Strand 10- Nerves and Muscles

general neuron structure

structural classification of neurones

• describes relationship of cell body and processes

  • multipolar neuron→ cell body has lots of dendrites (processes)

  • bipolar neuron→ 2 main processes (axon and main dendrite)

  • unipolar neurone→ One process

functional classification of neurones

• describes function of cell in system:

  • motor neuron→ carries to effectors

  • interneuron→ sit between sensory and motor neurons

  • sensory neuron→ detecting sensory stimuli

classification of nervous system

• central nervous system:

  • Brain

  • Spinal cord

• Peripheral nervous system:

  • Autonomic

    • sympathetic

    • parasympathetic

  • somatic

autonomic nervous sytem

• regulates involuntary processes e.g. heart rate, respiration, digestion, pupil contraction

• operates automatically without conscious direction

somatic nervous system

• carriers sensory info from sensory organs to CNS and relays motor commands to muscle→ control voluntary movements

brain within the nervous system

• divided into 3 major parts:

  • fore brain

  • mid brain

  • hind brain

central vs peripheral nervous system

• CNS→ brain and spinal cord

• peripheral nervous system→ nerves and ganglia outside brain and spinal cord

• PNS links CNS to rest of body

CNS- nuclei and tracts

• neuronal cell bodies reside in nuclei and cortex→ grey matter

• tracts contain axons→ white matter

CNS-meninges

• 3 membranes that overlie brain and spinal cord:

  • outer→ dura mater

  • mid→ arachnoid mater

  • inner→ pia mater

• clinical relevance

  • infection (meningitis)

  • bleeds (extradural, subdural, subarachnoid)

  • tumours (meningioma, metastasis) 

PNS- spinal nerves

• 31 pairs of spinal nerves:

  • cervical nerves→ C₁-C₈

  • thoracic nerves→ T₁-T₁₂

  • Lumbar nerves→ L₁-L₅

  • Sacral nerves→ S₁-S₅

  • coccygeal nerve→ C₀

arrangement of nerves in spinal cord

cranial nerves

areas innervated by somatic nervous system

• dermatones→ show areas of skin supplied by one spinal nerve

• myotomes→ muscle groups innervated by one spinal nerve

somatic pathways

• somatic sensory→ afferent:

  • target tissue to central nervous system

• somatic motor→ efferent:

  • CNS to effector

sympathetic nervous system vs parasympathetic nervous system

• sympathetic→ fight or flight

• parasympathetic→ rest and digest

autonomic pathways

• preganglionic neurone in CNS→ postganglionic neurone in PNS

• preganglionic neurones:

  • thoracic and lumbar segments of spinal cord in sympathetic

  • sacral spinal cord and brain stem in parasympathetic

glial cells

• non-neuronal cells in CNS and PNS

  • have different glia

• Many roles:

  • myelin formation

  • nutritional support

  • structural support

  • some have immune functions

astrocytes

• central nervous system

• many roles:

  • metabolic support for neurons

  • structural support

  • form blood-brain barrier with capillaries

  • repair following injury→ glial scar

oligodendrocytes

• form myelin sheaths in CNS

• one oligodendrocyte can myelinate multiple axons

• clinical important as site of damage in demyelinating diseases such as multiple sclerosis

CNS- microglia

• resident immune cells of CNS→ related to macrophages

• respond to infectious agents

• perform general maintenance:

  • clear up damaged neurons

  • prune unnecessary synapses

  • scavenge amyloid plaques

CNS- ependymal cells

• lining cells of ventricular system of the brain and central canal of spinal cord

• ciliated surface aids flow of cerebrospinal fluid

• modified ependymal cells contribute to CSF production at choroid plexus in ventricles

PNS-schwann cells

• support neurons in PNS

• responsible for myelin formation in PNS
  some Schwann cells provide support without forming myelin→ ‘non myelinating’ schwann cells

