Nerve conduction Neurotransmitters NMJ.pptx

Synapse NMJ

1. Nerve conduction, Neurotransmitters and Neuromuscular Junction Prof. Vajira Weerasinghe Senior Professor of Physiology Department of Physiology, Faculty of Medicine, University of Peradeniya and Consultant Neurophysiologist, Teaching Hospital Peradeniya www.slideshare.net/vajira54

2. ILO Describe Neurotransmitters Describe Neuromuscular transmission Describe Basic structure of neuromuscular junction Identify Disorders of neuromuscular transmission Define Different types of nerve conduction Describe Alteration in nerve conduction in nerve injuries

3. Synapse Synapse is a gap between two neurons More commonly chemical Rarely they could be electrical (with gap junctions) which are pores (as shown in the electron micrograph) constructed of  connexin  proteins

4. Typical synapse Presynaptic membrane Synaptic Cleft Postsynaptic membrane

5. Basic structure Presynaptic membrane Contains neurotransmitter vesicles Synaptic cleft Postsynaptic membrane Contains receptors for the neurotransmitter

6. Different types of synapses

7. Types of synapses Axo -dendritic synapse Most common Axon terminal branch (presynaptic element) synapses on a dendrite Axo -somatic synapse Axon terminal branch synapses on a soma (cell body) Axo-axonic synapse Axon terminal branch synapses on another axon terminal branch (for presynaptic inhibition) Dendro -dendritic synapse Dendrite synapsing on another dendrite ( localised effect)

8. Axo -dendritic synapse Most common Axon terminal branch (presynaptic element) synapses on a dendrite Axo -somatic synapse Axon terminal branch synapses on a soma (cell body) Axo-axonic synapse Axon terminal branch synapses on another axon terminal branch (for presynaptic inhibition) Dendro -dendritic synapse Dendrite synapsing on another dendrite ( localised effect)

9. Synaptic ultrastructure The presynaptic enlargement (bouton, varicosity, or end plate) contains synaptic vesicles (20 nm diameter) and synaptic protein chains Pre- and postsynaptic plasma membranes are separated by a synaptic cleft (20 nm wide) The cleft contains glycoprotein linking material and is surrounded by glial cell processes Astrocyte is a glial cell which provide nutrition as well as aid in recycling some neurotransmitters Synaptic proteins

10. Presynaptic events Presynaptic membrane contains voltage gated calcium channels Membrane depolarisation opens up Ca 2+ channels Ca 2+ influx will occur Neurotransmitter molecules are released in proportion to the amount of Ca 2+ influx, in turn proportional to the amount of presynaptic membrane depolarization

11. Details of presynaptic events in the resting state, the presynaptic membrane has resting membrane potential when an action potential arrives at the end of the axon the adjacent presynaptic membrane is depolarised voltage-gated Ca 2+ channels open and allow Ca 2+ influx (driven by [Ca 2+ ] gradient) elevated [Ca 2+ ] activates synaptic proteins (SNARE proteins: Synaptobrevin , Syntaxin , SNAP 25) and triggers vesicle mobilization and docking with the plasma membrane vesicles fuse with presynaptic plasma membrane and release neurotransmitter molecules (about 5,000 per vesicle) by exocytosis neurotransmitter molecules diffuse across the cleft & bind with postsynaptic receptor proteins neurotransmitter molecules are eliminated from synaptic clefts via pinocytotic uptake by presynaptic or glial processes and/or via enzymatic degradation at the postsynaptic membrane molecules are recycled subsequently, presynaptic plasma membrane repolarises

12. Synaptic transmission Action potential passes from the presynaptic neuron to the postsynaptic neuron Although an axon conducts both ways, conduction through synapse is one way (retrograde transmission also can occur) A neuron receives more than 10000 synapses Postsynaptic activity is an integrated function

