Block 2: neuroanatomy

Question 1

Describe the function of low threshold mechanoreceptors

Answer 1

LTMs detect non-noxious touch. There are four types of mechanoreceptors which vary in terms of rate of adaptation, receptive field sizes, and depth within the skin tissue. Receptive field size refers to the area of skin which is detected from a particular receptor. Rate of adaptation refers to the corresponding APs resulting from activation- fast adapting mechanoreceptors fire when pressure is applied, but stop firing if it is maintained (and may fire again when released, therefore detect changes in pressure); slow adapting mechanireceptors with continue to fire if stimulus is sustained, stopping only when it is released (therefore detect displacement)

Merkel’s disks are found at the epidermal-dermal border, have small receptive field sizes, and are slow adapting.
Meissner’s corpuscles are found at the epidermal-dermal border, have small receptive field sizes, and are fast adapting.
Pacinian corpuscles are found deep in the skin tissue, have large receptive field sizes, and are fast adapting.
Ruffini’s endings are found deep in the skin tissue, have large receptive field sizes, and are slow adapting.

There are also hair follicle afferents, and these have highly variable properties.

Question 2

Describe the structure and function of thermoreceptors

Answer 2

Thermoreceptors are free nerve endings which densely populate tiny “spots” of the skin. These are temperature sensitive, and each nerve ending responds a specific temperature range (there are cold and warm thermoreceptors. Thermoreceptors detect non-noxious temperatures.

Question 3

Describe the structure and function of nociceptors and itch receptors

Answer 3

Nociceptors and itch receptors are free nerve endings, and the former can be found all over the body in various tissues (itch only in skin). Some nociceptors are finely tuned to only respond to specific stimuli, but others will detect a range (known as polymodal nociceptors). Silent nociceptors are not active under normal conditions, but become active when tissue is damanged. Itch receptors typically respond to chemical stimuli (there are two kinds, one which responds to noxious stimuli and one which does not).

Question 4

Explain how mechanical and thermal stimuli are transduced

Answer 4

Mechanical stimuli are activated by mechanosensitive ion channels. Various channels have been identified, one important one is Piezo2 (a large protein with over 30 transmembrane domains).
Thermal transduction relies on a family of transient receptor potential (TRP) cation channels. The first one to be identified and cloned was TRPV1, a channel which responds to high temperature (>43C), as well as low pH, and capsaicin (the molecule in chilli which makes it spicy). Interestingly, menthol is an agonist of TRP-channels which detect cold temperatures. TRPV1 is likely to have an important role in perception of noxious heat, and TRPV1 of noxious cold, however there are other channels which are involved.

Question 5

Describe the path of primary afferents and the different types of primary afferent fibres.

Answer 5

Primary afferent neurons are pseudo-unipolar- the cell body is typically set off to the side in the dorsal root ganglion (once the fibre passes the DRG, it is considered in the CNS). Primary afferents enter the spinal cord via the dorsal root.

Axons can be divided into myelinated and unmyelinated (A- and C- fibres, respectively). Myelinated fibres tend to be either large or small in diameter (but not usually medium), and these are referred to as A-beta (6-12um diameter; conduct at 35-75m/s) or A-delta (1-5um; conduct 50-30m/s), respectively. C-fibres tend to be very small in diameter (<1um), and conduct at ~1m/s (they also outnumber A-fibres 4:1 in cutaneous nerves).

AB fibres are almost all low threshold mechanoreceptors (hair afferents are often C-fibres). Most nociceptors, thermoreceptors, and itch receptors are either A-delta or C-fibres (A-delta typically characterise sharp, well localised pain; C-nociceptors are associated with dull, poorly localised pain). AB afferents give local branches to dorsal horn of the spinal cord, as well as branching and projecting up the dorsal columns to the medulla (rostrally travel). Adelta and C-fibres only give local branches to the dorsal horn – they do not project rostrally. The dorsal horn of the spinal cord grey matter consist of laminae I-VI, with the “superficial layers” being laminae I and II, and the “deep layers” being laminae III-VI. Fine afferents usually terminate in the superficial layers (Adelta and C). Large diameter mechanoreceptors usually terminate in the deep layers of the dorsal horn (as well as giving rise to the ascending branch).

Question 6

Define motoneurons and explain their function, as well as motor units and motoneuron pools.