PNS- satellite cells

• surround cell bodies in sensory, sympathetic and parasympathetic ganglia

• suggested to regulate extracellular environment of neurons in ganglia

• express various ion channels and transporters for neurotransmitters

myelination

• increases conduction velocity→ allows saltatory conduction

• Ion channels concentrated at nodes of Ranvier to regenerate signal

• lowers total charge transfer needed to conduct action potential→ reduces work the neuron must do to maintain electrolyte balance

nerve fibre classification

• Aα:

  • largest diameter

  • fastest transmission

  • sensory receptor: proprioceptors of skeletal muscle

• Aβ:

  • second largest diameter

  • second fastest transmission

  • receptor: mechanoreceptors in skin

• Aδ:

  • second smallest diameter

  • second slowest transmission

  • receptor: pain temperature

• C:

  • smallest diameter

  • slowest transmission

  • receptor: temperature, pain, itch

resting membrane potential

-70mV

what determines the resting membrane potential

• difference in concentrations of Na⁺ and K⁺ ions:

  • very little Na⁺ moves into cell via leaky Na⁺ channels down EC gradient

  • a lot of K⁺ moves outside of cell via K⁺ leaky K⁺ ion channels

  • sodium potassium ATPase pump→ 3Na⁺ out, 2K⁺ in

action potential generation

1. excitatory stimulus depolarises membrane→ membrane potential increases

2. crosses threshold value→ -55mV

3. Voltage gate Na⁺ channels open allowing Na⁺ into cell→ more positive

4. results in depolarisation to about +30mV

5. voltage gates Na⁺ channels start to inactivate

6. At the same time, K⁺ VG channels open→ K⁺ out 

7. membrane potential starts to decreases→ repolarisation

8. small overshoot due to excess K⁺ efflux causes hyperpolarisation

9. K⁺ channels close and Na⁺ channels closed

10. Na⁺/K⁺ ATPase restores Na⁺/K⁺ gradient across membrane

stages of voltage gated Na⁺ channel

• 3 stages:

  • open

  • closed

  • inactive

• has inactivation gate that blocks Na⁺ influx shortly after depolarisation→ stays in this state until cell repolarises and enters closed state again

action potential refractory period

• absolute refractory period→ cell is incapable of repeating an AP in that part of the membrane

  • ensures action potential travels in one direction

• during relative refractory period, larger stimulus can result in action potential in this area of the membrane

nature of action potential

• all or nothing:

  • nerve membrane has to be depolarised beyond threshold for action potential to be generated

  • further increase above threshold→ higher AP frequency not larger AP amplitude

  • a neurone either fires AP or does not, regardless of signal size→ all or nothing

propagation of action potential down non-myelinated neurones

1. in response to signal, soma end of axon becomes depolarised

2. depolarisation spreads down axon

3. meanwhile, first part of membrane depolarises:

   • Na⁺ and K⁺ channels are inactivated and additional K⁺ channels have opened→ membrane cannot depolarise again

4. action potential continues to travel down axon

propagation of action potentials down myelinated axons

1. Na⁺ channels locally open in response to stimulus→ generates action potential here

2. depolarising current passively flows down the axon

3. nodes of Ranvier are only areas where current can pass through membranes and only areas where membrane depolarises

4. impulse travels in jumps from one node to the next→ saltatory conduction

temporal and spatial summation

• spatial→ signals coming from multiple simultaneous inputs from a number of presynaptic neurones

• temporal→ comes from repeated inputs from presynaptic neurone

motor neurone disease

• Amyotropic lateral sclerosis→ prevalent form

• fatal disease of nervous system→ progressive voluntary muscle weakness and paralysis

• selective for somatic neurones→ sensory and autonomic function remains intact

  • mind and memory unaffected

• starts with degradations of upper and lower motor neurones→ messages that originate in motor cortex don’t reach muscles to trigger voluntary contractions