13. Neurotransmitters Chemicals that facilitate signal transmission across a synapse Neurotransmitters are released on the presynaptic side and bind to receptors on the postsynaptic side Earliest neurotransmitter discovered was acetylcholine There are different chemical types Amines Norepinephrine, Epinephrine, dopamine, serotonin (5HT), histamine Amino acids GABA, Glycine, Glutamate, Aspartate Peptides Beta endorphin, enkephalins, dynorphin Others Acetylcholine, nitric oxide

14. Neurotransmitter release “At rest”, the synapse contains numerous synaptic vesicles filled with neurotransmitter Intracellular calcium levels are very low Arrival of an action potential causes opening of voltage-gated calcium channels Calcium enters the synapse Calcium triggers exocytosis and release of neurotransmitter Vesicles are recycled by endocytosis

15. Neurotransmitter receptors Once released, the neurotransmitter molecules diffuse across the synaptic cleft When they “arrive” at the postsynaptic membrane, they bind to neurotransmitter receptors Two main classes of receptors: Ionotropic receptors Metabotropic receptors

16. IONOTROPIC RECEPTORS Neurotransmitter molecule binds to the receptor Cause a ligand-gated ion channel to open Become permeable to either sodium, potassium or chloride Accordingly depolarisation (excitation) or hyperpolarisation (inhibition) Quick action, short lasting

17. Metabotropic Receptors Neurotransmitter attaches to G-protein-coupled receptors (GPCR) which has slower, longer-lasting and diverse postsynaptic effects They can have effects that change an entire cell’s metabolism Activates enzymes that trigger internal metabolic change inside the cell Activate cAMP Activate cellular genes: forms more receptor proteins Activate protein kinase: decrease the number of proteins Sometimes open up ion channels also

18. Excitation 1. Na + influx cause accumulation of positive charges causing excitation 2. Decreased K + efflux or Cl - influx 3. Various internal changes to excite cell, increase in excitatory receptors, decrease in inhibitory receptors.

19. Inhibition 1. Efflux of K + 2. Influx of Cl - 3. activation of receptor enzymes to inhibit metabolic functions or to increase inhibitory receptors or decrease excitatory receptors

20. Excitatory effects of neurotransmitters EPSP: excitatory post synaptic potential Inhibitory effects of neurotransmitters IPSP: inhibitory post synaptic potential

21. Postsynaptic activity Synaptic integration On average, each neuron in the brain receives about 10,000 synaptic connections from other neurons Many (but probably not all) of these connections may be active at any given time Each neuron produces only one output One single input is usually not sufficient to trigger this output The neuron must integrate a large number of synaptic inputs and “decide” whether to produce an output or not

22. Neuromuscular junction

23. Neuromuscular junction This is a modified synapse Consists of Presynaptic membrane (nerve terminal) Synaptic cleft Postsynaptic membrane (motor end plate)

24. Presynaptic terminal (terminal knob, boutons, end-feet or synaptic knobs) Terminal has synaptic vesicles and mitochondria Mitochondria (ATP) are present inside the presynaptic terminal Vesicles containing neurotransmitter (Ach)

25. Presynaptic terminal (terminal knob, boutons, end-feet or synaptic knobs) Presynaptic membrane contain voltage-gated Ca channels The quantity of neurotransmitter released is proportional to the number of Ca entering the terminal Ca ions binds to the protein molecules on the inner surface of the synaptic membrane called release sites Neurotransmitter binds to these sites and exocytosis occur

26. Ca 2+ https://learn.zoom.us/j/6987416752 Ca 2+ Synaptic proteins

27. Ach vesicle docking With the help of Ca entering the presynaptic terminal Docking of Ach vesicles occur Docking: Vesicles move toward & interact with membrane of presynaptic terminal There are many proteins necessary for this purpose These are called SNARE (soluble NSF attachment protein receptor) proteins Syntaxin , synaptobrevin , SNAP25 Botulinum toxin cleaves all three SNARE proteins Tetanus toxin causes cleavage of synaptobrevin