Answer 6

Motoneurons are responsible for carrying output pathways to muscles to produce movement – they integrate all the signals from descending, segmental (reflex), and intrinsic (central pattern generated) pathways. Skeletal muscle fibres are innervated by alpha-motoneurons (large fibres) and originate in the ventral horn of the grey matter of the spinal cord. Axons project out via the ventral root, which converges with the dorsal root to form a spinal nerve which branches into various nerves and can innervate muscle fibres. Although each skeletal fibre is innervated by one motoneuron, a motoneuron can branch to innervate many extrafusal muscle fibres (each axon can innervate up to 1000 muscle fibres). A single motoneuron, along with all the fibres it innervates, form a functional unit called a motor unit. Where fine control is more important than generation of force (e.g. the eyes or the fingers), motor units are much smaller than where force is more important than control (e.g. the back or thighs). A motoneuron pool is the population of motoneurons that innervates a whole muscle, and these motoneuron pools have a topological organisation in the spinal cord.

Question 7

Define motoneurons and explain their function, as well as motor units, motoneuron pools, and motocolumns.

Answer 7

Motoneurons are responsible for carrying output pathways to muscles to produce movement – they integrate all the signals from descending, segmental (reflex), and intrinsic (central pattern generated) pathways. Skeletal muscle fibres are innervated by alpha-motoneurons (large fibres) and originate in the ventral horn of the grey matter of the spinal cord. Axons project out via the ventral root, which converges with the dorsal root to form a spinal nerve which branches into various nerves and can innervate muscle fibres. Although each skeletal fibre is innervated by one motoneuron, a motoneuron can branch to innervate many extrafusal muscle fibres (each axon can innervate up to 1000 muscle fibres). A single motoneuron, along with all the fibres it innervates, form a functional unit called a motor unit. Where fine control is more important than generation of force (e.g. the eyes or the fingers), motor units are much smaller than where force is more important than control (e.g. the back or thighs). The mechanism by which muscle contraction force is graded is by altering the number of motor units which are being recruited. A motoneuron pool is the population of motoneurons that innervates a whole muscle, and these motoneuron pools have a topological organisation in the spinal cord. These collections of motoneurons in the ventral horn are sometimes referred to as motonuclei, however, what they actually form is a column along the length of the spinal cord. Every muscle in the body has a motocolumn in the spinal cord – the most distal muscles have the most distal motocolumns (e.g. leg muscles in lumbosacral), and more caudal muscles have more caudal motocolumns (e.g. bicep in cervical).

Question 8

Describe the stages of a monosynpatic reflex, using the knee jerk reflex as an example.

Answer 8

1) Hammer strikes tendon, displacing it and tugging the attached muscle (extensor, quadricep), stretching it
2) Muscle spindle receptors (sensitive stretch receptors) fire action potentials along the sensory 1a afferent fibres- these are the fastest conduction velocity fibres in the nervous system
3) They project to the spinal cord (for knee jerk L3/L4) via the dorsal root, where they enter via the dorsal horn, then synapse on the same side with motoneurons at the ventral horn (monosynaptic circuit)
4) 1a afferents release glutamate (excitatory)- if there is sufficient excitation, the post-synaptic motoneurons fire action potentials, which travel to the effector muscle (extensor)
5) At the neuromuscular junction, the motoneurons release acetylcholine, inducing action potentials in the skeletal muscle fibres (causing contraction – mechanical shortening of the muscle pulls on the tendon, giving a “jerk” of the lower limb)

Question 9

Describe the stages of a polysynaptic reflex, using the flexor/crossed-extensor reflex as an example.

Answer 9

Polysynaptic reflexes (flexor/crossed-extensor reflex) are mediated by chains of interneurons – excitatory and inhibitory interneurons produce appropriate actions on different motoneuron pools. The flexor/crossed-extensor reflex involves potentially noxious stimuli being detected by nociceptors (causes withdrawal from harmful stimulus by contracting flexor muscle (e.g. hamstring) and relaxing extensor muscle (e.g. quadricep), and doing the opposite on the either side to maintain balance).

Group III cutaneous afferent fibres carry signals from nociceptors via the dorsal root, they synapse onto chains of interneurons in the central grey matter. On the ipsilateral side, chains of excitatory interneurons eventually synapse onto flexor motoneurons, and chains of inhibitory interneurons synapse onto extensor muscles- this is the flexor component. However, there are also axon collaterals which decussate and have the opposite effect on the contralateral side- this is the crossed-extensor component (supports weight). There are also many other divergences of this pathway which affect the actions at the hip, ankle, and more. There are also examples of convergence of signals in neural circuits.

Question 10

What is the function of CNI (olfactory nerve).

Answer 10

Called a special sensory nerve – this is because only this nerve that allows you to smell (there are no other nerves which can do this). Smell comes from the nasal mucosa of each nasal cavity, the nasal septum (divides the two cavities), and the superior conchae (folds of cartilage). Olfactory nerve fibres are the only ones known to be able to completely regenerate- have been used to treat people with spinal cord lesions and regained function (olfactory and sheathing cells in particular). The loss of sense of smell is called anosmia.

