cord through ventral root → spinal nerve
• Axon flows out of ventral rami
• Directly innervates muscle at neuromuscular junction

Visceral 

Afferent (sensory information) 

• Receptors in viscera
• Info conveyed along peripheral axon → Soma (in dorsal root ganglion)
• Info conveyed along proximal axon → spinal cord (CNS)
• Info → ascending fibers (white matter) → brain for processing

Efferent (smooth muscle) 

• Neuronal cell bodies in lateral horn of grey matter
• Cell axon leaves spinal cord through ventral root → spinal nerve
• Axon flows out of ventral rami
• Axon synapses with peripheral ganglia
• Peripheral ganglia innervates internal viscera
  • Smooth muscle/glandular tissue/cardiac muscle

Neuronal Physiology 

What is neurotransmission? 

• Neuron → neuron/cell/organ/muscle/etc. Communication 
• Point of communication → the synapse 

Terminology

Presynaptic neuron	The sender neuron
Synaptic cleft	Gap between cells
Postsynaptic cell	Receiver cell
Synaptic potential	Drive for transmission that mobilizes the synaptic vesicles to presynaptic membrane

Neuron-neuron neurotransmission 

Note: Neurons synapse with each other in 3 ways 

Three types of synapses 

• Axo-somatic
  • Axon → cell body 
  • For modulatory effects 
• Axo-axonic
  • Axon → axon 
  • For all/nothing signals 
• Axo-dendritic
  • Axon → dendrite 
  • For multiple inputs to a neuron 

https://openbooks.lib.msu.edu/neuroscience/chapter/synapse-structure/

Key ions in neurotransmission 

Na+	Influx	To depolarize membrane to initiate/propagate an action potential
K+	Efflux	To repolarize the membrane to resting potential once action potential has passed
Ca2+	Influx	To trigger exocytosis of neurotransmitter into synaptic cleft

Neuronal action potentials 

1. Resting potential: all voltage-gated channels closed
2. At threshold, Na+ activation gate opens and [Na+] rises
3. Na⁺ enters cell, causing explosive depolarization to +30 mV, which generates rising phase of action potential
4. At peak of action potential, Na⁺ inactivation gate closes and [Na⁺] falls, ending net movement of Na+ into cell. At the same time, K⁺ activation gate opens and [K⁺] rises
5. K⁺ leaves cell, causing its repolarization to resting potential, which generates falling phase of action potential
6. On return to resting potential, Na⁺ activation gate closes and inactivation gate opens, resetting channel to respond to another depolarizing triggering event
7. Further outward movement of K⁺ through still-open K⁺ channel briefly hyperpolarizes membrane, which generates after hyperpolarization
8. K⁺ activation gate closes, and membrane returns to resting potential

https://www.researchgate.net/figure/Phases-of-action-potential-12_fig2_334605708

Refractory periods during action potential 

• Basically, the total time between a stimulus creating an action potential and the MP returning to rest.
  • Determines how soon a neuron can respond to another stimulus.
• Divided into 2 sub-periods:
  • Absolute Refractory Period – no additional stimulus (no matter how large) can initiate a further action potential.
  • Relative Refractory Period – If an additional stimulus is to initiate another action potential during this time, it must be larger in order to reach threshold.

Two factors that influence the speed of an action potential 

1. Axon diameter → larger = quicker
2. Presence of myelin (white matter) → impulse jumps from exposed axon-region to the next instead of having to open and close ion channels across the axon’s entire length (which would be slow)

Phases of neurotransmission 

1. Action potential reaches axon terminal, opens voltage-gated Ca⁺ channels

• Influx of Ca⁺ into axon terminal causes vesicles of neurotransmitter to migrate to the axon terminal.
• ‘Neurotransmitter’ released by exocytosis from the sending (pre-synaptic) neuron.
• Neurotransmitter (acetylcholine/noradrenaline/dopamine/glutamate/gaba/etc) diffuses across synaptic cleft between 2 neurons.

https://www.jobilize.com/course/section/chemical-synapse-nervous-system-by-openstax

2. Neurotransmitters bind to ligand-gated ion channels, causing change in membrane potential of postsynaptic neuron (dendrite) → creating graded potentials

• Graded Potentials can either Excite, or Inhibit the postsynaptic Neuron.
  • If GP depolarizes membrane, it is excitatory
  • If GP hyperpolarizes membrane, it is inhibitory

https://www.researchgate.net/figure/Different-cases-of-IPSP-and-EPSP-summation-12_fig4_308369018

3. Sum of graded potentials may cause membrane potential to reach threshold, triggering action potential. Neurotransmitter Inactivation by enzymes (e.g., ACh-Esterase) or reabsorption prevents continued stimulation.

Two types of postsynaptic receptors 

Ionotropic (ligand-gated ion channels)

Mechanism: Binding of neurotransmitter → opening of ion channel → excitation/inhibition of cell 

• Excitatory: Na⁺/Ca⁺ channel – opening → Na⁺/Ca⁺⁺ Influx → Depolarisation of Membrane → “Excitatory Postsynaptic Potential” (EPSP)
• Inhibitory: Cl^– Channel – opening → Cl^– Influx → Hyperpolarization of membrane → K⁺ Channel – opening → K⁺ Efflux → Hyperpolarization of Membrane → “Inhibitory Postsynaptic Potential” (IPSP)

Metabotropic (G-protein linked receptors) 

Mechanism: Binding of neurotransmitter → Activates G-protein → activates ‘effector’ proteins → activate secondary messengers (e.g., cAMP) → Regulates ion channels/activates enzymes/alters metabolism 

Ionotropic Receptors	Metabotropic Receptors

https://ib.bioninja.com.au/options/option-a-neurobiology-and/a5-neuropharmacology/neuromodulators.html

Actions of neurotransmission 

• Direct physiological action
  • e.g., Neuromuscular junction → muscle contraction 
  • e.g., Sympathetic synapse at SA node → ↑HR
• Links in a chain
  • e.g., Peripheral sensory neuron → spinal cord → ascending sensory pathways → thalamus → cortex 
• Modulation
  • i.e., exerting a positive/negative influence on transmission by another neuron

Neurotransmitters

For a chemical to be a neurotransmitter, it must have 

Dedicated synthesis 

• Amine & amino-acid neurotransmitters are synthesized in the axon-terminal, however, peptide neurotransmitters are synthesized in the cell body & transported to the axon terminal.
  • (This is because peptide synthesis requires gene transcription & translation which require a nucleus & rough endoplasmic reticulum.)
• There is a rate-limiting step for all neurotransmitter synthesis.
  • (e.g., Activity/amount of an enzyme, substrate availability)

Active packaging 

• Amine & amino-acid nt’s actively packaged into vesicles, driven by H⁺ gradient within vesicle. (i.e., H⁺-filled vesicles exchange H⁺ for neurotransmitter)
• Peptide NT’s packaged by Golgi apparatus & transported to axon terminal

Controlled release 

• Various proteins involved in vesicle mobilization are activated by Ca⁺⁺ influx (Note: Many such proteins are destroyed by botox, giving botox recipients expressionless faces)
• Vesicle-membrane fuses with presynaptic-membrane, creating a release-pore → NT diffuses across synaptic-cleft. often some NT’s end up in other neighboring synapses

Receptive post-synaptic cell 

• Neurotransmitter activates either
  • Ionotropic receptors (ligand-gated ion channels) 
  • Metabotropic receptors (G-protein linked receptors → secondary messengers) 

Signal termination mechanism 

• To prevent over-release of NT, autoreceptors exist on presynaptic membrane
  • Provide negative feedback by inactivating adenylate cyclase → ↓cAMP → closes Ca⁺⁺ channels → stop vesicle mobilization and release 
• To prevent on-going stimulation, a NT’s signal is terminated by either
  • Synaptic enzyme (destroy NT in synapse) 
  • Rapid re-uptake (note: for NT’s taken bac up, there are 2 fates)
    • Recycling (repacked into synaptic vesicles) 
    • Enzymatic degradation (NT is broken down into metabolites) 

http://what-when-how.com/neuroscience/neurotransmitters-the-neuron-part-1/

Regulation of receptor response 

• If NT is over-released and/or not terminated → on-going stimulation → receptor activity is altered
  • Desensitization
    • ↓response to NT due to ↓sensitivity of receptor 
  • Down-regulation
    • ↓response to NT due to ↓# of receptors 
    • Note: This functions to block out ‘noise’ 
• If NT is under-released or if antagonist is administered for too long → receptor activity is altered
  • Supersensitization
    • ↑response to NT due to ↑sensitivity of receptor 
  • Up-regulation
    • ↑response to NT due to ↑# of receptors 

Neuromodulation 

i.e., the fine-tuning (‘volume control’) of a signal 

• A neuromodulator can be conceptualized as a neurotransmitter that is not reabsorbed by the presynaptic neuron or broken down into a metabolite. such neuromodulators end up spending a significant amount of time in the CSF (cerebrospinal fluid), influencing (or modulating) the overall activity level of the brain.
• Hence creates a broad signal across the brain → synchronous activation of separate regions → elicits markedly different level of responses from synaptic activity.
• Neuromodulators may either be released into a synaptic cleft, or extracellular fluid.