28. Ach release An average human end plate contains 15-40 million Ach receptors Each nerve impulse release 60 Ach vesicles Each vesicle contains about 10,000 molecules of Ach Ach is released in quanta (small packets)

29. NMJ Postsynaptic membrane contain nicotinic acetylcholine receptor This receptor contains several sub units (2 alpha, beta, gamma, delta) Ach binds to alpha subunit Na+ channel opens up Na+ influx occurs End Plate Potential (EPP) This is a graded potential Once this reaches the threshold level AP is generated at the postsynaptic membrane

30. Na+ influx causes depolarisation of the membrane End Plate Potential (EPP) This is a graded potential Once this reaches the threshold level AP is generated at the postsynaptic membrane

31. End plate potential Even at rest small quanta are released Which creates a minute depolarising spike called Miniature End Plate Potential (MEPP) When an impulse arrives at the NMJ quanta released are increased in several times causing EPP

32. Acetylcholinerase (AchE) After the Ach binding is over Cholinesterase present in the synaptic cleft will hydrolyse Ach into choline and acetate Choline is reuptaken to the presynaptic terminal AchE is also found in RBC membranes

33. Situations where NMJ blocking occurs In the animal world to kill a prey snake uses poison which contains NMJ blocker South American hunters used arrow poison to kill animals and the arrow poison contains NMJ blocking property In suicide commonest poison used is insectide which is an organophosphate which has NMJ blocking property Useful in general anaesthesia to facilitate inserting tubes Muscle paralysis is useful in performing surgery In serious neuromuscular disorder called myasthenia gravis NMJ blocking occurs Miracle drug – botulinum toxin works by blocking NMJ

34. Earliest known NMJ blocker - Curare Curare has long been used in South America as an extremely potent arrow poison Darts were tipped with curare and then accurately fired through blowguns made of bamboo Death for birds would take one to two minutes, small mammals up to ten minutes, and large mammals up to 20 minutes NMJ blocker used in patients is tubocurarine Atracurium is now used

35. Competitive NMJ blockers (Non- depolarising NMJ blockers) eg. Curare Atracurium Rocuronium Vencuronium Competitive or non-depolarizing type Physically similar to Ach but no chemical (ligand) action Act by competing with Ach for the Ach receptors Binds to Ach receptors and blocks Prevent Ach from attaching to its receptors No depolarisation Late onset, prolonged action Ach can compete & the effect overcomes by an excess Ach Anticholinesterases can reverse the action by destroying cholinesterase and increasing Ach level

36. Depolarising NMJ blockers (Non-competitive NMJ blockers) eg. Succinylcholine non-competitive, chemically act like Ach Bind to motor end plate and once depolarizes Not easily removed by acetylcholinesterase Persistent depolarisation leads to a block Due to inactivation of Na channels Ach cannot compete with depolarising blockers Succinylcholine has quick action start within 1 min and last for 12 min  Hydrolysed by plasma cholinesterase (also called pseudocholinesterase) produced in the liver

37. Na + Acetylcholine Depolarization Na + - - - - + + + + - - - - + + + + + + + + + + + + - - - - - - - -

38. Na + Acetylcholine Tubocurarine Na + + + + + - - - - - - - - + + + + Competitive neuromuscular blocking drugs

39. Na + Depolarized Na + PHASE I Membrane depolarizes resulting in an initial discharge which produces transient fasciculations followed by flaccid paralysis - - - - + + + + + + + + - - - - - - - - + + + + + + + + - - - - - - - - Depolarizing Neuromuscular blocking drugs

40. Repolarized PHASE II Membrane repolarizes but the receptor is desensitized to effect of acetylcholine + + + + - - - - + + + + - - - - - - - - + + + + - - - - + + + + Depolarizing Neuromuscular blocking drugs