Question 11

What is the function of CNI (olfactory nerve)?

Answer 11

Called a special sensory nerve – this is because only this nerve that allows you to smell (there are no other nerves which can do this). Smell comes from the nasal mucosa of each nasal cavity, the nasal septum (divides the two cavities), and the superior conchae (folds of cartilage). Olfactory nerve fibres are the only ones known to be able to completely regenerate- have been used to treat people with spinal cord lesions and regained function (olfactory and sheathing cells in particular). The loss of sense of smell is called anosmia.

Question 12

What is the function of CNII (optic nerve)?

Answer 12

Special sensory nerve – it is the only nerve which can allow for sight (vision from the retina). Exits the optical canal via the optic chiasm (crossing point of left and right fibres- only some of them decussate). Multiple sclerosis typically affects the myelin of the optic nerves – it can affect patients’ vision and can cause blindness in severe cases.

Question 13

What is the function of CNIII (oculomotor nerve)?

Answer 13

Somatic motor fibres – originate in the midbrain. Innervates the superior rectus, medial rectus, inferior oblique, and levator palpebrae superioris muscles. These are extra-ocular muscles- they surround the eye for movement of the eyeball. It also has visceral motor fibres (parasympathetic), innervating the sphincter pupillae (smooth muscle constricts the eye for pupillary light reflex) and ciliary muscle (controls accommodation – focusing the lens to see near or far objects). Oculomotor nerve projects via the ciliary ganglion (parasympathetic fibres). Compression of CrN III due to raised intracranial pressure (aneurisms, diabetes, inflammation, trauma, etc) can cause unimpeded action of the other motor nerves of the eye, resulting in eyes pointing downward and outward (this nerve pulls them up and inward).

Question 14

What is the function of CNIV (trochlear nerve)?

Answer 14

Somatic motor fibres – supplies motor function to one muscle – the superior oblique (medial rotation and abduction - moves eye downward and outward). Isolated palsy of this nerve will cause diplopia (double vision), but it is rarely paralysed on its own.

Question 15

What is the function of CNV (trigeminal nerve)?

Answer 15

Has 3 branches (all general sensory fibres) – first is the ophthalmic nerve (CNV1 or CNVa) which gives sensation from the cornea, skin of forehead, scalp, eyelids, nose, mucosa of nasal cavities, and paranal sinuses. The second branch is the maxillary nerve (CNV2 or CNVb), and gives sensation from the face over the maxilla, upper lip, maxillary teeth (superior alveolar nerve), and maxillary sinuses (vocal resonance and lightening of skull). The mandibular division (CNV3 or CNVc) innervates the side of the mandible, the mandibular teeth (inferior alveolar nerve), mucosa of the mouth and anterior 2/3 of the tongue. The mandibular division also has a motor function – the branchial motor division (four muscles of mastication – masseter (elevates mandible to close mouth); temporalis (elevates and retracts mandible); lateral pterygoid (opens mouth and helps side to side movement); medial pterygoid (elevates mandible and aides closure of the jaw, also assists side to side movement).

Question 16

What is the function of CNVI (abducens nerve)?

Answer 16

Originates in the pons, somatic motor innervation to one muscle – the lateral recuts (abducts eyeball to look out the way). It can be stretched due to raised intracranial pressure (due to bleed, trauma, hydrocephalus, etc). Patient would be unable to move eye laterally to affected side, and would typically be medially rotated at rest due to the other muscles.

Question 17

What is the function of CNVII (facial nerve)?

Answer 17

There are 43 muscles of facial expression which are located around the orifices (Eyes, nose, and mouth)- this is an odd number because there’s a single muscle which innervates the lips on both sides. The facial nerve also innervates the scalp and the stapedius (smallest muscle in the body – helps to prevent loud sounds from damaging our auditory apparatus). It also has special sensory fibres – supplies taste from anterior 2/3 of the tongue and palate. It also has visceral motor fibres (parasympathetic innervation to submandibular and sublingual salivary glands, as well as the lacrimal gland and glands of nose and palate).

Question 18

What is the function of CNVIII (vestibulocochlear nerve)?

Answer 18

Originates in the brainstem- special sensory nerve for hearing and balance. Auditory sensation comes from the spiral organ, and vestibular sensation comes from the semi-circular canals. Internal acoustic neuroma/vestibular schwannoma is a benign tumour which grows over years, can cause dizziness and loss of hearing, tinnitus, headaches, double vision (if it grows large, it can affect the facial nerve and cause numbness or weakness of the face on the ipsilateral side.