Types of neuromodulators 

Some examples

• Metabolic products (e.g., adenosine, ATP, H⁺)
• Hormones (e.g., estrogen) 
• Gases (e.g., nitric oxide, CO₂)
• Amines (e.g., dopamine, serotonin, histamine, acetylcholine)
• Proteins 
• Prostaglandins 

The major neurotransmitters (classified by structure) 

Amines (“classical neurotransmitters”) 

• Acetylcholine (ACh) 
• Dopamine 
• Noradrenaline/norepinephrine (NA/NE) 
• Serotonin/5-Hydroxyl tryptamine (5-HT) 

Amino acids 

• Glutamate (#1 excitatory neurotransmitter of the brain) 
• GABA (𝝲-amino Butyric acid) (#1 inhibitory neurotransmitter of the brain) 
• Glycine 

Peptides 

• Cholecystokinin
• Encephalins (e.g., endorphins, opioids) → turn off nociceptive/pain pathways
• Neuropeptide Y → regulates food intake/hunger 
• Somatostatin 
• TRH
• Vasoactive intestinal peptide (VIP) 

Acetylcholine/ACh (cholinergic nerves) 

Roles

• Brain functions
  • Voluntary motor control 
  • Memory & learning pathways 
  • Arousal 
  • Sleep/wake cycles 
• Peripheral functions
  • Contraction of skeletal muscle 
  • Parasympathetic activity in the heart/GI/eye/salivary glands/lacrimal (tear) glands 

https://commons.wikimedia.org/wiki/File:Acetylcholine_Pathway.png

https://commons.wikimedia.org/wiki/File:Cholinergic_synapse.svg

Acetylcholine synthesis 

• Choline + Acetyl CoA are combined by choline-acetyl-transferase (CAT)  to form acetylcholine + CoA
  • Hence, choline & acetate group from the acetyl-CoA combine → ACh 
  • Note: This occurs in the cytosol of the neuron at the axon terminal 

Acetylcholine packaging 

ACh is concentrated into vesicles by an ACh-transporter

Acetylcholine release 

Via Ca⁺⁺ mediated vesicular exocytosis 

Cholinergic receptors (2 types)

• Muscarinic
  • G-protein linked/metabotropic receptors 
  • Parasympathetic NS 
• Nicotinic 
  • Ligand-gated ion channels/ionotropic receptors 
  • Neuromuscular junction/CNS/PNS

ACh signal-termination 

• ACh is degraded within the synapse by acetyl-choline esterase → choline + acetate 
• The choline released is actively transported back into the presynaptic cell by a choline transporter 

Rate-limiting step 

• The reuptake of choline, because the availability of choline determines the amount of ACh synthesis 

Catecholamines [dopamine/NE(NA)/epinephrine (adrenaline)]

Dopamine 

Roles 

• Brain functions
  • Voluntary motor control 
  • Cognition 
  • Reward center
  • Emotions and behavior 
  • Vomiting 
• Peripheral functions
  • Cardiovascular function (↑HR & contraction) 
  • Renal vasodilation at JG apparatus (↑filtration) 

Synthesis 

• Starts with tyrosine (amino acid) 
• Tyrosine is converted to dopa by tyrosine-hydroxylase 
• Dopa is converted to dopamine by dopa-decarboxylase 

Packaging 

• Dopamine is packaged into vesicles in axon terminal 

Release 

• Via Ca⁺⁺ mediated vesicular exocytosis 

Dopaminergic receptors 

• Are metabotropic (G-protein linked receptors) 
• Note: All catecholamine receptors are metabotropic

Dopamine signal-termination 

• Active reuptake into the axon via Na⁺-dependent transporters → repackaged/destroyed
  • Note: If destroyed via enzymatic degradation by mono-amine oxidase (MAO) 

Rate-limiting step 

• Conversion of tyrosine → dopa by tyrosine-hydroxylase 
• Hence, the activity of tyrosine-hydroxylase is rate-limiting for all catecholamine synthesis 

https://commons.wikimedia.org/wiki/File:Cholinergic_synapse.svg

https://www.psypost.org/2020/11/neuronal-ensembles-in-the-nucleus-accumbens-appear-to-be-reward-specific-58560

Norepinephrine 

Roles 

• Brain functions
  • Attention/arousal (fight/flight response) 
  • Sleep-wake cycle 
  • Learning & memory 
  • Anxiety 
  • Pain 
  • Mood 
• Peripheral functions
  • Sympathetic responses 
  • ↑HR + BP
  • ↑Glycolysis + gluconeogenesis + fat metabolism 
  • ↑Blood flow to muscles 
  • ↑Blood flow to coronary circulation 

Synthesis 

• Starts with tyrosine (amino acid) 
• Tyrosine is converted to dopa by tyrosine-hydroxylase 
• Dopa is converted to dopamine by dopa-decarboxylase 
• Dopamine is packaged into vesicles in axon terminal 
• Dopamine is converted to norepinephrine (NA) by dopamine-hydroxylase inside the vesicles 

Packaging 

Via Ca⁺⁺ mediated vesicular exocytosis 

Adrenergic receptors 

Are metabotropic (G-protein linked receptors) 

Note: All catecholamine receptors are metabotropic 

Signal-termination 

Active reuptake into the axon via Na⁺-dependent transporters → repackaged/destroyed 

Note: If destroyed, via enzymatic degradation by mono-amine oxidase (MAO) 

Rate-limiting step 

• Conversion of tyrosine → dopa by tyrosine hydroxylase 
• Hence, the activity of tyrosine-hydroxylase is rate-limiting for all catecholamine synthesis 

https://commons.wikimedia.org/wiki/File:Norepinephrine_Part_1.png

http://what-when-how.com/wp-content/uploads/2012/04/tmp1474_thumb1.jpg

Serotonin 

Roles 

• Brain functions
  • Pain 
  • Wakefulness/arousal 
  • Sleep-wake cycle 
  • Mood and emotions 
  • Vomiting 
  • Circadian rhythm (indirectly by conversion to melatonin) 
• Peripheral functions
  • GI tract
  • Platelet function 

Synthesis 

• Starts with tryptophan 
• Tryptophan is converted to 5-HTP by tryptophan hydroxylase
• 5-HTP is converted to 5-HT (serotonin) by 5-HTP-decarboxylase 

Packaging 

Serotonin is packaged into vesicles in axon terminal 

Release 

Via Ca⁺⁺ mediated vesicular exocytosis 

Serotonergic (5-HT) receptors 

“5-HT” receptors (can have ionotropic & metabotropic types) 

Signal-termination 

Active reuptake into the axon via Na⁺-dependent transporters → repackaged/destroyed 

Note: If destroyed, via enzymatic degradation by mono-amine oxidase (MAO) 