41. Anticholinesterases AchE inhibitors Inhibit AchE so that Ach accumulates and causes depolarising block Reversible Competitive inhibitors of AChE eg. physostigmine, neostigmine, edrophonium used to diagnose and treat myasthenia Irreversible Binds to AChE irreversibly eg. Insecticides (organophosphates), nerve gases (sarin)

42. Organophosphates Phosphates used as insecticides Action AchE inhibitors Therefore there is an excess Ach accumulation Depolarising type of postsynaptic block Used as a suicidal poison Causes muscle paralysis and death Nerve gas (sarin)

43. Snake venom Common Krait ( bungarus caeruleus) Produces neurotoxin known as bungarotoxin Very potent Causes muscle paralysis and death if not treated Cobra venom contain neurotoxin

44. Myasthenia gravis Neuromuscular disease Antibodies form against acetylcholine nicotinic postsynaptic receptors at the NMJ Characteristic pattern of progressively reduced muscle strength with repeated use of the muscle and recovery of muscle strength following a period of rest Present with ptosis, fatiguability, speech difficulty, respiratory difficulty Treated with cholinesterase inhibitors

45. Type Neurotransmitter Amines Serotonin (5HT), Dopamine, Norepinephrine, Acetylcholine, Histamine Amino acids Gamma- aminobutyric acid (GABA), Glycine, Glutamate, Aspartate Opioids Beta-endorphin, Enkephalins , Dynorphin , Nociceptin , Kyotorphin Neurokinins Substance P, Neurokinin A, B Endocannabinoids Endocannabinoids ( Anandamide , 2AG) Mixed types Nitric oxide and Carbon monoxide (CO) ATP, ADP CART (cocaine and amphetamine regulated transcript) Neuropeptide Y Orexin Other Angiotensin, Calcitonin, Glucagon, Insulin, Leptin , Atrial natriuretic factor, Estrogens, Androgens, Progestins , Thyroid hormones, Cortisol. Hypothalamic releasing hormones, Corticotrophin-releasing hormone (CRH), Gonadotropin releasing hormone ( GnRH ), Luteinizing hormone releasing hormone (LHRH), Somatostatin , Thyrotropin releasing hormone (TRH), Growth hormone releasing hormone (GHRH), Pituitary peptides, Corticotrophin (ACTH), Growth hormone (GH), Lipotropin (opioid), Alpha-melanocyte-stimulating hormone(alpha-MSH), Oxytocin, Vasopressin, Thyroid stimulating hormone (TSH), Prolactin, Gut hormones Cholecystokinin (CCK), Gastrin,  Motilin ,  Pacreatic  polypeptide, Secretin, Vasoactive  intestinalpeptide (VIP), Bombesin , Bradykinin , Carnosine (antioxidant), Calcitonin G related peptide CGRP (useful in migraine), Delta sleep inducing peptide (DSIP), Galanin (neuropeptide), Melanocyte concentrating hormone (MCH)

46. Acetylcholine (Ach) earliest neurotransmitter discovered secreted at the following sites neuromuscular junction (skeletal muscle contraction excitatory) heart (inhibitory) autonomic ganglia (both sympathetic and parasympathetic) adrenal medulla parasympathetic postganglionic nerve endings central pathways in the brain (neocortex, hippocampus) and basal forebrain (cognition, memory, arousal, attention) brainstem (REM sleep) large pyramidal cells of the motor cortex basal ganglia (striatum) receptors nicotinic (N N : autonomic ganglia, N M : NMJ) – ionotropic receptors Na + influx muscarinic (parasympathetc terminal) sub types: M1, M2, M3, M4, M5 metabotropic receptors with G protein and second messenger cAMP and K+ channel opening

