1. Neural Control Mechanisms Section A John Paul L. Oliveros, MD

2. Neural Tissue Neuron: basic unit of the nervous system Serves as integrators Neurotransmitters: chemical messengers released by nerve cells Parts: Cell body Dendrites Axon Axon terminals

3. Neural Tissue Parts of a neuron Cell Body Contains nucleus and ribosomes Genetic information and machinery for protein synthesis Dendrites Receive inputs from other neurons Branching increases the cell’s receptive surface area Axon AKA nerve fiber Single long process that extends from the cell body to its target cells INITIAL SEGMENT AKA axon hillock Portion of axon closest to the cell body plus parts of the cell body “Trigger zone” Collaterals Main branches of the axon Axon Terminal Ending of each branch of axon Releases neurotransmitters Varicosities Bulging areas along the axon Also releases neurotransmitters

4. Neural Tissue Myelin Sheath Layers of plasma membrane wrapped around the axon by a nearby supporting cell Speeds up conduction of electrical signals along the axons and conserves energy Oligodendroglia: CNS Schwann cells: PNS Nodes of Ranvier Spaces between adjacent sections of myelin Axons plasma is exposed to ECF

5. Neural Tissue Axon Transport Movement of various organelles and materials from cell body to axon and its terminal To maintain structure and function of the axon Microtubules Rails along which transport occurs Linking proteins Link organelles and materials to microtubules Function as motors of axon transport and ATPase enzymes Provide energy from split ATP to the motors Axon Terminalcell body Opposite route of transport Route for growth factors and other chemical signals picked up at the terminals Route of tetanus toxins and polio and herpes virus

6. Neural Tissue

7. Neural Tissue synapse Specialized junction between two neurons where one alters the activity of the other Presynaptic neuron Conducting signals toward a synapse Postsynaptic neuron Conducts signals away from a synapse

8. Neural tissue Glial Cells/Neuroglia 90% of cells in the CNS Occupy only 50% of CNS Physically and metabolically support neurons Types: Oligodendroglia Form myelin covering of CNS axons Astroglia Regulate composition of ECF in the CNS Remove K+ ions and neurotransmitters around syapses Sustain neurons metabolically (provide glucose and remove ammonia) Embryo: guide neuron migration and stimulate neuron growth Many neuron like characteristics Microglia Perform immune functions in te CNS Schwann cells Glial cells of the PNS Produce myelin sheath of the peripheral nerve fibers

9. Neural Growth and degeneration Embryo: Precursor cells: develop into neurons or glial cells Neuron cell migrates to its final location and sends out processes Growth cone: specialized tip of axons that finds the correct route and final target of the processes Neurotropic factors: growth factors for neural tissue in the ECF surrounding the growth cone or distant target Synapses are then formed once target tissues are reached Neural development occurs in all trimesters of pregnancy and upto infancy permanent damage by alcohol, drugs, radiation, malnutrition, and viruses Fine tuning: Degeneration of neurons and synapses after growth and projection of axons 50-70% of neurons die by apoptosis Refining of connectivity in the nervous system

10. Neural growth and regeneration Neuron damage Outside CNS Does not affect cell body Severed axon can repair itself and regain significant function Distal axons degenerates Proximal axon develops growth cone and grows back to target organ Within CNS No significant regeneration of the axon occurs at the damage site No significant return of function

11. Section B Membrane Potentials

12. Basic principles of electricity Electric potential Potential of work obtained when separated electric charges of opposite signs are allowed to come together Potential differences/potential Difference in the amount of charge between two points Volts: unit of electric potential Millivolts: measurement in biological systems Current Movement of electric charge Depends on the potential differences between charges and the material on which they are moving Resistance Hindrance to electric charge movement Ohms law: I= E/R Insulator Materials with high electrical resistance Conductor Materials with low electrical resistance e.g. water

13. Resting Membrane Potential Resting membrane potential The potential difference across the plasma membrane under resting conditions Inside cell: negative charge (-70mV)

14. Resting membrane potential Magnitude of membrane potential is determined by: Differences of specific ion concentrations in the intracellular and extracellular fluids Differences in membrane permeabilities to the different ions