Question 19

What is the function of CNIX (glossopharyngeal nerve)?

Answer 19

Has many functions:

1) Somatic motor to stylopharyngeus (raises larynx and pharynx, and dilates pharynx to allow bolus to pass)
2) Visceral motor to the parotid gland (parasympathetic stimulation causes serous secretion)
3) Visceral sensory innervation to the parotid gland, pharynx, and middle ear
4) Special sensory fibres innervate posterior 1/3 of the tongue for taste
5) Somatic sensory fibres innervate the external ear (earlobe)

Question 20

What is the function of CNX (vagus nerve)?

Answer 20

Longest of all cranial nerves – supplies many structures external to the head and neck. Somatic motor fibres innervate muscles of the pharynx, intrinsic muscles of the larynx, muscles of the palate, and upper 2/3 of the oesophagus. Visceral motor fibres provide parasympathetic innervation to the trachea, bronchi, gastrointestinal tract, and heart (slows breathing and heart rate, increases gut motility – rest and digest). Visceral sensory fibres innervate the tongue, larynx, respiratory tract, upper GI tract, and left colic flexure. Also has special sensory fibres which innervate the epiglottis and palate (taste). General sensory fibres innervate the auricle and external auditory meatus (earlobe and ear canal).

Question 21

What is the function of CNXI (spinal accessory nerve)?

Answer 21

Somatic motor nerve innervating two muscles – the sternocleidomastoid and trapezius. The sternocleidomastoid goes from behind your ear to your collar bone and sternum – when it contracts it turns head to opposite side, and causes head to move slightly upwards (if both contract, flexion of head will occurs- bending forward). The trapezius helps elevate the scapula (shoulder-blades).

Question 22

What is the function of CNXII (hypoglossal nerve)?

Answer 22

Projects from the brainstem, somatic motor innervation to intrinsic and extrinsic muscles of the tongue (except the palatoglossus, which is innervated by the vagus nerve). Palsy of this nerve will cause tongue to move to affected side when stuck out (due to unopposed contraction of the working side).

Question 23

What is an aphasia? What are Broca’s and Wernicke’s aphasias?

Answer 23

An aphasia is a partial or complete loss of language ability without necessarily affecting cognitive faculties (it is also not associated with inability to move muscles of speech). Most of our early knowledge of language processing comes from aphasias as results of lesions to specific areas of the brain. In the mid 19th century, Paul Broca described the first aphasia (Broca’s aphasia) in a patient who could only say “tan”. The patient had a severe deficit in speech production due to a lesion in the left interior dorsolateral prefrontal cortex, thereafter referred to as Broca’s area. Two decades later, another neurologist, Karl Wernicke, encountered a patient with very poor language comprehension but good speech production (Wernicke’s aphasia). This time, the lesion was to the superior surface of the left temporal lobe (just behind the auditory cortex) – thereafter named Wernicke’s area.

Question 24

What is the Wernicke-Geschwind model?

Answer 24

The Wernicke-Geschwind model describes in a simplified way how language processing is organised when you repeat a spoken word:

1) Input enters the auditory cortex
2) Signals are sent to Wernicke’s area, where sounds are perceived as words
3) This information is transmitted to Broca’s area through the arcuate fasciculus, where motor planning of speech is carried out
4) These signals are sent to the motor cortex, which sends signals to the mouth and lips to carry out the speech

Question 25

Describe the Wada procedure.

Answer 25

The Wada procedure evaluates the function of hemispheres by putting one of them to sleep – this is done by injecting barbiturate (such as sodium amytal) into the internal carotid artery of the side you want to put to sleep. This produces a transient aphasia (about 10 minutes) of one brain hemisphere, allowing you to test if that hemisphere is dominant for a particular function. As this is a very invasive technique, it is only used when there is contradicting evidence from other procedures (i.e. before an important surgery such as tumour removal).

Question 26

Explain the procedure and purpose of split-brain studies and tachiscopic presentation.

Answer 26

Split-brain studies involve surgical disconnection between the two hemispheres (severing of the corpus callosum and anterior commissure), causing complete loss of intercerebral communication. This procedure is usually only done in patients with severe epilepsy, where excessive excitation is spreading from one hemisphere to the other. These split-brain patients can be used for studies afterwards to evaluate how the brain is organised. One experiment which can be done is vision-independent stereognosis, where the patient uses one hand at a time to feel an object and report what that object is without seeing it. Usually (if the patient has left-sided language processing), the patient will be able to recognise the object in their right hand (due to decussation) but will only be able to rudimental descriptions of the object in the left hand (or no description at all).