Rate-limiting step 

• Availability of tryptophan in the extracellular fluid (tryptophan is an essential amino acid) 
• Hence, a dietary deficiency of tryptophan → depletion of serotonin in the brain 

https://www.brainfacts.org/diseases-and-disorders/mental-health/2019/rethinking-serotonins-role-in-depression-030819

https://commons.wikimedia.org/wiki/File:Serotonin_%28Illustration%29.png

Amino acid neurotransmitters 

Glutamate 

Roles 

Most common neurotransmitter in the brain 

Synthesis 

• Begins with conversion of glucose → ɑ-Ketoglutarate via glycolysis and TCA cycle 
• Then conversion of ɑ-Ketoglutarate → glutamate via a transaminase reaction 

Packaging 

Active packaging in vesicles 

Release 

Ca⁺⁺ dependent exocytosis 

Receptors 

• Ionotropic
  • NMDA receptor 
  • Kainate receptor 
  • AMPA receptor 
• Metabotropic
  • mGluR receptor 

Signal-termination 

K⁺ dependent reuptake into presynaptic neuron → repackaged into vesicles 

https://link.springer.com/chapter/10.1007/7854_2016_40

GABA (Gamma Amino Butyric Acid) 

Roles 

Inhibitory neurotransmitter in brain 

Synthesis 

• Begins with conversion of glucose → ɑ-Ketoglutarate via glycolysis and TCA cycle 
• Then conversion of ɑ-Ketoglutarate → glutamate via a transaminase reaction 
• Then conversion of glutamate → GABA by glutamic-acid-decarboxylase (+VitB₆) 

Packaging 

Packaged into vesicles by the vesicular GABA transporter (VGAT) 

Release 

Ca⁺⁺ dependent exocytosis 

Receptors 

• GABA_A → ligand-gated Cl^– channels (ionotropic) stimulation → Cl^– influx → hyperpolarizes 
• GABA_B → G-protein linked (metabotropic) stimulation → K⁺ efflux → hyperpolarizes 

Signal-termination 

K⁺ dependent reuptake into presynaptic neuron → destruction by GABA-transaminase 

https://commons.wikimedia.org/wiki/File:GABA_Synapse.svg

Glycine 

Roles 

• Inhibitory NT in the forebrain, brainstem, spinal cord
  • Motor functions 
  • Sensory functions 

Synthesis 

Begins with glucose → 3-phospho glycerate → serine → glycine 

Packaging 

Vesicles 

Release 

Ca⁺⁺ dependent release 

Receptors 

Ionotropic Cl^– receptors → Cl^– influx → hyperpolarization 

Signal-termination 

Reuptake of glycine into presynaptic neuron 

https://n.neurology.org/content/77/7/677

Neurobiology of Memories

Process of memory creation 

External stimuli 

Sensory input bombards the brain, and is sent to the cerebral cortex

Temporary storage (cerebral cortex) 

• Sorts and evaluates the information 
• Depending which inputs you focus on, determines what info is sent to short term memory
  • Input not focused on is forgotten 

Short term memory 

• In medial temporal lobe (hippocampus, amygdala, surrounding cortical areas) 
• Excitement/rehearsal/association/emotion → transfer to long term memory
  • Input not subjected to the above is forgotten

Long term memory

• Requires ACh → for declarative; or dopamine → for non-declarative
  • Declarative: stored in prefrontal cortex
  • Non-declarative: stored in premotor cortex 

https://qbi.uq.edu.au/brain-basics/memory/where-are-memories-stored

Short term memory (STM) 

• Based in hippocampus
  • However, small links are established with cortex (visual/auditory/olfactory/gustatory)
  • These links are made by changes to neuron signaling that don’t require protein synthesis (quicker)
• Last seconds → several hours maximum (aka: “crammers” memory)
  • i.e., changes to neurons are transient (temporary) 
• Limited to ~7-8 “chunks” of information 
• Amnesia = damage to connection between STM & LTM 

Working memory 

• Note: Often grouped with STM 
• Temporary retention, integration (with other brain areas), manipulation of sensory information to facilitate a response 
• e.g., crossing the road
  • Look left (remember position of cars) 
  • Look right 
  • Look left again (compared position of cars to the initial look → is it safe to cross?) 
• Associated with prefrontal cortex
  • Closely tied to STM 
• Neurotransmitter
  • Dopamine

https://www.researchgate.net/figure/Atkinson-Shiffrin-3-stage-model-of-human-memory_fig1_338116821

Long term memory (LTM) 

• Based in hippocampus
• Limitless capacity → the amount we can remember depends on access rather than capacity 
• Usually requires STM input
  • Generally LTM-creation requires the info to pas through STM first 
  • However, some information can bypass STM by ‘hijacking’ existing LTM links (e.g., typing a fact to a previously-learned fact) 
• LTM creation – influenced by 4 factors
  • Genetics 
  • Age 
  • Trauma 
  • Malnutrition 
• LTM creation – improved by
  • Positive/powerful emotional state 
  • Rehearsal 
  • Association of new data with old data 
  • The belief that memory is important 
• Requires remodeling the neuron/synapse via long term potentiation and long term depression 

Long term potentiation (LTP) 

• Definition: “A long-lasting postsynaptic depolarisation, induced through repetitive stimulation & summation of excitatory postsynaptic potentials.”
  • Simply: a persistent increase in synaptic strength 
• Calcium
  • #1 mediator of LTP 
  • NMDA-mediated Ca⁺⁺ influx → activation of enzymes that cause
    • ↑NT release 
    • Or changes in postsynaptic receptors 
• The #1 NT: glutamate → binds to NMDA and/or AMPA receptors
  • NMDA receptors
    • Act as coincidence detectors (simultaneous signals) 
    • i.e., detects coupling of occurrences 
    • Is essentially a ligand (glutamate)-gated Ca⁺⁺ channel 
    • Has a voltage-dependent Mg⁺-block → acts as a voltage gate
    • Therefore, NMDA receptor is ligand and voltage-gated 
  • AMPA receptors
    • Is a ligand-gated Na⁺ channel 
    • When glutamate binds → channel opens → depolarization → AP
    • AP kicks out of the Mg⁺ block on the NMDA receptor 
• 3 Phases of LTP 
  • Induction (synaptic plasticity)
    • Alleviating of the NMDA receptor’s Mg⁺ block
      • This may be done by
        • AMPA-receptor mediated AP 
        • Metabotropic-receptor linked to ion channel → AP 
  • Expression (synaptic augmentation)
    • Modify proteins in postsynaptic terminal or ↑in presynaptic neurotransmitter release → strengthens response to subsequent stimuli
    • Activation of genes in postsynaptic neuron’s nucleus → synthesis of synaptic proteins → ↑synaptic strength
  • Maintenance (long term loss/continuation of LTP)
    • Rise in mRNA levels → augmented synthesis of proteins linked to memory
      • This ↑in protein synthesis is regulated by a (+)transcription factor: “cAMP response element binding” protein (CREB).
      • This perpetual ↑protein-synthesis → long-lasting ↑synaptic strength that is believed to underlie memory.

https://openstax.org/books/biology-2e/pages/1-introduction

Long term depression (LTD) 

• Definition: The weakening of a neuronal synapse that lasts from hours-days
• Calcium, the #1 mediator of LTP
  • NMDA-mediated Ca⁺⁺ influx → activation of phosphatases that cause
    • De-phosphorylation of AMPA-receptors
      • → in hippocampus → AMPA dephosphorylation → ↓amplitude of postsynaptic potential to the normal level (prior to LTP)
      • → can also remove receptors from post-synaptic membrane & place them in reserve
• Results from
  • Strong synaptic stimulation (cerebellum) or 
  • Persistent weak synaptic stimulation (hippocampus) 
• Function in
  • Overall
    • Plays a role in modulating impact of formed memories to prevent overload 
  • Hippocampus
    • Thought to return LTP’d synapses back to a normal level so they will be available to store new information
  • Cerebellum
    • Thought to promote motor learning 

2 types of long term memory 

Declarative (explicit) 

• Brain regions
  • Hippocampus 
  • Para-hippocampal regions (medial temporal lobe) 
  • Areas of cerebral cortex 
  • Thalamus + hypothalamus 
• Learning “WHAT”
  • Facts/words/ideas/concepts/events 