47. Glutamate The most abundant and the main excitatory neurotransmitter in the brain (70% of all synapses) Does not cross BBB, synthesised at the nerve terminal using glutamine secreted from glial cells Ca2+ is necessary for release Reuptake to the presynaptic terminal or glial cells by excitatory amino acid transporter (EAAT) receptors Ionotropic receptors NMDA, AMPA and Kainate receptors NMDA receptor is normally blocked by Mg2+, membrane depolarisation removes Mg2+, then glutamate binds to NMDA receptor with the co-activator glycine. open up Na+ Ca2+ (K+) channels, Ca2+ influx, activates protein kinases and several actions Metabotropic receptors: G protein coupled second messenger system, act thru inositol phosphate and cAMP, opens up Na+ channel and other intracellular events Important for learning and memory functions and pain mechanism Have been implicated in neurological disorders such as stroke, epilepsy, Alzheimer's disease

48. GABA The main inhibitory neurotransmitter in the brain (occurring in about 40% of all synapses Causes both presynaptic and postsynaptic inhibition Reuptake up GABA transporter receptors GABA A receptor (ionotropic): postsynaptic, open up Cl- channel, hyperpolarisation , inhibition, alcohol, antiepieptics ( barbirurates ), benzodiazepine (diazepam), activate these receptors GABA B receptor (metabotropic): presynaptic , G protein coupled action, increase K+ efflux, inhibit Ca2+ influx through presynaptic Ca2+ channels GABA C receptor is also known to be present Increased GABA activity causes sedative effect Main neurotransmitter which produces SWS sleep GABA decreases serotonergic, noradrenergic, cholinergic and histaminergic neuronal activity Secreted by the neurons originating in striatum terminating in globus pallidus & substantia nigra. Also present in the spinal cord, cerebellum & many other areas of the Cx

49. Dopamine Dopamine (DA) is present in several important areas and pathways in the brain involved in reward pathway Ventral tegmental area (VTA) of the midbrain Nucleus accumbens (NA) of basal forebrain (brain pleasure centre) Mesocortical pathway from midbrain to prefrontal cortex Mesolimbic pathway from midbrain to limbic system Nigrostriatal pathway from substantia nigra to striatum in the limbic system Involved in motor control, dopamine levels are low in Parkinson disease Involved in reward behavior and addiction and in psychiatric disorders such as schizophrenia Receptors (metabotropic) D1, D2, D3, D4 D5 D1-like (D1 and D5) increases cAMP and D2-like (D2, D3 and D4) decreases cAMP Overstimulation of D2 receptors may lead to schizophrenia Reuptake by dopamine transporter Drug addiction is due to increased dopamine levels Cocaine and methamphetamine act by inhibiting dopamine transporters and thereby increasing dopamine level in the brain to a unimaginably high levels , Opioids and heroin act directly on DA neurons or inhibit GABA inhibition of DA neurons Cannabis and marijuana activate endocannabinoids which act presynaptically , inhibit GABA, increases DA levels Nicotine: More complex mechanism increasing DA

50. Serotonin Chemically: 5Hydroxy tryptamine (5HT) present in high concentration in platelets and in the GIT, within the brain stem in the midline raphé nuclei, which project to a wide area of the CNS including the hypothalamus, limbic system, neocortex, cerebellum and spinal cord After secretion, reuptake by serotonin transporter (SERT) Once inside the presynaptic terminal it is metabolised by MAO Receptors Metabotropic : 5HT1 (A,B,D,E,F), 5HT2 (A,B,C), 5HT4, 5HT5 (A,B), 5HT6, 5HT7 Ionotropic : 5HT3 Regulate arousal, mood and social behavior, appetite and digestion, sleep, memory, and sexual desire Low levels are known to be involved in depression Selective serotonin reuptake inhibitors – SSRI (fluoxetine, citalopram) blocks serotonin transporter and increases serotonin levels or SNRI (Serotonin Norepinephrine reuptake inhibitors) are also used Serotonin is involved in migraine (serotonin agonists are used), 5HT1 B,D,F receptors are stimulated by antimigraine drug sumatriptan Serotonin antagonists are useful in vomiting Tricyclic antidepressants (TCAs) inhibit the reuptake of norepinephrine & serotonin 5HT1A acts as autoreceptor 5-HT2A receptor has been implicated in the cognitive process of working memory. Useful in schizophrenia