Tachistoscopic presentation is another method for this – visual stimuli are briefly presented in the left or right visual field, and the patient is asked to report what was seen. Results from these tests found that the majority of patients could not report what was seen or felt on their left side, because these signals were not able to cross into the left cortex from the right where language is processed. However, these studies also revealed the power of the unconscious brain processing – when asked to draw what was written on the left field of view, the patient can draw it, but cannot report it verbally.

Question 27

Describe the structure and functions of the PNS glia (satellite and schwann cells).

Answer 27

Satellite cells are small, flattened cells which surround the outer surface of nerve cell bodies. Satellite cells are typically found in ganglia (sensory and autonomic). Their main known functions are to regulate the micro-environment within the ganglia (e.g. control diffusion between external environment and neuron they are attached to); respond to neuronal injury/inflammation (e.g. receptors and transporters for ATP and bradykinin); and to act as a protective barrier. They are implicated in chronic pain, as they sensitise sensory neurons in dorsal root ganglia, resulting in hyperalgesia. They can also highten the stress response by communicating with the neuron they are associated with- when a neuron releases ATP, purine receptors on the satellite cell detect this and release TNFa in response.

Schwann cells are responsible for synthesising the melin sheath in the PNS. Myelin is composed of 70% lipid (mostly phospholipid and cholesterol) and 30% protein. The myelin sheath forms internodes of approx. 1mm length. One single schwann cell wraps around and myelinates a single axonal internode.

Question 28

Describe the structure and functions of oligodendrocytes.

Answer 28

One single oligodendrocyte can myelinate multiple internodes on a single axon, and can myelinate many different axons (forms up to 50 internodes). The soma of the oligodendrocyte is completely distinct from the myelin sheath. Myelin within the CNS is ~30% thinner than in the PNS, and has a different protein composition. Degeneration of oligodendrocytes leads to demyelination in multiple sclerosis. The loss of a single oligodendrocyte can impact neurotransmission of many nerves and nerve pathways (results in symptoms of loss of co-ordination, muscle weakness and fatigue, and loss of sensation (all due to reduced conduction velocity).

Question 29

Describe the structure and functions of astrocytes.

Answer 29

The most numerous glial cell within the CNS (up to 40% of all glial cells in the CNS), and comprise of 20-50% of total brain volume. They can be identified histologically by staining for glial fibrillary acidic protein (GFAP). There are two types of astrocytes; fibrous and protoplasmic. Fibrous astrocytes are present in white matter – have very few organelles and long, fine, unbranched processes (which may have end feet allowing them to wrap around blood vessels); protoplasmic astrocytes are normally present in the grey matter- they have lots of organelles and short, highly branched processes.

1) End-feet of fibrous astrocytes are called perivascular end-feet. These play a role in the regulation of potassium ion balance in extracellular space and extracellular volume.
2) They are also associated with neurons and are often involved in synaptic transmission. They are part of the tripartite synapse (express lots of potassium channels to regulate extracellular potassium concentration; provide metabolic support (see next)
3) Astrocytes are involved in the link between neural activity and blood flow- neural activity is detected by astrocytes, resulting in influx of calcium ions into the atrocyte, leading to release of vasoactive factors by the pervascular end-feet, leading to changes in vascular smooth muscle tone (this is known as neurovascular coupling). This allows the astrocyte to nourish the neurons with lactate and remove harmful metabolites.
4) They can secrete anti-inflammatory cytokines (e.g. TGFB and GDNF) and pro-inflammatory cytokines in response to injury/disease.
5) They are a principal component of the BBB, as they maintain tight junctions between the epithelial cells.

Question 30

Describe the structure and functions of microglia.

Answer 30

Microglia are the immune cells of the CNS, and are extremely numerous (~20% of total cells in brain). They are highly motile and responsive to injury or infection – they have a surveillance role where they continually monitor the environment and detect any changes to CNS homeostasis (use long processes to do this). Based on their location and cells around them, microglia can be divided into perineuronal microglia (associated with neurons), parenchymal (not associated with a particular cell type), and perivascular (associated with blood vessels). Functional states of microglia include:

1) Systemic-sensing – they will detect the presence of any neurotoxic substances or inflammatory mediators within the systemic circulation (will become active if they detect anything)
2) General surveillant microglia – detect if neurons are dying or damaged as well as changes to CNS homeostasis
3) Pruning microglia – remove surplus of synapses which are not required (important in development)
4) Neuromodulatory microglia – may be associated at CNS synapses along with astrocytes
5) Phagocytic microglia – active state of microglia (become round) clean up debris, removing toxic mediators, pathogens, dying cells, etc
6) Proliferating microglia – are not produced in bone marrow like systemic immune cells are – they can proliferate in the brain to maintain their numbers