Non-declarative (implicit) 

• Learning “HOW” – how to do things/how to recognize things
  • Procedural
    • Walking 
    • Driving a car 
    • Doing algebra 
    • How to get home 
  • Priming (anticipation) – i.e., the use of a trigger to pull out a memory
    • Ache in gut if you get a letter from tax office – due to previous association 
    • Reaction to seeing your partner 
  • Classically-conditioned
    • Emotional
      • e.g., fear when seeing a shark 
      • e.g., ringing bell → dog salivates 
    • Motor 
  • Non-associative
    • Isolated events not linked to anything 

Circuit of declarative memory 

• Outside stimuli
  • Afferent sensory information → sensory nerves → spinal cord → medulla → brain (somatosensory cortex) 
• Somato-sensory cortex
  • Sensory information is sorted and evaluated 
  • Whatever is the main focus of your attention is prioritized → sent to STM in medial temporal lobe (hippocampus, amygdala, surrounding cortical areas) 
• Medial temporal lobe areas
  • Role: memory consolidation and retrieval via communication with thalamus & prefrontal cortex
  • Basal forebrain
    • Primes the medial-temporal lobe and prefrontal cortex with ACh → triggers LTP in hippocampus 
    • Enables LTM formation (loss of ACh in Alzheimer’s ↓Memory formation & retrieval) 
• Feedback to association cortices
  • Facilitates retrieval of memories 

https://slideplayer.com/slide/13703013/

Circuit of non-declarative (procedural) memory 

• Sensory & motor input
  • Afferent sensori-motor information → spinal cord → medulla → brain (association cortices) 
• Association cortices
  • Somatosensory/visual/auditory/etc.
  • Relay sensori-motor inputs to the basal nuclei 
• Basal nuclei
  • Relays sensori-motor inputs through the thalamus to the premotor cortex
  • Substantia-nigra
    • Releases dopamine onto basal nuclei → prime this circuit (note: loss of dopamine input: i.e., Parkinson’s → interferes with procedural memory) 
• Premotor cortex
  • Plans and organizes learned actions 

https://slideplayer.com/slide/13703013/

Common memory disorders 

Alzheimer’s 

• What?
  • Progressive memory loss (“mild cognitive impairment”), dementia, overwhelming retrograde & anterograde amnesia 
  • No real diagnostic tests 
• Genetic etiology (autosomal dominant)
  • Amyloid precursor-protein gene
  • Presenilin 1 gene 
  • Presenilin 2 gene 
• Symptoms due to
  • Loss of ACh innervation onto prefrontal cortex & medial-temporal lobe (hippocampus) by basal forebrain 
• Affects
  • Basal forebrain cholinergic system (i.e., loss of ACh innervation) 
  • Striatum (caudate & putamen) → part of basal ganglia 
  • Thalamus 
  • Cerebellum 
• Inability to
  • Define simple words 
  • Understand use of common items 
  • Comprehend numbers
    • i.e., loss in declarative memory 
• Emotional disturbances
  • Confusion 
  • Agitation 
  • Delusion 
  • Paranoia 

Amnesia 

• Typically declarative memory loss (therefore hippocampal damage) 
• Commonly caused by temporal lobe damage (hippocampus and/or thalamus)
  • L-hippocampus = language 
  • R-hippocampus = spatial memory 
• Anterograde
  • Inability to form new memories from time of injury/damage onwards 
  • Non-declarative memory is unaffected
• Retrograde
  • Inability to recall memories from time of injury/damage backwards 

Korsakoff

• Anterograde & retrograde amnesia 
• Caused by severe thiamine deficiency (alcoholics & severe malnutrition) 
• → loss of connection between temporal lobes (hippocampus) and frontal cortex 

Seven ‘sins of memory’ – types of memory deficits 

1. Transience – memory ‘fade’
2. Absent-mindedness – brushing teeth when already brushed them 
3. Blocking – when a memory is on the ‘tip of the tongue’ 
4. Misattribution – where you misremember where you saw/heard something, or even if 
5. Suggestibility – where someone suggests that you saw/heard something (when you didn’t) and you ‘remember’ seeing/hearing it 
6. Bias (negative bias) – tend to recall only the negative things 
7. Persistence – remember a single failure rather than multiple successes (e.g., post exam briefings) 
8. … Confabulation – when you elaborate on a memory 

Neurobiology of Emotions 

Definitions 

Affect	Experience of a feeling/emotion that’s not related to bodily changes
Emotion	A mental and physiological reaction to stimuli, experienced as affect plus physiological changes in the body
Feelings	A partly mental, partly physical response to a person, thing, or situation, marked by pleasure, pain, attraction, or repulsion
Arousal	The visceral (body’s) response to stimuli, including autonomic nervous system and neuro-endocrine activity
Cognition	The process of knowing, including both awareness and judgment
Behavior	The active response to stimuli (posture, facial expression, speed, eye movement, vocalization, etc.)

Emotion 

Why does it exist? 

• Critical to survival
  • Both the ability to experience emotion, and to recognize others’ emotions 
  • Gut reactions 
  • Recognizing danger, fried/foe
  • Vital to decision making 
  • Important role in learning 

Theories of emotion 

• A link exists between physiological responses to stimuli & effect of emotion, but which comes first?
  • Cannon-Bard Theory
    • Conscious awareness of emotion comes first, then visceral reactions 
  • James-Lange Theory
    • Visceral reactions come first, then the conscious emotional experience follows 

https://www.brainkart.com/article/The-Many-Facets-of-Emotion_29432/

• Currently, the most plausible theory
  • Visceral reaction (physiological responses) comes first, causing the emotional experience (feelings & thoughts) 
  • However, the emotional experience can influence and/or perpetuate the visceral response 

3 phases/components/types of emotion 

Primary emotions 

• What is felt first → the first instantaneous emotion (usually the simplest/primitive emotions) 
• General independent of culture (universal)
  • Joy
  • Sadness 
  • Anger 
  • Fear
  • Surprise 

Secondary emotions 

• What is felt second → what the primary emotion leads to (slightly more complex emotion) 
• Generally a combination of primary emotions + context
  • Affection/love
  • Lust 
  • Contentment 
  • Disgust 
  • Envy 
  • Guilt 

Tertiary emotions 

• An aggregate of primary and/or secondary emotions (the most complex emotions) 
• Generally the result of a decision, taking into account many factors
  • Satisfaction 
  • Hope 
  • Frustration 
  • Gloom 
  • Contempt 

Physiological context of emotions 

• The physiological state of a person and body can influence resulting emotions and emotional reactivity
  • Well-being 
  • Depression 
  • Calm 
  • Tense 
  • Fatigue 

Brain regions involved in recognition, induction, and regulation of emotions 

Thalamus 

• Funnels sensory information to amygdala, and the cerebral and cingulate cortices 
• Important in fact-based (explicit) memory 

Cingulate gyrus 

• Regulates attention 
• Emotional ‘coloring’ 

Ventromedial prefrontal cortex

Conscious recognition of emotions 

Cerebral hemispheres 

• R-brain → more associated with negative emotions
• L-brian → more associated with positive emotions

Sensory cortices & association areas 

• Recognition of stimuli 
• Sensory cortices: visual, auditory, olfactory, gustatory, tactile 
• Sensory association areas: novel VS. familiar 

Insula 

Involved with recognition and feeling of disgust 

The Papez circuit 

1. Thalamus relays sensory input to cingulate cortex
2. Cingulate cortex gives you the emotional experience; it also relays to the neocortex, which gives context/coloring to the emotion; also relays to hippocampus 
3. Hippocampus relays to the hypothalamus, causes emotional expression (visceral response) 