• nerve death causes innervating muscles to shrink and waste away

cause of motor neurone disease

• exact cause unknown

• excessive levels of glutamate (neurotransmitter) in synapse cause motor neurones to become overexcited→ damage and death

• build up of glutamate is doe to loss of glutamate transporters (EAAT2)→ ‘mop’ up glutamate in synapse

• toxicity due to Ca²⁺ flooding the cell

  • prolonged Ca²⁺ inside cell causes damage and can activate programmed cell death

myelination

• myelin→ insulating layer around nerve axon in CNS and PNS

• consists of protein and fatty substances→ speeds up transmission along axon

• In CNS→ oligodendrocyte is responsible for myelination of axon:

  • cells extend processes that wrap around the axons to form myelin sheath

  • one can myelinate 3-50 neurones

• PNS→ myelin sheath formed by Schwann cells→ one Schwann cell provides myelination for one axon

demyelinating disease

• results in damage to myelin sheath

• nerve impulses slow/stop→ deficiency in sensation, movement, cognition, other functions

• axonal degradation and often cell body degeneration

• usually secondary to inflammation

classification of demyelinating diseases

• classified on basis of cause

• demyelinating leukodystrophic diseases- primary:

  • myelin is abnormal and degenerates→ genetics responsible

• demyelinating myelinoclastic diseases- secondary:

  • healthy myelin destroyed by toxin, infectious agent, chemical or autoimmune substance

multiple sclerosis

• most common demyelinating disease of CNS→ sensory and motor neurones affected

• autoimmune degenerative nerve disorder→ immune system attacks myelin sheath

• results in multiple areas of scarring (sclerosis)→ impedes nerve signalling

• symptoms vary widely from person to person and can affect any part of the body:

  • difficulty walking

  • blurred vision

  • numbness or tingling in parts of body

  • problems with balance and coordination

  • problems with thinking, learning and planning

cause of multiple sclerosis

• exact cause is unknown

• viruses trigger autoimmune attack in susceptible individuals via molecular mimicry

  • structural similarity between foreign and self molecules of mammalian host

  • resulting in production of autoreactive T cells and antibody producing B cells which attack host as well as foreign body

Guillain-Barre syndrome

• demyelinating disease of PNS

• myelin and schwann cells around sensory and motor neurones destroyed:

  • conduction block and axonal degeneration

• autoimmune disease often triggered by preceding viral/bacterial infection e.g. cytomegalovirus, Epstein-Barr virus, COVID

• symptoms: symmetrical ascending muscle weakness and paraesthesia in arms and legs, loss of sensation, autonomic dysfunction

stimulus detection

• sensory receptors→ modified nerve ending of sensory neurones

• tuned to detect specific signals→ sensory modalities

types of receptors

• Mechanoreceptors→ touch, pressure, vibration, stretch

• thermoreceptors→ hot, cold, temperature change

• photoreceptors→ light

• chemoreceptors→ chemicals

• nociceptors→ pain (usually chemicals)

pacinian corpuscle

• found around the ends of sensory neurones→ pressure detectors

• consists of layers of connective tissue with gel in between→ gel has Na⁺ ions

• sensory neurone ending contains stretch mediated Na⁺ ion channels→ open when corpuscle is deformed by pressure

  • when open→ Na⁺ from gel can flow into neurone, generating small depolarisation in sensory neurone ending- generator potential

• If large enough, receptor potential leads to action potential being generated and fired off along the sensory axon towards the CNS

receptor potentials (generator potentials)

• graded potentials→ size determined by size of stimulus

• can summate to give rise to an action potential in the neurone

• depolarising event resulting from an inward current flow e.g. Na⁺

• influx of current can bring membrane potential of sensory receptor towards threshold for triggering action potential

muscle proprioreceptors

• sensory receptors in muscles

• muscle spindle located within muscle and stimulated when muscle is passively stretched

• when a muscle is passively stretched the spindle is activated and initiates a reflex causing the muscle to contract