Many factors can be detected by microglia to activate them, including serum factors in the bloodstream (e.g. complement, immunoglobulins, etc); pathogens in the bloodstream; and abnormal proteins within the CNS (e.g. b-amyloid). When activated, they change morphology and start engulfing stuff. They also release cytokines which can be pro-inflammatory or anti-inflammatory (based on their cytokine profile – gene transcription). There is a huge amount of cross-talk between microglia and neurons (via neurotransmitters, chemokines, trophic factors, and cytokines) and microglia and astrocytes (via cytokines and prostaglandins).

Question 31

Describe the structure and functions of ependymal cells.

Answer 31

Ependyma is a specialised epithelium consisting of ciliated simple columnar epithelial cells known as ependymal cells (or ependymocytes). Ependyma lines the ventricles of the brain and the central canal of the spinal cord. The cilia help to aid the flow of CSF. Within the ventricles of the brain, there is also the choroid plexus (a network of modified ependymal cells and capillaries). It is responsible for the production of CSF (not found in the central canal of the spinal cord – only the ventricles). These specialised ependymal cells are not ciliated. They form folds of microvilli. They also act as a barrier between blood and CSF.

Question 32

What are the four distinct phases in the life of an oligodendrocyte?

Answer 32

1) The birth, migration, and proliferation of oligodendrocyte precursor cells (OPCs – happens in waves, more cells are produced than are required).
2) Morphological differentiation – oligodendrocyte establishes an expansive network of processes (projections of myelin called “process”).
3) Axonal contact, leading to ensheathment and generation of compact myelin around target axons (it may retract, will only ensheath axon if it forms a stable contact).
4) Long term trophic and metabolic support of the encased axon.

Question 33

Describe the process of CNS myelination.

Answer 33

Processes begin with an inner tongue (lamelopod). The lamelopod binds to the opposite side of the axon relative to the oligodendrocyte, and wraps around axon many time in concentric circles to an outer tongue. At the same time, the myelin expands along the length of the axon- this is driven by actin (found at the leading edge of the lamelopod).

The inside of the processes is filled with cytoplasm. Intracellular surfaces come together to form the major dense lines (cytoplasmic apposition), faint double lines are intraperiod lines (extracellular apposition) – this forms compact myelin, which has no cytoplasm between the layers. The myelin sheath abuts the axon at the paranode (on either side of the node of Ranvier, where the myelin sheath connects) - there is an indent here, showing that the myelin compresses it. Compact myelin provides insulation to increase conduction velocity of nerve impulses; non-compact myelin is important for allowing transport of molecules from the cell body where they are synthesised out to the myelin where they are needed. Myelin basic protein (MBP) holds layers of oligodendrocytes together on the cytoplasmic side – it is synthetised in myelin and responsible for producing compact myelin. The reason its synthesised in the myelin is so that it can reach the deepest parts of the myelin (if it were synthesised in the cell body and transported it may not reach the innermost layers as they would be cut off).

The thickness of myelin sheaths correlates very closely with the diameter of the axon it is around – the G-ratio is the ratio of axon diameter to fibre diameter (including myelin) (=axon diameter/fibre diameter). In humans, the G-ratio is ~0.6 (high G-ratio indicates thinner than normal myelin – above 0.7 is irregular). The extent of myelination in certain new-born animals (e.g. antelope calves) is the reason they are able to stand and walk/run whereas human babies are not.

Question 34

Describe the composition of CNS myelin and how this compares to PNS myelin.

Answer 34

PLP, and its major isoform DM20 are the major proteins of CNS myelin, whereas P0 is the main protein of PNS myelin. Knocking out PLP in myelin makes little difference to the sheath, but affects the axon greatly (see mitochondria congregated around the juxtaparanode of the axon, which is irregular). This shows that the health of the axon is dependent on the oligodendrocyte.

Question 35

Describe the histology and basic circuitry of the cerebellum.