The limbic system 

Amygdala 

• #1 structure involved in emotion → the “heart” of the limbic system.
• “The fight/flight center”
• Linked to all but 8 areas of the cortex → thought to be #1 integrator of cognitive & emotional info
• Afferents (receives input from)
  • Brainstem – inputs associated with physical states (BP/HR/etc)
  • Hypothalamus – inputs associated with physical states (BP/HR/etc)
  • Thalamus – sensory info
  • Hippocampus – inputs associated with explicit memory
  • cortex – sensory inputs & decisions related to perceived threats
• Efferents (sends output to)
  • Brainstem – influences visceral fear-driven, fight/flight responses
  • Hypothalamus – influence on memory & aggression
  • Thalamus – influences processing of new sensory info
  • Hippocampus – fear is an important driver for learning & memory
  • Prefrontal cortex – fear is important in decision making & cognition
• Regulates
  • Fear & aggression
  • Vigilance & attention
  • Recognition of emotion (in self & others)
  • Emotional contribution to memory (emotional implicit memory)

Hypothalamus 

• Visceral responses to emotion 
• Aggression 
• Sex drive 

Brainstem 

• Visceral responses to emotion 

https://integraleyemovementtherapy.in/limbic-system/

Neurotransmitters and emotion 

Noradrenaline (a target for antidepressants) 

• Activated by novel, unexpected stimuli 
• Released by
  • Locus coeruleus (a nucleus in the pons involved with physiological responses to stress and panic) 
• Regulates
  • Mood/arousal 
  • Anxiety 
  • Pain 
  • Sleep/wake cycles 
  • Motor activity 

Serotonin (a target for antidepressants) 

• Activated by general activity/arousal 
• Released by raphe nuclei ( a group of nuclei in the brainstem) 
• Regulates
  • Mood 
  • Emotions 
  • Sleep/wake cycles 
  • Dominance/aggression 
  • Anxiety 

Dopamine 

• Activated by pleasurable activities 
• Released by
  • Ventral tegmental area (VTA) 
  • Substantia nigra 
• Regulates
  • Somehow plays a role in regulation of perception of emotion 
  • Involved in reward center 

Glutamate & GABA

Reduces anxiety

Acetylcholine 

• Released by basal & septal nuclei of Meynert 
• Regulates
  • Cognitive processing 
  • Arousal and attention 

The emotion of fear 

• Brain structures involved
  • Thalamus → amygdala 
  • Thalamus
    • → primary sensory cortex 
    • → association cortices 
• Long and short pathways
  • Long
    • Info processed by higher brain centers and hippocampus
    • Results in a more complex response 
  • Short
    • Info sent straight to amygdala 
    • Results in a basic response (Recoil from stimulus/freeze) 
    • Advantage = no cortical processing means quicker reaction times = ↑survival 
• Process of fear
  • Sensory information enters brain → thalamus 
  • Thalamus sends information to amygdala (via long/short route) 
  • Amygdala activates visceral responses through hypothalamus 
  • Amygdala activates ventromedial prefrontal cortex (allows conscious recognition of the emotion) 
  • Visual cortex also informs prefrontal cortex about the threat 

https://thebrain.mcgill.ca/flash/a/a_04/a_04_cr/a_04_cr_peu/a_04_cr_peu.html

Aggression 

• Affective aggression VS. predatory aggression
  • Predatory aggression is related to feeding behavior and isn’t accompanied by sympathetic physiological response with which affective aggression is associated 
• Associated structures
  • Cerebral cortex
  • Amygdala 
  • Hypothalamus 
  • Periaqueductal grey matter (PAG) 
  • Ventral tegmental area (VTA) 

i.e., Aggression is controlled by a neural pathway from amygdala through hypothalamus, PAG, and VTA.

• Neurotransmitter: serotonin 
• Possible hormonal link: adenosine 

Pleasure and reward: the ‘reward circuit’ 

• Brain structures involved
  • VTA 
  • Nucleus accumbens 
  • Amygdala 
  • Prefrontal cortex 
  • Thalamus 
• Neurotransmitters involved
  • Dopamine → VTA & nucleus accumbens 

https://thebrain.mcgill.ca/flash/a/a_03/a_03_cr/a_03_cr_que/a_03_cr_que.html

Somatosensory Processing

Sensation types 

Note: Sensations are initiated by receptor activation

Tactile 

• Touch 
• Vibration 
• Stretch 
• Pressure 
• Itches 

Temperature 

Hot/cold

Pain 

Aka ‘nociception’ 

Visceral 

• Blood pressure 
• pH
• O₂
• CO₂

What are sensory receptors? 

Specialized nerve endings that monitor and respond to the environment. 

Classification of sensory receptors based on 3 things 

Physical location 

Exteroceptors	Located in skin (respond to external stimuli)
Interoceptors	Located viscerally (respond to internal stimuli)
Proprioceptors	Located in muscle/bone/tendon

Type of stimulus

Mechanoreceptors	Respond to physical forces
Thermoreceptors	Respond to temperature
Nociceptors	Respond to damaging stimulus
Chemoreceptors	Respond to chemicals (smell/taste OR blood O2/CO2/H+)
Photoreceptors	Respond to light (eyes)

Receptor structure

Simple	Naked (“free”) nerve endings (pain & temperature)
Complex	Structurally elaborate nerve endings (pressure, vibration, stretch) (enhances specificity)

Why are pain receptors ‘simple’?

Pain, a basic survival mechanism, would have been first to evolve and its receptors have been sufficient since. Hence there has been no need for pain receptors to evolve further.

https://www.flickr.com/photos/dundeetilt/29923768703

Receptor transduction 

• Receptors respond to stimuli by transduction them into electrical signals 
• These electrical signals = ion movements across the membrane → changes in membrane potential
  • These changes in membrane potential are graded (i.e., stimulatory/inhibitory, depolarization/hyperpolarization) 
  • These graded potentials at the receptor level = receptor potential 

• Receptor potentials may summate to threshold → initiating an action potential
  • These action potentials at the receptor level = general potentials 

Receptors: nature of activity 

When are they active? 

• Tonic receptors: continually firing (e.g., proprioceptors) 
• Phasic receptors: fire only with a change in the environment (e.g., thermoreceptors) 

When do they inactivate? (How quickly do they adapt?) 

Note: Adaptation = time taken for receptor to stop firing during sustained stimulation 

• RARs – rapidly adapting receptors
  • Receptor quickly stops firing under continuous stimulus 
  • e.g., touch receptors (can’t feel clothes after a while) 
• SARs – slowly adapting receptors
  • Receptor maintains firing under continuous stimulus 
  • e.g., muscle stretch receptors (proprioceptors) 

Receptive fields

A receptive field: the area monitored by 1x receptor (i.e., touch anywhere in that field, the sensation will come from the entire receptive field) 

https://www.coursehero.com/study-guides/austincc-ap1/pain/

• Large receptive fields
  • Low receptor density 
  • Poor localization 
  • e.g., skin on your back 

• Small receptive fields
  • High receptor density 
  • Good localization 
  • e.g., skin on your fingertips 
  • Note: 2 point discrimination is best with small, dense receptor areas 

Receptor types 

Receptor speed

• Varies by diameter and myelination – affects speed of conduction and therefore type of sensory information
  • Larger + myelinated = fastest 
  • Smaller + non-myelinated = slowest 
• Proprioceptors are fast to ensure fine motor control 
• There are 2 types of paint receptors: the fastest is responsible for initial (sharp) pain
  • Slowest is responsible for dull ache that follows 

https://slideplayer.com/slide/7797833/

Initial processing by thalamus 

• Once sensory input enters CNS, it travels to the Thalamus (sorting station of the brain)
  • Impulses are sorted on the basis of where they came from and the type of sensation
  • They are then sent to their relative functional areas on the cortex (brain surface).
• Response: If a response is required, then a discrete area of the brain will activate it.
  • Primary motor cortex: voluntary motor
  • Language & Speech Centres: vocalization
  • Hypothalamus & Brain Stem: visceral responses (chest/abdominal – pulse/sweat/BP)

https://nigerianscholars.com/tutorials/sensory-systems/perception/

Functional sensory areas of the brain 

• Primary visual area – receives visual information from the retina of the eye.
• Primary motor area – controls voluntary skilled movements of our skeletal muscles
• Pre-motor cortex – controls learned motor skills (musical instruments/typing/etc)
• Primary auditory area – sound energy stimulates hearing receptors and is interpreted as pitch/vol/location
• Primary somatosensory area – receives information from the general (somatic) sensory receptors
• Primary gustatory area – perception of taste stimuli
• Primary Olfactory area – info from smell receptors

https://commons.wikimedia.org/wiki/File:1604_Types_of_Cortical_Areas-02.jpg

Somatosensory association area 

• The somatosensory cortex has connections to the somatosensory association areas
• Gives meaning to the received information, store it in memory, relate it to past experiences & decide on plan of action