51. Norepinephrine present in the autonomic nerves, brain stem, hypothalamus, locus ceruleus of the pons NE transporter is the NE reuptake pump located on the presynaptic noradrenergic nerve terminal Metabolised by MAO (monoamine oxidase); MAO inhibitors are used as antidepressants Increases BP and HR send nerve fibres to widespread areas of the brain and help control the overall activity of the brain and the mood. Mostly it causes excitation but sometimes inhibition also happens regulate mood, arousal, cognition, pain and other functions Receptors: α1A, α1B, α1D, α2A, α2B, α2C , 1, 2, 3 Metabotropic receptors G protein coupled, second messenger: cAMP or Ca2+ and protein kinase with norepinephrine having a greater affinity for α-adrenoceptors and epinephrine for β-adrenoceptors Locus ceruleus is the principal site of norepinephrine in the brain, involved in arousal, stress reaction, attention, sleep-wake cycle beta1 (heart), beta2 (bronchial muscles, blood vessels), beta3 (adipose tissue) play a role in the consolidation of memory through actions within the amygdala

52. Opioid Peptides Peptides originally known to be similar to morphine Different types of  Endorphin: present in pituitary, earliest discovered opioid peptide enkephalins: met-enkephalin, leu-enkephalin: present at substantia gelatinosa in the spinal cord & brain stem reticular nuclei, widely distributed Dynorphin: recently discovered Opioid peptides are involved in the descending pain inhibitory pathway receptors: , , : metabotropic, GPCR Activation of μ receptors increases K+ conductance, hyperpolarizing central neurons and primary afferents. Activation of κ receptors and δ receptors closes Ca2+ channels Dynorphin Nociceptin Similar to dynorphin A, bind to nociceptin receotor Kyotorphin it acts by releasing an met-enkephalin, lower in patients with persistent pain, is a neuromodulator

53. Glycine An inhibitory neurotransmitter in the spinal cord It is also known to be present in retina Co-activates NMDA receptor with gulutamate It has ionotropic receptor: Activate Cl- channels and cause hyperpolarisation Action of glycine is antagonised by strychnine Strychnine poisoning causes muscle spasms, convulsions and muscle hyperactivity Reuptake by transporter Parallel circuits potentiate GABA inhibition

54. Endocannabinoids The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults The ECS is comprised of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids Endogenous cannabinoids are 2-AG (2-arachidonoyl glycerol) and anandamide (arachidonoyl ethanolamide ) The most abundant cannabinoid receptor is the CB1 cannabinoid receptor, however CB2 cannabinoid receptor is also described Postsynaptic neuron releases endocannabinoids which then bind to cannabinoid receptors on the presynaptic terminal via in retrograde transmission Exogenous cannabinoids, such as tetrahydrocannabinol (Cannabis), produce their biological effects through their interactions with cannabinoid receptors However, exogenous cannabinoids have very high addictive properties Retrograde transmission

55. Histamine present in pathways from hypothalamus to cortical areas & spinal cord receptors: H1, H2, H3 (all present in brain) functions related to arousal, sexual behaviour , drinking, pain  H1 receptors: Apart from periphery these receptors are distributed in the thalamus, cortex, and cerebellum. H1 receptor is the mediator of allergy, sedation and weight gain produced by a number of antipsychotic and antidepressant drugs. H2 receptors: Apart from periphery, H2 receptors are widely expressed in the neocortex, hippocampus, amygdala, and striatum and produces excitatory effects in neurons of the hippocampal formation and thalamus. Several studies indicates that the stimulation of these receptors produces antinociceptive effects.   H3 receptors:   These are located presynaptically on axon terminals. Those located on histaminergic terminals act as autoreceptors . In addition, H3 receptors are located on nonhistaminergic nerve terminals, where they act as heteroreceptors to inhibit the release of a variety of neurotransmitters - including norepinephrine, dopamine,acetylcholine , and serotonin. Particularly high levels of H3 receptor binding are found in the frontal cortex, striatum,amygdaloid complex, and substantia nigra. Antagonists of H3 receptors have been proposed to have appetite suppressant,arousing , and cognitive-enhancing properties. H4 receptors: It has identified recently and is detected predominantly in the periphery, in regions such as the spleen, bone marrow, and leukocytes.