  • protects muscle being overstretched

golgi tendon organ

• located in the tendon→ responds to excessive tension (stimulated when associated muscle contracts)

• when stimulated, it causes its associated muscle to relax by interrupting its contraction

• prevents tendon from tearing and muscle damage

reflex arc

• autonomic and rapid response to stimulus→ minimises damage to body from potentially harmful conditions

components of a reflex arc

1. receptor

2. sensory neuron

3. interneuron

4. motor neuron

5. effector

muscle spindle- stretch reflex

• stretching of muscle activated spindle→ increased discharge of sensory afferent (1a) neurone

• results in increased firing of motor neurone to muscle that is stretched→ contracts

• no spinal neurone involved

• contraction usually accompanied by simultaneous reflex inhibition of antagonistic muscle

• effect→ dampens stretch of muscle to protect it

muscle spindle reflex- maintaining muscle tone

• weight of fluid in glass→ bicep stretches

  • afferent signals from muscle spindle relayed to motor neurone in spinal cord

  • efferent signals sent back to muscle to cause it contract

• since muscles are always under some degree of stretch, reflex circuit normally responsible for steady state level of tension in muscles→ muscle tone

golgi tendon reflex

• excess tension in tendon caused by muscle contraction is detected in golgi tendon organ

• GTO sends sensory signals along sensory afferent (1b) to CNS

  • results in reflex inhibiting the muscle from contracting

  • usually accompanied by reciprocal contraction of antagonistic muscle

• effect is to reduce tension in tendon→ protects it

golgi tendon reflex in action

• amount of tension generated in tendon by bicep increases with each increasing weight→ rate of GTO firing increases

• at some point, excessive GTO firing occurs→ indicated no more force should be generated by muscle otherwise tendon connecting muscle to bone might tear

  • GTO reflex interrupts contraction causing muscle to relax

synapses

• neurones communicate via synapses

• two types:

  • electrical

  • chemical

electrical synapse

• direct physical connection between pre and post synaptic neurone

• connection takes form of channel→ gap:

  • allows current (ions) to flow directly from one cell into another

• transmit signals more rapidly than chemical synapses

• bidirectional transmission

• enable synchronised activity of groups of cells→ epileptogenic

gap junction

• formed by coming together of subunits called connexons→ present in both pre and post synaptic membranes

• pores of channels connect to one another, creating electrical continuity between two cells

• connexons themselves are made of 6 protein units→ connexins

chemical synapse

• connections between two neurones or between neuron and non-neuronal cell e.g. muscle cell at NMJ

• one neuron releases chemical substance→ neurotransmitter

• neurotransmitter binds to receptors on postsynaptic cell and depending on nature of neurotransmitter it can excite or inhibit post synaptic cell

• neurotransmitters cleared from synapse by:

  • enzymatic digestion

  • reuptake by specific transporters on presynaptic cell or adjacent glial cell

  • diffuse out of synapse

types of post synaptic receptors

• ionotropic

• metabotropic

ionotropic receptors

• transmembrane ion channels

• open/close in response to binding of neurotransmitter

  • ligand gates ion channels

• fast acting

• cause immediate change in membrane potential

• e.g. nAChR

metabotrpic receptors

• require G proteins

  • G-protein coupled receptors

• second messengers to indirectly modulate ionic activity in neurones

• generally slower, more persistent response

• e.g. mAChR

neurotransmitters

• substance that is released at a synapse by one neurone that affects another cell, either neuron or effector organ in a specific manner

• classified either by structure or function

types of neurotransmitters

• excitatory→ promotes AP generation in post-synaptic cell e.g. glutamate, ACh

• inhibitory→ reduce electrical excitability at post synaptic membrane, preventing generation and propagation of AP e.g. GABA, Glycine

chemical groups of neurotransmitters

• acetylcholine

• biogenic amines

• peptide neurotransmitters

• amino acid neurotransmitters

biogenic amines

• serotonin

• dopamine

• adrenaline

• noradrenaline

• histamine

peptide neurotransmitter

• endorphins

• substance P

amino acids neurotransmitters

• glutamate

• gamma-aminobutyric acid (GABA)