Answer 35

Deep transverse fissures divide the cerebellum into 10 lobules (each of which include lots of folia) – the purpose of these is to increase the surface area as much as possible so it can be packed with neurons. Each of the folds of the cerebellum is very organised into layers. There are 3 main layers – the molecular (most superficial) layer, the purkinje layer (thin layer), and a dense, granular layer containing central white matter. There are many types of neuron within the layers of the cerebellar cortex. The molecular cell layer is a synaptic zone made up of branching dendrites of purkinje cells and axons of granule cells (also contains basket cells). The purkinje layer is a single row of purkinje cell bodies, whose dendrites extend into the molecular, branching in to one flattened plane. Purkinje cell axons project deep into the cerebellar nuclei – they are the major cells of the cerebellar circuitry, receiving input from two major places- climbing fibres (from the inferior olive) and mossy fibres (from the pons). The granule cell layer is packed with interneurons (mostly granule cells, but also unipolar brush cells and golgi cells). The white matter contains the deep cerebellar nuclei (relay information to the brainstem and beyond). Deep cerebellar nuclei include the dentate nucleus, emboliform nucleus, globose nucleus, and fastigial nucleus.

Climbing fibres from the inferior olive synapse to purkinje cell dendrites in the molecular layer. The inferior olive integrates information from muscle proprioceptors, and each purkinje cell receives input from one inferior olive cell (however, this includes hundreds of excitatory synapses). Mossy fibres from the pontine nuclei can synapse directly to the deep cerebellar nuclei, but they can also synapse onto granule cells (very small and numerous and tightly packed). Granule cell axons project upwards into the molecular layer, where they branch at right angles (at this point called parallel fibres). These parallel fibres synapse with up to 450 different purkinje cells, and each purkinje cell receives input from up to 100,000 different parallel fibres. Basket cells are scattered throughout the molecular layer – their dendrites receive input from the granule cells, and their axons synapse with purkinje cells. Stellate cell dendrites receive input from granule cells and axons synapse with purkinje cells, golgi cell dendrites receive input from parallel fibres and axons synapse with granule cell dendrites.

Question 36

List the structures of the limbic brain and briefly discuss their role in emotional regulation.

Answer 36

Cingulate cortex*

Amygdala- mainly associated with the emotion of fear. The amygdala is a bilateral complex of nuclei located at the pole of the temporal lobe. Removal of the temporal lobe in Rhesus monkeys dramatically reductions in aggressive tendencies and fearful response. Humans with amygdala lesions have similar symptoms. Many sensory circuits feed into the amygdala – the sensory cortex, brainstem visceral nuclei, hypothalamus, anterior limbic cortex, olfactory bulb, thalamus. It also has a huge range of outputs – brainstem visceral nuclei, sensory cortex, limbic cortex, ventral striatum (basal ganglia), thalamus, hypothalamus. It is difficult to establish the functional role of it because research relies on lesions which are not consistent (e.g. may be to different extents, affecting different areas, and may also be subjected to variation). Lesions to the amygdala largely result in inability to recognise fear in facial expressions (but can still recognise it in voices – only visual perception is affected). Electrical stimulation of the amygdala can lead to anxiety, fear, and aggression. The amygdala responds to pain, and can be conditioned to respond to other stimuli (via paired stimuli). By pairing auditory stimuli with pain, then removing the painful stimulus and just using the auditory stimulus, you can induce a fear response. Auditory signals arrive in the basolateral nucleus of the amygdala, and then project to the central nucleus. From the central nucleus, efferents sent to the hypothalamus regulate the autonomic response of fear (increased heart rate and ventilation, etc), and efferents sent to the periaqueductal grey matter of the brains stem mediate the behavioural reaction (i.e. motor action). From the basolateral nucleus, efferents to the cerebral cortex mediate the emotional response.

Hippocampus- C-shaped structure tucked into the pole of the temporal lobe. There is debate as to whether it is involved in processing of emotional behaviours, but it is definitely involved in memory and learning.

Nucleus accumbens- A deep seated nucleus in the brain, deep brain stimulation (DBS) has been shown to alleviate pain (and gives off an intense feeling of well-being, comparable to the intake of heroin). This is because it becomes flooded with dopamine. It is not fully understood, but is clearly involved in the experience of pleasurable emotions. It receives its inputs from the amygdala, hippocampus, cortex, and thalamic nuclei (as well as ventral tegmental nuclei). It projects to the hypothalamus, brainstem nuclei, and globus pallidus (GP projection important for limbic-motor interaction).

Hypothalamus- associated with homeostasis, reproduction, and emotional behaviours. It is a small structure and encompasses <1% of the CNS, but is a “nodal” point of many circuits (mediates physiological processes such as feeding, fluid balance, temperature regulation, sleep-wake cycles, and sexual activity). It receives input from a number of brain areas, including the nucleus of the solitary tract (autonomic sensory), olfactory cortex (gustatory behaviour), the retina (relating to circadian rhythm), and other limbic system structures. Its output affect behaviour and physiological functions by modulating activity in the cerebral cortex (ultimately influencing limbic structures, autonomic output, and controlling hormone production by the pituitary).