56. Neurokinins Substance P Neurokinin A and B found in primary nerve ending in the spinal cord mediator of pain in the spinal cord

57. Nitric oxide (NO) is a neurotransmitter in the central, peripheral, and enteric nervous systems Inhibitory (smooth muscle relaxation) It has a role in a variety of neuronal functions including learning and memory processes, cortical arousal, nociception, food intake, penile erection, yawning, blood vessel dilatation and immune response Neurons synthesize NO as a response to the activation of N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate NO is generated in the neuronal cells by the enzyme nitric oxide synthase (NOS) with calcium and calmodulin as cofactors NO has been described as an unconventional neurotransmitter, because it is not stored in synaptic vesicles and not released upon membrane depolarization but released as soon it is synthesized

58. Adenosine G protein coupled receptors A1, A2A, A2B, A3 Widely distributed Is a neuromodulator Sleep promoting substance A1 receptors inhibits the release of glutamate, Ach, noradrenaline, serotonin, dopamine A2 receptors facilitate GABA release Modulate neuronal excitability, synaptic plasticity, coordination of neural networks and in ischemia Caffeine

59. Others CART (cocaine and amphetamine regulated transcript) hypothalamus and midbrain enriched neurotransmitter with an antioxidant property can be found in mitochondria, which is the main source of reactive oxygen species Systemic administration of CART has been found to ameliorate dopaminergic neuronal loss and improve motor functions in PD It is a potential neurotrophic factor and is involved in the regulation of hypothalamic-pituitary-adrenal axis and stress response as well as in energy homeostasis. CART is also highly expressed in limbic system Possess antidepressant properties Neuropeptide Y influences many physiological processes, including cortical excitability, stress response, food intake, circadian rhythms, and cardiovascular function increases eating and promotes obesity Neuropeptide Y inhibits orexin Leptin inhibits neuropeptide Y Orexin (hypocretin) Involved in arousal, wakefulness, and appetite Narcolepsy is caused by a lack of  orexin  in the brain due to the destruction of the cells that produce it CGRP (Calcitonin gene related polypeptide) Present in the pain pathway at the first synapse, involved in causing headache in migraine, CGRP antagonists which are monoclonal antibodies are useful in migraine

60. Different types of nerve conduction Sensory conduction Motor conduction Mixed neve conduction

61. Different types of nerve conduction Orthodromic conduction Antidromic conduction In an orthodromic study, the recording electrodes measure the action potential traveling in the physiologic direction. In an antidromic study, the recording electrodes measure the action potential traveling opposite the physiologic direction.

62. Mixed nerve A nerve comprised of large number of bundles of nerve fibres When a nerve is electrically stimulated compound action potential is generated This can be recorded using surface electrodes kept on the skin surface overlying the nerve

63. Conduction Velocity If the distance form the stimulating electrode (cathode) to the recording electrode (cathode) is known the conduction velocity can be calculated in m/s distance Velocity = --------------------------- time Sensory conduction velocity and motor conduction velocity can be calculated Conduction velocity is proportional to the degree of myelination of nerve fibres

64. Describe Alteration in nerve conduction in nerve injuries. Nerve injury causes Demyelination Nerve conduction velocity is slow down Axonal degeneration Amplitude of compound action potential is reduced