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Y1S1 Nervous System Toby Falodun and Melisa KoyuncuOverview ● Nervous system structure and function, from cells to systems ● Action potentials & resting membrane potential ● Neurotransmission and synaptic integration ● Excitation contraction coupling and reflexes ● Neuromuscular disorders - mechanisms & impactsBasic Anatomy of Nervous System Central Nervous System ▶ Brain ▶ Spinal Cord ▶ Ventral roots = motor ▶ Dorsal roots = sensory Peripheral Nervous System ▶ Long axons radiate from CNS ▶ Innervates rest of body ▶ Sensory/afferent axons send information from PNS to CNS ▶ Motor/efferent axons send information from CNS to PNSAfferent v Efferent Afferent (Sensory) ▶ Carried in dorsal root Efferent (Motor) ▶ Carried in ventral root Spinal nerves contain a mix of afferent and efferent axonsCells of the Nervous System Neurons ▶ Excitable cells: basic functional unit of the nervous system, transmit electrical currents ▶ Dynamic polarisation - unidirectional 2. Glial cells ▶ Schwann cells: provide myelin sheath for PNS ▶ Oligodendrocytes: provide myelin sheath for CNS ▶ Astrocytes: most numerous, regulate chemical content of ECF ▶ Microglia: specialised macrophages of CNSPhospholipid membrane & Ion Pumps (active) /Channels (passive) - Phospholipid membrane impermeable to ions - Na/K pumps actively pump out 3 Na ions and take in 2 K ions - Leak potassium channels are open at rest, allowing K in - These two will ensure neurons at rest have a negative resting membrane potential - ECF: high Na, hich Cl, low K - Cytoplasm: low Na, low Cl, high K Control of Muscle Innervation Autonomic ▶ Sympathetic Nervous System: “fight or flight” ▶ Parasympathetic Nervous System: “rest and digest” Somatic ▶ Under voluntary control and generates behavior ▶ Upper motor neuron vs lower motor neurons ▶ Organised into motor units and motor neuron poolsHigh-Yield Questions! What is the resting membrane What two things contribute to this potential of a neuron? resting potential? ▶ About -65mV to -70mV 1. Sodium-potassium pump ▶ 3Na+ out, 2K+ in ▶ Requires ATP 2. Leak potassium channels ▶ Open at rest when cell is not excited ▶ Regulated by pH, oxygen tension and stretchHigh-Yield Questions! Select the answer that most accurately describes the movement of ions at point B a) A period in which the membrane potential becomes more negative than the resting membrane b) Voltage-gated Na ion channels open c) Na/K pump and leak K channels at work d) Voltage-gated Na ion channels close while voltage gated K ion channels openHigh-Yield Questions! Select the answer that most accurately describes the movement of ions at point B a) An excessive efflux of K ions causes a refractory period b) Voltage-gated Na ion channels open c) Na/K pump and leak K channels at work d) Voltage-gated Na ion channels close while voltage gated K ion channels openAction potentialrSaltatory Conduction ▶ Node-to-node propagation of the action potential ▶ Nodes of Ranvier = spaces between myelin sheaths, high concentration of ion channels ▶ Improves conduction speed ▶ Action potential jumps from gap to gap ▶ Minimises the length of the membrane that must depolarise for an AP to propogateNeurotransmitter Release 1. Action potential invades the presynaptic terminal 2. Membrane depolarisation occurs 3. Voltage-gated calcium channels open 4. Increase in calcium promotes vesicle fusion 5. Vesicles release neurotransmitters into the synaptic cleftPostsynaptic ReceptorsExcitatory Vs Inhibitory Synapses Excitatory neurotransmitters ▶ Trigger ion channels that cause depolarization ▶ Common examples include acetylcholine, glutamate, noradrenaline Inhibitory neurotransmitters ▶ Trigger ion channels that cause hyperpolarization ▶ Common examples include GABA and glycineSummation of excitatory inputsOverview of the nervous system Autonomic Nervous System Sympathetic Nervous System (SNS) ▶ A response to dangerous or stressful situations ▶ Heart races, vasoconstriction ▶ Airways expand (beta-agonist for asthma) ▶ Slow digestion (divert energy) ▶ Preganglionic neuron release ACh at synapse with postganglionic neuron ▶ Postganglionic neuron release NA at synapse with target organ ▶ There are different