Somatosensory cortex 

• Roles
  • Detection of sensation & conscious awareness of sensation
  • Feature/quality recognition (ie. texture/size/shape)
• Exhibits ‘somatotopy’ (body mapping)
  • i.e., specific cortical areas responsible for particular body regions
  • Receptor density in a body region determines the size of the respective cortical area

https://blogs.iu.edu/sciu/2019/02/12/brain-organization/

Somatosensory pathways 

First order neurons (peripheral afferent nerves) 

• e.g., dorsal root of spinal nerves and sensory cranial nerves 
• Sensory information is frequency coded 
• Enter spinal cord via dorsal nerve root → terminate in dorsal horn 
• Note: Cell bodies of the pseudounipolar-neuron receptors culminate in the dorsal root ganglion

Second order neurons (ascending pathways of spinal cord) 

• Once inside the spinal cord, 1st order neurons → synapse with 2nd order neurons 
• 2nd order neurons
  • Often responsible for decussation (crossing of fiber tracts to the other side of the body) 
  • Different sensory information takes different ascending pathways to the brain 

Third order neurons 

• Note: 3rd order neurons are only relevant to the dorsal column and the spinothalamic pathways
  • Spinocerebellar pathway terminates in the cerebellum with 2nd order neurons 
• Carry sensory information from thalamus to the primary somatosensory cortex in parietal lobe
  • Thalamus sorts incoming sensory information → sends it to the cortex 

https://courses.lumenlearning.com/suny-ap1/chapter/central-processing/

The 3 ascending pathways 

Dorsal column pathway 

• Synapses with 2nd-order neurons in medulla
• Decussate in the medulla
• Neurons are
  • Large & myelinated
  • Rapidly adapting
• Sensory info
  • Touch
  • Vibration
  • 2-point discrimination
  • Proprioception

Spinothalamic pathway 

• Synapses with 2nd-order neurons in spinal cord at level of spinal root
• Decussate in spinal cord at level of spinal root
• Neurons are
  • Small & myelinated
  • Slowly adapting
• Sensory info
  • Crude touch & pressure
  • Pain
  • Temperature

Spinocerebellar pathway 

• Synapse with 2nd-order neurons in spinal cord
• Doesn’t decussate – remains ipsilateral
  • (“On the same side of the body”)
• Neurons are
  • Large & myelinated
  • Slowly adapting
• Sensory info
  • Proprioception from
    • Muscle spindles
    • Golgi tendon organs
    • Joint capsules
  • → coordinate skeletal muscle activity

Neurotransmitters (NTs) and receptors 

At the sensory nerve 

• TRPV₁-Receptor (Ca⁺⁺ Channel)(“TRP Vanilloid Receptor₁”). Opened by:
  • Capsaicin (from hot chillies)
  • Heat
  • Mechanical (Mechanism unclear)
  • H⁺ (Acid) (often a result of inflammation)
• Bradykinin receptors
  • Bradykinin receptor activates TRPV₁-Receptor → Depolarization → Nociception
• Prostanoid receptors
  • Sensitive to prostaglandins
  • Open Na⁺ channels →*
  • Inhibit K⁺ channels →* 
  • Open TRPV₁-receptors →*

*→ ↑MP → Lowers threshold → ↑sensitivity

• ASIC – (“acid sensitive (gated) ion channel”)
  • Acid → ASIC-stimulation → depolarisation of cell → nociception
• Opiate/cannabinoid receptors
  • Sensitive to opioid & cannabinoids
  • Open K⁺ channels → K⁺-efflux → ↓MP (hyperpolarizes cell) → ↓sensitivity

At the dorsal horn 

• Afferent pathway
  • Substance P
  • Glutamate (AMPA & NMDA receptors)
• Efferent pathway – sensory modulation via pain-gate mechanism
  • Opioids  activate descending inhibitory pathways & directly inhibit dorsal horn synapse
  • Noradrenaline directly inhibits dorsal-horn synapse
• Serotonin (5-HT) directly inhibits dorsal-horn synapse
• Encephalins directly inhibit dorsal-horn synapse
• Note: Low-dose tricyclic antidepressants can treat neuropathic pain by blocking reuptake of NE, 5-HT, & encephalins in dorsal horn synapse

Motor Processing

Hierarchy of structures – the levels of motor control 

1. Ready (strategy) – deciding “what to do” 

• Prefrontal cortex 
• Somatosensory association cortex (area 5) 
• Basal ganglia (Note: Basal ganglia are the interface between strategy and tactics)

2. Set (tactics) – deciding “how to do it” 

• Basal ganglia 
• Pre–motor area (PMA) 
• Supplementary motor area (SMA) 

3. Go (execution) – “action” 

• Primary motor cortex (M1) 
• Cerebellum 
• Brainstem 
• Descending tracts
• Spinal nerves 
• Peripheral motor neurons 

https://link.springer.com/article/10.1007/s00701-018-3474-3

Roles of these brain regions (in motor processing) 

Prefrontal cortex 

Consciously decides “what movement” is required for the desired outcome (managerial function) 

Somatosensory association areas 

Tells the brain where the body is in space (proprioception) 

Premotor area & supplementary motor areas 

• Plans “how to do the movement” 
• Is also the memory bank of complex, patterned, and highly skilled learned movements 

Primary motor cortex (M1) 

• “Initiates the movement” (typically precise or skilled voluntary movement) 
• Note: M1 also exhibits somatotopy – the bigger the cortical area, the more precise the movements 
• Receives direct and indirect inputs
  • Direct → from: prefrontal cortex, SMA/PMA, somatosensory areas 
  • Indirect → from: cerebellum (via thalamus) 
• Broca’s area controls the muscles responsible for speech (tongue/jaw/lips/face) 

https://medicoapps.org/wp-content/uploads/2018/10/1522570629.jpg

Basal ganglia 

• Involved in action-selection and initiation of voluntary & patterned movements (e.g., walking)
  • Motor control 
  • Motor learning 
  • Note: also has a role in cognition & memory 
• A loop exists between cortex → basal ganglia → thalamus → premotor cortex → cortex
  • Receives inputs from the entire cortex
    • SMA/prefrontal cortex/sensory cortex/M1 
    • Information travels through basal ganglia in this order: striatum → globus pallidus 
  • Sends information to the PMA & SMA via the ventro-lateral nucleus of the thalamus (VLo) 
• Consists of
  • Striatum
    • Caudate nucleus (cognition + behavior) 
    • Putamen (motor) → automatic performance of previously learned movements 
  • Globus pallidus 
• Other associated structures
  • Subthalamic nuclei
  • Substantia nigra (eye movement + motor planning, reward seeking, learning, addiction) 

http://brainmind.com/GlobusPallidus.html

Note: The globus pallidus is spontaneously active! 