• glycine

other neurotransmitters

• nitric oxide

• ATP

• CO

function of acetylcholine

• found in motor neurones at NMJ

• involved in body movement, learning, memory

• involved in parasympathetic NS

Glutamate

• major excitatory neurotransmitter

• involved in learning, memory

gamma-aminobutyric acid

• major inhibitory neurotransmitter

• plays major role in controlling nerve cell hyperactivity (often occurs in stress, anxiety, fear)

dopamine

• reward and pleasure pathways

noradrenaline

• cardiovascular system

• alertness

• arousal

• decision making

• attention

adrenaline

• fight or flight response

• homeostasis

serotonin

• sleep

• appetite

• mood regulation

components of a motor unit

• motor unit→ all the skeletal muscle fibres innervated by a single motor neurone

• when motor neurone fires AP, all muscle fibres that it innervates contract within the unit at the same time

• size of motor unit dependant on function of muscle

how do motor units differ in different sites of the body

• most fibres= most force

  • thigh muscles can have thousands of muscle fibres in each motor unit

  • smaller muscles have few muscle fibres in each motor unit→ enables fine precision

• synapse between motor neurone and muscle cell→ neuromuscular junction

• a motor neurone innervating several muscles cells will have many axon terminals forming NMJs

neuromuscular junction

• chemical synapse between motor neurone and muscle fibre

• site of transmission of action potentials from nerve to muscle

• 1:1 transmission→ ensures that every presynaptic action potential results in a postsynaptic one

• unidirectional process

• has inherent time delays

functional anatomy of neuromuscular junction

resting neuromuscular junction

• once every second, one synaptic vesicle randomly fuses with presynaptic terminal and release its content of ACh into synapse

• ACh binds to nAChR opening up Na⁺ channels

• entry of Na⁺ across muscle membrane produce small depolarisation (0.4 mV)→ MEPP

activated neuromuscular junction

1. arrival of AP causes depolarisation of axon terminal

2. voltage gated Ca²⁺ channels open

3. Ca²⁺ enter causing fusion of vesicles with presynaptic terminal and release of ACh

4. several quanta of ACh release into synapse where they activate numerous nAChR

5. Na⁺ channels and depolarisation of muscle membrane

6. each quantum can generate MEPP in muscle membrane, several quanta will lead to EPP forming

7. if EPP can depolarise muscle membrane to threshold, it triggers AP

excitation contraction coupling

1. links excitation of muscles by nervous system to their mechanical contraction

2. EPP triggers AP in the muscle membrane

3. AP propagated along muscle membrane→ depolarisation passes down T-tubules

4. within T tubules depolarisation is sensed by DHP receptors

5. once activated, DHP receptors stimulate opening of ryanodine receptors (RyR) on sarcoplasmic reticulum→ Ca²⁺ released into cytoplasm

6. Ca²⁺ causes muscle contraction

removal of acetylcholine from the synapse

• ACh binds briefly to nAChR on postsynaptic cell

• following dissociation from receptor, ACh is rapidly hydrolysed by acetylcholinesterase

  • hydrolyses ACh to acetate and choline

• choline recycled back into presynaptic terminal to make more ACh

• acetate diffuses into surrounding medium

• some ACh will just diffuse out of synaptic cleft

SARIN

• acetylcholinesterase inhibitor

• acetylcholine cannot be broken down

strcuture of nicotinic acetylcholine receptor (nAChR)

• ACh-gated Na⁺ channel

• made up of 5 polypeptide subunits:

  • 2 alpha subunits

  • one beta subunit

  • one gamma subunit

  • one delta subunit

• 2 ACh molecules required to stimulate receptor→ binding surface of receptor appears to be primarily on the alpha subunits near outer surface of molecule