adrenergic receptors ▶ Alpha-1 = smooth muscle arterioles = vasocontraction ▶ Alpha-2 = coronary arteries = vasodilatation ▶ Beta-1 = cardiac muscle = increased contractility ▶ Beta-2 = Sino-Atrial node, smooth muscle of bronchi = increased HR, bronchodilatation Autonomic Nervous System Parasympathetic Nervous System (PSNS) ▶ Relaxes your body after periods of stress or danger ▶ Slows down the heart, vasodilation* ▶ Constricts airway ▶ Digestion (peristalsis, salivation) ▶ Preganglionic neuron release ACh towards nicotinic receptors at synapse with postganglionic neuron ▶ Postganglionic neuron release ACh towards muscarinic receptors at synapse with target organ ▶ There are different muscarinic receptors ▶ M1 = excitatory = in CNS & gastric parietal cells ▶ M2 = inhibitory = in heart ▶ M3 = excitatory = smooth muscles, vascular endothelium ▶ M4&5 - in CNS - to do with memory, attention, arousal▶ Sympathetic preganglionic fibres are short and synapse at the sympathetic chain ganglion to longer postganglionic neurons ▶ Parasympathetic preganglionic fibres are long and synapse with shorter postganglionic neurons ▶ Exception! For the adrenal medulla, preganglionic sympathetic fibres will synapse directly to itSomatic Nervous System ▶ Under voluntary control ▶ Consist of two components ▶ Upper motor neuron: Cerebral cortex in brain → Spinal cord level ▶ Lower motor neuron: (ventral part of) Spinal cord → skeletal muscle at neuromuscular junction (NMJ) ▶ Lower motor neurons consist mostly of alpha motor neurons which are responsible in generation of force by muscle ▶ Motor unit is all the muscle fibre that a single alpha motor neuron innervates ▶ Motor neuron pool is all the motor unit which innervates a single muscle ie. biceps ▶ This arrangement maintains normal muscle activity when damage to a single motor neuron occursStructure of muscle fibre ▶ Muscle fibre is an individual cell, it contains all the components you’d expect ie. cell membrane, endoplasmic reticulum, nucleus, mitochondria ▶ Cell membrane = sarcolemma ▶ Endoplasmic reticulum = sarcoplasmic reticulum = Ca ion store ▶ Cytoplasm = sarcoplasm ▶ Myofibrils = responsible in generation of force (sliding filament theory) Excitation-Contraction Coupling 1. Terminal nerve impulse triggers release of ACh (AP causes influx of Ca2+ → exocytosis of ACh) 2. ACh binds to nicotinic ACh receptors at the motor end plate 3. Influx of Na+ ions → generation of action potential 4. Inwards spread of AP, depolarizes along the T tubules (inward fold) 5. Release of Ca2+ from the sarcoplasmic reticulum into sarcoplasm (cytoplasm of muscle) 6. Ca2 binds to troponin C → conformational change of tropomyosin → expose myosin binding site 7. Formation of cross-linkage → power stroke → contraction *Relaxation occurs when Ca2+ or ATP levels reduceSliding Filament Theory Actin 1. Ca2+ binds to troponin C 2. Conformational change of tropomyosin 3. Reveals myosin binding site (ready to bind myosin head) Myosin 1. High-energy state myosin head (ADP+Pi) binds to myosin binding site on actin 2. Release of ADP+Pi from myosin head causes power stroke and slides the actin filament 3. Detachment of myosin head from actin and binding of new ATP (low-energy state) 4. Hydrolysis of ATP cocks myosin head into high-energy state (ready to bind actin) Rigor Mortis - ATP is required to break actin-myosin cross bridges but there is depleted ATP causing muscle unable to relax (irreversible fusion of actin and myosin) until decomposition (48-60 hours)Reflexes ▶ An involuntary movement in response to a stimulus without brain involvement ▶ Stretch: stretch or myotatic reflex ▶ Nociception (pain): cross-extensor reflex ▶ Involve reciprocal innervation of flexors and extensorsStretch reflex: knee-jerk reflex 1. Stretch receptors in leg trigger action potential in sensory neuron 2. Sensory neurons excite interneurons and motor neurons 3. Motor neurons excite(contract) extensor muscles, inhibit(relax) flexor muscles 4. Leg extends ▶ Agonist: quadriceps ▶ Antagonist: hamstringsCross-extensor reflex/withdrawal reflex 1. Pain receptors trigger action potential in sensory neuron 2. Sensory neurons excite interneurons and motor neurons 3. Motor neurons excite(contract) muscles to