Insula- a cortical area, but is not seen from a superficial view of the brain (resides beneath the frontal and temporal lobes). It has been widely studied using fMRI and PET imagine, and is usually activated by pain, disgust, hunger, etc, as well as language processing. It is involved in processing a number of emotional behaviours, but its exact role is not understood. It is linked to the other limbic brain areas as well.

Question 37

What are the basal ganglia?

Answer 37

The basal ganglia are a cluster of sub-cortical structures comprising several interconnected nuclei in the forebrain, midbrain, and hindbrain. They are typically associated with motor control (anatomical studies found it was heavily connected it the motor cortex, animal studies shows that neurons of basal ganglia discharged with particular movements, and clinical observations of lesions to the basal ganglia were associated with movement disorders). The basal ganglia also have a role in cognition, emotion, and eye movement.

The basal ganglia include the striatum (caudate nucleus, putamen, and nucleus accumbens), the subthalamic nucleus, the globus pallidus (internal and external segments), and the substantia nigra (pars compacta and pars reticulata).

Question 38

Describe the basic circuitry of the basal ganglia.

Answer 38

The nuclei can be divided into 3 distinct functional categories – input nuclei (striatum), output nuclei (globus pallidus internal and substantia nigra pars reticulata), and intrinsic nuclei (subthalamic nucleus, globus pallidus external, and substantia nigra pars compacta).

The striatum is the largest subcortical brain structure in the mammalian brain. It receives input from the cerebral cortex and other subcortical structures. There are two types of striatal neurons – projection neurons (90%) and interneurons (10%). Projection neurons are medium sized, spiny, inhibitory (GABAergic) neurons – they project to the globus pallidus and substantia nigra. It receives excitatory (glutamatergic) input from the cerebral cortex.
Projections from the cerebral cortex to the striatum are roughly topographical (organised). This topography is the basis for the functionally different circuits of the basal ganglia (underlying cognitive, somatomotor, oculomotor, and limbic circuits). There are many parallel circuits (i.e. those which follow very similar paths, but are functionally distinct). These parallel circuits originate in the cerebral cortex, input to the striatum, then project to other basal ganglia (output nuclei), then to the thalamus, and feed back to the cerebral cortex. These circuits do not operate completely independently, there is cross-talk between them. The convergence and divergence between these parallel circuits is crucial, and happens by virtue of the large dendritic fields of the medial spiny neurons.

The subthalamic nucleus (STN) receives excitatory input from the frontal cortex and inhibitory input from the globus pallidus external. The globus pallidus external (GPe) and the substantia nigra pars compacta (SNpc) receive and send the bulk of their inputs and outputs to other basal ganglia nuclei. The SNpc receives GABAergic input from the striatum, and sends dopaminergic projections to the striatum (this pathway has significance in the pathology of Parkinson’s). Due to its significance, it is the most studied nucleus of the basal ganglia. The feedback pathway from the dopaminergic projections has a major role in mediating the outputs from the striatum.

The globus pallidus internal (GPi) comprises of large neurons which project out of the basal ganglia primarily to the thalamus. It receives inhibitory input from the striatum, which can either be direct or indirect (i.e. via the STN and GPe). The substantia nigra pars reticulata (SNpr) is also a pathway which projects out of the basal ganglia to the thalamus.

Question 39

Discuss the 3 hypotheses for the actual function of the basal ganglia.

Answer 39

1) Responsible for automatic execution of learned movement sequences (i.e. patients with PD have difficulty moving several body parts simultaneously or sequentially)- This comes down to parallel processing (sensorimotor, association, limbic, and oculomotor circuits must all work in coordination, if there is damage to the cross-talk). Damage to these circuits may prevent the integration of information (e.g. oculomotor circuit may not be able to influence motor circuit, may result in poor coordination).
2) Facilitating or inhibiting cortical targets by keeping direct/indirect pathways in balance- Increased activity of the indirect pathway results in increased basal ganglia output (because it is primarily excitatory, whereas the direct pathway is primarily inhibitory). Increased basal ganglia output may induce involuntary movements, tremors, rigidity, etc.
3) The output of the basal ganglia is inhibitory to posture and movement pattern generators in the cerebral cortex (basal ganglia acts as a brake)- Thalamic cells which project to the frontal lobe are excitatory (the feedback loop), but the output neurons which project to these thalamic cells are inhibitory. If the output cells increase inhibition, it will decrease excitation of the frontal lobe from the thalamus (and visa versa). The basal ganglia therefore can be said to activate in order to prevent excitation of the cerebral cortex (act as a brake) to prevent its output.