• ACh binding to receptor causes Na⁺ influx→ membrane depolarisation

• nAChR at autonomic ganglia and in brain have different subunit composition

neuromuscular blockade

• many drugs produce muscle paralysis by affecting ACh receptors e.g. succinylcholine

  • used during surgery

  • use of muscle relaxants requires patient to be artificially ventilated

selective neuromuscular blockade

• several compounds which selectively block NMJ

• botulinum toxin prevents exocytosis of ACh from synaptic vesicles→ no ACh released and muscle does not contract

  • toxin marketed as botox

• can be used to help patient with strabismus (cross eye), blepharospasm (eyelid spasms) or cerebral palsy

• cosmetic uses helps reduce appearance of fine lines and wrinkles

myasthenia gravis

• autoimmune response→ antibodies competitively inhibit nAChR on motor end plate→ NMJ less responsive to ACh→ muscle weakness

• Symptoms:

  • Muscle weakness that increase during periods of activity and improves after rest

  • eye related issues as initial symptom:

    • ptosis→ eyelid drooping

    • diplopia→ double vision

  • symptoms involving face and throat muscles:

    • altered speech

    • difficulty swallowing (dysphagia), chewing

    • loss of facial expression

  • 20-25% of patients with thymoma also have myasthenia gravis

pathology at NMJ for myasthenia gravis

• antibodies against ACh receptor block receptors on postsynaptic membrane

  • also get accelerated degradation of nACh receptor

• reduction of nACh receptors at motor endplate and flattening of postsynaptic folds reduced EPP even though normal amounts of ACh released

• reduced neuromuscular transmission→ reduced AP production on motor end plate

treatment of myasthenia gravis

• long term acting anti-cholinesterase→ prevent breakdown of ACh- more ACh available in synapse to compete with antibodies

• immunosuppressives→ steroids

• surgical thymectomy

lambert-eaton myasthenic syndrome

• autoimmune disease

• antibodies formed against voltage-gated Ca²⁺ on presynaptic nerve terminal at NMJ- prevent ACh release

• many people also have small lung cancer

• symptoms:

  • weakness in muscle limbs

  • fatigue

  • autonomic dysfunction (e.g. dry mouth, blurred vision)

  • symptoms almost always precede detection of cancer

pathology of lambert-eaton at NMJ

• antibodies disrupt function of Ca²⁺ channels on presynaptic neuron→ block Ca²⁺ influx

• Ca2+ entry during depolarisation important for ACh release into synapse

• Reduced Ca2+ influx→ reduces ACh release from presynaptic membrane→ reduced muscle activation→ muscle weakness

treatment of lambert-eaton

• treatment of underlying malignancy resolves symptoms

• use immunosuppressants

• use K+ channel blocker e.g. amifampridine:

  • blocks VG K+ channels on presynaptic nerve

  • delays repolarisation→ prolongs depolarisation of presynaptic membrane→ enhances Ca2+ entry through channel into terminal→ facilitates ACh release

types of muscle

• skeletal

• smooth

• cardiac

skeletal muscle

• striated

• multinucleated

• attached to skeleton→ involved in movement

• controlled voluntarily by somatic NS

smooth muscle

• not striated

• single nucleus

• found in walls of organ, glands and blood vessels→ controlled involuntarily by ANS

cardiac muscle

• striated

• generally uninucleated

• branched network

• controlled involuntarily by ANS

structure of skeletal muscle

• 3 layers of connective tissue:

  • epimysium→ covers entire muscle

  • perimysium→ around each fasciculus

  • endomysium→ within each fasciculus

structure of a skeletal muscle fibre

• sarcolemma→ muscle plasma membrane

• sarcoplasmic reticulum→ smooth endoplasmic reticulum in muscle fibre- stores Ca²⁺

• transverse tubules→ carry action potentials deep into muscle fibre