move away from pain 4. Coordinated activity with antagonist muscle group to stabilise joint 5. Successfully pull away from source of painVestibulo-ocular reflex (VOR) ▶ Allows us to fix our eyes onto an object even though our head is moving ▶ Can be important in a stressful/ fight-or-flight situationMultiple Sclerosis (MS) ▶ Definition: chronic autoimmune disease, characterised by inflammation of the CNS and the demyelination and destruction of oligodendrocytes ▶ Epidemiology: Female > Male (3:1), with peak onset at 20-30 years ▶ Risk factors: ▶ Genetic: 35% disease concordance among monozygotic twins & 3–4% disease concordance among first-degree relatives. HLA-DR2 ▶ Environment ie. smoking, low vitamin D levels, Epstein-Barr Virus (molecular mimicry) ▶ Pathophysiology: ▶ Disease of the CNS with ‘multiple lesions, varied in time and space’. The area of demyelination (‘plaque’) disrupts the conduction of a nerve impulse (i.e. saltatory conduction is blocked)Clinical features - MS ▶ Blurred vision - typically will present first (unilateral; colour perception can be affected too) ▶ Uncontrolled voluntary movements ▶ Loss of sensation ▶ Balance & coordination issuesMultiple Sclerosis - Disease Progression Stage of MS Characteristics Clinically isolated A single episode of neurological symptoms resulting from CNS demyelination syndrome (CIS) Relapsing-remitting MS Exacerbations occur. Symptoms remit almost (RR-MS) completely between exacerbations. Secondary Progressive A progression of RR-MS characterized by continuous MS (SP-MS) worsening of neurological function that occurs independently of exacerbation events *Some patients may have primary progressive MS (it is like this from the start for them)Management - MS ▶ No cure ▶ Aim = symptom control/reducing frequency of relapses/progression of disability ▶ Symptomatic control ▶ Corticosteroids – reduce chronic inflammation ▶ Plasmapheresis - plasma exchange ▶ Disease modifying drugs e.g. –zumabs/ Betaseron/ Avonex/ Copaxone. Reduce relapses by up to 70% ▶ Introduction of these drugs caused some controversy: ~£15K /year for newer drugs (zumabs) ▶ Rehabilitation - physiotherapy, occupational ▶ Psychosocial supportAmyotrophic Lateral Sclerosis (ALS) ▶ Rapid and fatal progressive neurodegeneration of upper and lower motor neurons ▶ Genetic dysfunction leading to protein aggregation which results in neuronal dysfunction and cell death ▶ Symptoms ▶ Early stage: impairment of voluntary muscles/somatic control ▶ Peripheral weakness in hands and limbs falling down (muscle wasting), slurred speech (tongue atrophy), twitching & involuntary movements ▶ Late stage: impairment of essential autonomic functions ▶ Respiratory failure, dysphagia (difficulty swallowing), paralysis, death ▶ Can be associated with cognitive and behavioural changesALS - Epidemiology and T reatment Risk factors: male sex, increasing age and hereditary disposition (10-15% have autosomal dominant aetiology) There is no known cure for ALS - mortality is 100% ▶ Average survival : 18 months to 3 years, 30% die within 1 year ▶ 5–10% of patients may survive for a decade or more Managed mostly through supportive care from a MDT ▶ Riluzole (glutamate antagonist) extends life by 2-3 months ▶ Respiratory support in later stagesCase Study Questions: Multiple Sclerosis or Amyotrophic Lateral Sclerosis (ALS)?Case study 1 A 61-year-old male presents with left-sided hand weakness and trouble with walking. He is not sure why these symptoms occur. On physical exam, tongue fasciculations are appreciated. He has slow speech. The left upper extremity shows forearm atrophy and depressed reflexes. The right lower extremity is hypertonic, with 3+ reflexes and positive Babinski sign.Case study 2 A 32-year-old women presents to her physician complaining of pain in the right eye. This has been very distressing for her. She has a past medical history significant for type 1 diabetes, treated with a continuous subcutaneous insulin pump. Upon further questioning, she mentions she experienced arm weakness and numbness that resolved spontaneously over the course of a couple weeks. Physical examination is notable for impaired balance and abnormal gait.UMN vs LMNExam-style MCQs!Which of these are