Globus pallidus → thalamus (inhibits thalamic-SMA activity → keeps the SMA “quiet”) 

https://commons.wikimedia.org/wiki/File:Blausen_0076_BasalGanglia.png

Cerebellum 

• Functions
  • Precise timing & appropriate patterns of skeletal muscle contraction – required for smooth, coordinated movements & agility needed for daily living (driving/typing/playing music/etc.)
  • Involved in the correct sequencing & coordination of muscle contractions
  • Involved in motor learning – compares intention with result & corrects for next time
  • Balance & posture
• Note: Cerebellar activity is subconscious (i.e., we have no awareness of its functioning)
• A loop exists between the cortex → pons → cerebellum → thalamus → M1 → cortex
  • Receives inputs from the cerebral cortex (M1, pma, *somatosensory areas) via the pons
    • Also receives proprioceptive feedback
  • Sends info to the primary motor cortex (M1) via the ventrolateral nucleus of the thalamus
    • Informs primary motor cortex (M1) about direction, force, & timing of movements
• Output into descending pathways:
  • Vermis → ventromedial pathways
  • Hemispheres → lateral pathways
• Cerebellar processing

1. Cortical motor areas notify the cerebellum (via ‘relay nuclei’ in the brainstem) of their intent to initiate voluntary muscle contractions.
2. Constant proprioceptive input (muscle/tendon tension, joint position, etc.) enables the cerebellum to evaluate the body’s position & momentum.
3. Cerebellum calculates optimum force, direction, & extent of muscle contraction to ensure smooth, accurate, & coordinated movements.
4. Cerebellum sends its “blueprint” for coordinating movement to the cerebral motor cortex via the superior peduncles. It also sends info to brainstem nuclei → influences motor neurons of the spinal cord.

• Analogy
  • Just as an ‘autopilot’ compares a plane’s instruments with its planned course, the cerebellum continually compares the higher brain’s intention with the body’s performance & makes appropriate corrections.

https://www.lecturio.com/concepts/cerebellum/

Descending tracts involved in motor functions

Descending motor pathways 

Lateral pathways 

• Roles 
  • Both tracts – voluntary movement of distal extremities
  • Particularly hands & feet 
• 2 divisions 
  • Corticospinal tract
    • Originates in primary motor cortex
    • Run through the internal capsule to the brainstem 
    • Decussate in medullary pyramids (medulla) 
  • Rubrospinal tract
    • Originates in red nucleus of midbrain 
    • Decussate immediately below red nucleus (in the pons) → → 
    • Continue down the spinal cord in the lateral white matter 
    • Terminate in ventral horn of spinal grey matter 

https://en.wikipedia.org/wiki/Corticospinal_tract#/media/File:1426_Corticospinal_Pathway.jpg

Ventromedial (indirect/extrapyramidal pathways) 

Tectospinal (aka “colliculospinal”) tract 

• Begins in the superior colliculus
• Decussates between midbrain & pons
• Function → visual tracking (head/eye coordination)

Vestibulospinal tract 

• Begins in the vestibular nuclei of the medulla 
• Does not decussate 
• Function → maintain balance during standing & moving 

Pontine & medullary reticulospinal tracts 

• Begin in the pontine reticular formation 
• Do not decussate 
• Function → maintains muscle tone & visceral motor functions 

https://healthjade.net/upper-motor-neuron/

https://slideplayer.com/slide/17905402/

• Note: These descending ‘upper motor neurons’ terminate in the ventral grey horns of the spinal cord grey matter by synapsing with either:
  • Spinal interneurons – enabling info to be sent to multiple outputs
    • Some interneurons are “central pattern generators”→ generate timing for patterned movements (e.g., walking)
  • Or lower motor neurons – that directly innervate skeletal muscle

Somatic reflexes 

• Rapid, automatic responses to stimuli 
• Occur over neutral pathways called reflex arcs
• Components of a reflex arc
  • Receptor → sensory neuron → CNS integration center → motor neuron → effector 

https://commons.wikimedia.org/wiki/File:The_extensor_digitorum_reflex.jpg

Visceral reflexes 

• Similar to somatic-NS, the ANS also has reflex arcs 
• Visceral reflex arcs components 
  • Visceral sensory neurons (chemical changes/stretch/irritation of viscera) → ganglionic neuron (integration center) → motor neuron → effector 

https://open.oregonstate.education/aandp/chapter/16-2-autonomic-reflexes-and-homeostasis/

https://www.austincc.edu/apreview/PhysText/PNSefferent.html

The Autonomic Nervous System 

Divisions of the autonomic nervous system 

The 2 divisions of the ANS (sympathetic & parasympathetic) serve the same visceral organs, but cause opposite effects. This dual innervation counterbalances each division’s activities → maintains homeostasis.

Sympathetic 

• “Fight/flight” 
• Mobilizes the body during activity 
• Effects are widespread 

Parasympathetic 

• “Rest/digest” 
• Conserves body energy & promotes maintenance functions 
• Has relatively short-lived effects (due to short-acting nature of ACh) 
• Effects are relatively localized 

https://slideplayer.com/slide/17251153/

Efferent pathways and ganglia 

As opposed to the somatic-NS which uses a mono-synaptic system (& hence lacks ganglia), the autonomic-NSuses a 2-neuron-chain system.

Preganglionic neuron

• The cell-body of the first neuron
• Resides in the brain or spinal cord
• Synapses with a ganglionic neuron

Ganglionic neuron

• Resides in an ‘autonomic ganglion’ outside the CNS
• Extends from the ganglion to the effector organ

Sympathetic & parasympathetic divisions differ anatomically in 3 ways 

• Site of origin 
• Fiber lengths 
• Location of ganglia 

Characteristic	Parasympathetic	Sympathetic
Origin	Craniosacral outflow: brainstem nuclei of CN III, VII, IX, X; spinal cord segments S2–S4	Thoracolumbar outflow: lateral horn of gray matter of spinal cord segments T1–L2
Location of ganglia	Ganglia in (intramural) or close to visceral organ served	Ganglia within a few cm of CNS: alongside vertebral column (sympathetic trunk, or chain, ganglia) and anterior to vertebral column (collateral, or prevertebral, ganglia)
Relative length of pre- and postganglionic fibers	Long preganglionic; short postganglionic	Short preganglionic; long postganglionic

https://study.com/academy/lesson/parasympathetic-nervous-system-definition-function-effects.html

Anatomy: the parasympathetic (craniosacral) division 

• Fibers originate from brainstem & sacral region of spinal cord
  • Preganglionic fibers – extend nearly all the way to the structures to be innervated
  • Postganglionic fibers – very short; extend from the terminal ganglia & synapse with effector cells
• Ganglia location: located very close to or within the target organs

The cranial outflow

• Fibers originate from cranial-nerve nuclei in the brainstem 
• Fibers extend to their terminal ganglia via 4 of the paired CN

CN III Oculomotor	Pupil constriction, lens accommodation (close sight)
CN VII Facial	Stimulate large glands in the head (nasal, lacrimal, submandibular, sublingual salivary)
CN IX Glossopharyngeal	Stimulate parotid salivary glands
CN X Vagus	Serves virtually all organs of the thoracic and abdominal cavities (except distal large intensities)

The sacral outflow

•  Fibers originate from neurons in the lateral gray matter of spinal cord segments S₂–S₄ 
• Fibers extend to their terminal ganglia via splanchnic nerves of the pelvic plexus
• Serve distal large intestine & the pelvic organs (bladder, ureters, reproductive organs)

https://anatomytool.org/content/openstax-anatphys-fig152-connections-sympathetic-nervous-system-english-labels

Anatomy: the sympathetic (thoracolumbar) division 

Note: Sympathetic-NS innervates more organs than the parasympathetic, and its effects are longer-lasting 

Fiber origin 

Cell bodies of preganglionic neurons in the lateral horns spinal cord segments T₁→L₂

Fiber lengths 

• Preganglionic fibers
  • Exit spinal cord via ventral root 
  • Pass through white ramus communicans 
  • Synapse adjoining sympathetic trunk (chain) ganglion)
    • Note: Fibers are short
• Postganglionic fibers
  • Exit sympathetic ganglion at/below/above their spinal level via grey ramus communicans 
  • Enters ventral spinal nerve at that level 
  • To the effector organs 

Note: The color of the rami communicans reveals whether or not their fibers are

myelinated. (pre: myelinated, post: unmyelinated) 

Ganglia location 

• Sympathetic trunks (chains of ganglia) flank each side of the vertebral column from neck to pelvis 
• Note: Although the sympathetic trunks exist along the length of the spinal cord, the fibers arise only from thoracic & lumbar cord segments 

https://pediaa.com/difference-between-sympathetic-and-parasympathetic-nervous-system/

https://bio.libretexts.org/Courses/Lumen_Learning/Book%3A_Anatomy_and_Physiology_I_(Lumen)/17%3A_Module_15-_The_Autonomic_Nervous_System/17.02%3A_Divisions_of_the_Autonomic_Nervous_System