responsible for myelinating the CNS? A. Ganglions B. Schwann Cells C. Oligodendrocytes D. Astrocytes E. MicrogliaWhich of these are responsible for myelinating the CNS? A. Ganglions B. Schwann Cells C. Oligodendrocytes D. Astrocytes E. MicrogliaSpinal nerves carry… A. Only afferent fibres B. The twelve cranial nerves C. Both afferent fibres and efferent fibres D. Only efferent fibresSpinal nerves carry… A. Only afferent fibres B. The twelve cranial nerves C. Both afferent fibres and efferent fibres D. Only efferent fibresYou see a spider and trigger the sympathetic response! What happens to your glucose storage and pupils? A. Glucose is converted to glycogen in the liver; pupils dilate B. Glucose is released from your liver into the bloodstream; pupils dilate C. Glucose is converted to glycogen in the liver; pupils constrict D. Glucose is released from your liver into the bloodstream; pupils constrictYou see a spider and trigger the sympathetic response! What happens to your glucose storage and pupils? A. Glucose is converted to glycogen in the liver; pupils dilate B. Glucose is released from your liver into the bloodstream; pupils dilate C. Glucose is converted to glycogen in the liver; pupils constrict D. Glucose is released from your liver into the bloodstream; pupils constrictThe contraction of muscles leads to the shortening of muscle fibres and a variety of actions such as peristalsis. Which is the best order to describe excitation-contraction coupling? 1. Exocytosis of ACh 2. Sliding actin/myosin filaments 3. AP in the alpha motor neuron 4. Ca2+ release from sarcoplasmic reticulum 5. Muscle contraction 6. Postsynaptic depolarisation A. 1, 3, 5, 2, 4, 6 B. 3, 1, 4, 6, 2, 5 C. 3, 1, 6, 4, 5, 2 D. 3, 1, 6, 4, 2, 5The contraction of muscles leads to the shortening of muscle fibres and a variety of actions such as peristalsis. Which is the best order to describe excitation-contraction coupling? 1. Exocytosis of ACh 2. Sliding actin/myosin filaments 3. AP in the alpha motor neuron 4. Ca2+ release from sarcoplasmic reticulum 5. Muscle contraction 6. Postsynaptic depolarisation A. 1, 3, 5, 2, 4, 6 B. 3, 1, 4, 6, 2, 5 C. 3, 1, 6, 4, 5, 2 D. 3, 1, 6, 4, 2, 5Match the following stages of action potential formation to their corresponding ion movements: Na/K pump and K leak channel ensure Na ions move out of the DEPOLARISATION cell while K ions come in Voltage gated Na channels open once threshold is reached REPOLARISATION Voltage gated Na ion channels close while voltage gated K HYPERPOLARISATION channels open up RESTING AP Excessive positive K ions leave the cell, going into the ECFMatch the following stages of action potential formation to their corresponding ion movements: Na/K pump and K leak channel ensure Na ions move out of the DEPOLARISATION cell while K ions come in Voltage gated Na channels open once threshold is reached REPOLARISATION Voltage gated Na ion channels close while voltage gated K HYPERPOLARIZATION channels open up RESTING AP Excessive positive K ions leave the cell, going into the ECFWhich of the following is an example of an disease affecting neurotransmission that attacks ACh receptors? A. Charcot-Marie-Tooth disease B. Myasthenia Gravis C. Multiple Sclerosis D. Guillain-Barre SyndromeWhich of the following is an example of an disease affecting neurotransmission that attacks ACh receptors? A. Charcot-Marie-Tooth disease B. Myasthenia Gravis C. Multiple Sclerosis D. Guillain-Barre SyndromeWhich of the following is an example of a disease in which a demyelinating disease attacks the myelin sheath in the PNS? A. Charcot-Marie-Tooth disease B. ALS C. Multiple Sclerosis D. Guillain-Barre SyndromeWhich of the following is an example of a disease in which a demyelinating disease attacks the myelin sheath in the PNS? A. Charcot-Marie-Tooth disease B. ALS C. Multiple Sclerosis D. Guillain-Barre Syndrome Thank you for coming! ▶ Slides will be sent out after the tutorial. ▶ If you have any more questions, feel free to contact us! :) Toby Falodun Melisa Koyuncu s2284068@ed.ac.uk s2291999@ed.ac.uk accessibilityinmedicine@gmail.comFeedback https://app.medall.org/feedback/feedback-flow?keyword=9443afdd9cb9d514ac26439b&organisation =accessibility-in-medicineQUESTIONS?