Physiology of the Autonomic Nervous System

Neurotransmitters of the PNS 

• Afferent (sensory)
  • Glutamate 
  • Calcitonin-gene-related peptide 
  • Substance P
• Efferent (motor)
  • Somatic/voluntary (skeletal muscle)
    • Acetylcholine (ACh) 
  • Autonomic
    • Sympathetic
      • Preganglionic → ACh (stimulate ganglia and adrenal medulla) 
      • Postganglionic → Norepinephrine (NE)
      • Adrenal medulla → stimulated by ACh to release epinephrine and NE into blood 
    • Parasympathetic
      • Preganglionic → ACh 
      • Postganglionic → ACh 

https://www.austincc.edu/apreview/PhysText/PNSefferent.html

• Somatic division
  • Axons extend from CNS to effector (skeletal muscles) 
  • Typically thick, heavy myelinated 
  • High conduction speed 
  • Neurot is ACh, effect is always stimulatory 
• Autonomic division
  • Preganglionic axons extend from CNS and synapse with either:
    • Peripheral autonomic ganglia OR 
    • Cells of the adrenal medulla 
  • Release ACh 
  • Postganglionic axons extend from ganglia to effectors and release either
    • ACh → parasympathetic
    • NE → sympathetic
  • Adrenal medullary cells release NE and epinephrine into the blood 

Note: Preganglionic fibers are thin & lightly myelinated & postganglionic fibers are thinner & unmyelinated. Hence, conduction speed within the autonomic neurons is slow – much slower than somatic NS.

Receptors of the ANS 

Parasympathetic (cholinergic (ACh) receptors) 

Nicotinic 

• Found on
  • Motor end-plates of skeletal muscle → somatic
  • Receptive regions of all ganglionic neurons (both sympathetic & parasympathetic)
  • Hormone-producing cells of the adrenal medulla
• Action
  • Binding of ACh → directly opens ion channels (:.ionotropic) → depolarize the postsynaptic cell → stimulatory

Muscarinic 

• Found on
  • All effector cells stimulated by postganglionic cholinergic fibers (i.e., All parasympathetic target organs & some sympathetic targets [eccrine sweat glands & some skeletal-muscle blood vessels])
• Action
  • Binding of ACh → Activates the receptor’s G-protein, which detaches from the receptor → Causes an intra-cellular signaling cascade (:.metabotropic). → may be stimulatory or inhibitory depending on the subclass of muscarinic receptor on the target organ
• Tissue-specific receptor subtypes
  • M1 – Brain
  • M2 – Heart
  • M3 – Smooth Muscle & Glands

Sympathetic (adrenergic receptors) 

• Receptors that respond to NE/epinephrine
• May be excitatory or inhibitory depending on which subclass of receptor predominates in that organ. (Organs responsive to NE/Epi often have more than one receptor subclass)
• Alpha: α_1/2
• Beta: β_1/2/3

https://www.chegg.com/homework-help/questions-and-answers/use-chart-text-notes-assist-question-follows-learned-parasympathetic-nervous-system-rest-d-q75990245

Clinical manipulation of the peripheral NS

Aim 

Use NS to regulate organ function

Drugs 

Mimic/enhance/block messages sent along the nerves 

Problem 

• Side effects – because the PNS only uses 2 neurotransmitters, side effects can be widespread 
• E.g., some illicit drugs have sympathomimetic side effects
  • Cocaine & amphetamines ↑↑ cardiovascular stimulation (tachycardia & hypertension) 
• Can reduce side effects by
  • Topical application 
  • Targeting the specific receptor subtypes with more specific drugs
  • Targeting tissue-specific differences in receptor subtypes 

Examples 

Somatic NS 

• ACh inhibitors: ↓Deactivation of ACh in synapse → ↑ACh action)
• Neuromuscular blockers (e.g., nicotinic antagonists)

Autonomic NS 

• Sympathetic
  • Agents that affect release/reuptake of catecholamines (NE, epi, & dopamine)
  • Adrenergic agonists & antagonists
• Parasympathetic
  • ACh inhibitors: ↓Deactivation of ACh in synapse→ ↑ACh action
  • Muscarinic agonists & antagonists

Ganglionic blockers 

• Drugs which block chemical transmission at autonomic ganglia – essentially denervates the entire autonomic nervous system (main effect – vasodilation [loss of vasomotor tone])
• Effects vary from tissue to tissue, depending on whether sympathetic/parasympathetic nerves are usually dominant in that tissue:
  • If sympathetic usually dominates, ganglionic blockers mimic parasympathetic stimulation
  • If parasympathetic usually dominates, ganglionic blockers mimic sympathetic stimulation

https://slideplayer.com/slide/11668755/

https://basicmedicalkey.com/neurotransmission-2/

Sympathetic and parasympathetic tone

Sympathetic (vasomotor) tone 

• The continual state of partial constriction of the vascular system that maintains BP (even @ rest)
• During activity, a higher BP is needed → the vasomotor fibers fire more rapidly → vasoconstriction
• Note: Alpha-blockers dull the effects of the sympathetic/vasomotor tone → control hypertension

Parasympathetic tone 

• Slows the heart, sets the normal activity levels of the digestive & urinary systems, & stimulates glandular secretion (except adrenal glands & skin glands)
• Note: The sympathetic division overrides this during times of stress
• Note: Drugs that block parasympathetic responses → ↑hr, fecal/urinary retention & ↓glandular secretion

Unique roles of the sympathetic NS

• Note: The sympathetic division is more wide-spread than the parasympathetic division – because it innervates more organs.
  • E.g., adrenal medulla, sweat glands, hair-follicle muscles of the skin, the kidneys, & most blood vessels only receive sympathetic fibers
• There are other uniquely sympathetic functions
  • Thermoregulatory response to heat
    • Cutaneous vasodilation 
    • Activation of sweat glands 
  • Thermoregulatory response to cold
    • Cutaneous vasoconstriction
  • Release of renin from the kidneys
    • Sympathetic impulses stimulate renin release 
    • Promotes increased BP 
  • Metabolic effects
    • Sympathetic stimulation → of of adrenal medullary hormones
      • Increased metabolic rate of body cells 
      • Increased blood glucose 
      • Mobilizes fat for use as fuels 
      • Puts skeletal muscle on red alert (contract more strongly and quickly) 

Central control of the autonomic NS

• ANS activity is regulated by a hierarchy of CNS controls
  • Hypothalamus 
  • Brainstem 
  • Spinal cord 
• Note: Subconscious cerebral inputs via limbic lobe influences hypothalamic functioning 

https://www.austincc.edu/apreview/PhysText/PNSefferent.html

Disorders of the peripheral nervous system 

Categories 

• Inflammation
  • Guillain Barre syndrome – immune mediated demyelinating neuropathy 
  • Myasthenia gravis – antibody attack on nicotinic ACh receptor in NMJ 
• Trauma
  • Spinal injuries 
• Metabolic
  • Diabetic neuropathies – macro/micro-vascular 
  • Vitamin deficiencies (B₁₂, B₆, E) 
• Toxicity
  • Urea 
  • Alcohol 
• Genetics 
• Infection
  • Shingles 
  • Diphtheria 
  • Leprosy 

Examples of homeostatic imbalances of the ANS 

Hypertension 

• Results from overactive sympathetic vasoconstriction promoted by chronic stress 
• Can be treated with β-blockers, other adrenergic antagonists

Raynaud’s disease

• Characterized by intermittent attacks of peripheral cyanosis
• Provoked by exposure to cold or emotional stress 
• An exaggerated vasoconstriction response 

Autonomic dysreflexia 

• Uncontrolled activation of autonomic neurons (mechanism unclear) in patients with quadriplegia 
• Increased arterial BP, headache, flushed face, sweating 
• Life-threatening