15. Resting membrane potential Equilibrium potential: the membrane potential at which flux due to concentration gradient is equal to the flux due to electrical potential but at opposite directions No net movement of ion because opposing fluxes are equal Membrane potential will not undergo further change Its value depends on the concentration gradient of an ion across the membrane

16. Resting membrane potential

17. Resting Membrane Potential In a resting cell, Na+ and K+ ion concentrations don’t change because the ions moved in and out by the Na+,K+-atpase pump equals that moved by the membrane channels electrical potential across membranes remain constant Electrogenic pump Pump that moves net charge across the membrane and contributes to the membrane potential Na+,K+-ATPase pump: Sends out 3 Na+ ions for moving in 2K+ ions Makes the inside of the cell more negative

18. Graded Potentials and Action Potentials Nerve cells transmit and process information through transient changes in the membrane potential from it s resting level Two forms of signals Graded potential Over short distances Action potential Long distance signals Depolarized Potential is less negative than the resting level Overshoot A reversal of the membrane potential polarity Cell inside becomes positive relative to the outside Repolarize When the depolarized membranepotential returns toward the resting value hyperpolarize The potential is more negative than the resting lavel

19. Graded potential Changes in the membrane potential confined to a relatively small region of the plasma membrane Die out within 1-2 mm of site Produced by a specific change in the cell’s environment acting on a specialized region of the membrane Magnitude of the potential change can vary Local current is decremental Amplitude decreases with increasing distance from the origin

20. Graded Potential

21. Graded Potential

22. Action Potentials Rapid and large alterations in the membrane potential 100mV from -70mV then reporalize to its resting membrane Excitable membranes: Plasma membranes capable of producing action potentials e.g. Neurons, muscle cells, endocrine cells, immune cells, reproductive cells Only cells in the body that can conduct action potentials Excitability: Ability to generate action potentials

23. Ionic basis of action potentials Resting state: K+ and Cl- ion membranes open Close to K+ equilibrium Depolarizing phase Opening of voltage-gated Na+ channels 100x More + Na ions enter the cell May overshoot: inside on the cell becomes positvely charged Short duration of action potentials Resting membrane returns rapidly to resting potential because Na+ channels undergo inactivation near the peak of the action potential to then close Voltage gated K+ channels begin to open

24. Ionic basis of action Potentials Afterhyperpolarization Small hyperpolarization of the membrane potential beyond the resting level Some of voltage gated K+ ions are still open after all Na+ have closed Chloride permeability does’t change during action potential The amount of ions involve is extremely small and produces infinitesimal changes in the intracellular ion concentration Na+,K+-ATPase pump makes sure that concentration gradient of each ions are restored to generate future action potentials

25. Mechanism of ion-channel changes 1st part of depolarization: Due to local current opens up voltage gated channels sodium influx  increase in cell’s positive charge  increase depolarization (positive feedback) Delayed opening of K+ channels Inactivation of Na+ channels: Due to change in the conformation channel proteins Local anesthetics e.g. Procaine, lidocaine Block voltage gated Na+ channels Prevent sensation of pain Animal toxins: Puffer fish: tetrodotoxin Prevent na+ component of action potential In some cells: Ca++ gates open prolonged action potential

26. Threshold and the all-or-none response The event that initiates the membrane depolarization provides an ionic current that adds positive charge to the inside of the cell Events: K+ efflux increases Due to weaker inside negativity Na+ influx increases Opening of voltage gated channels by initial depolarization As depolarization increaes mor voltage gated channels open Na+influx eventually exceeds K+ efflux positive feedback starts action potential Threshold potential Membrane potential when the net movement of positive charge through ion channels is inward Action potential only occurs after this is reached About 15mV less neative than Threshold Stimuli strong enough to depolarize the membrane to threshold potential Subthreshold potentials Weak depolarizations Membrane returnsto resting level as soon as stimuli is removed No action potential generated Subthreshold stimulus Stimuli that causes subthreshold potentials

27. Threshold and the all-or-none response Stimuli more than threshold magnitude elicit action potentialswith exactly the same amplitude with that of a threshold stimulus Threshold: membrane events not dependent on stimulus strength Depolarization generates action potential because the positive feedback is operating All-or-none response Action potentials occur maximally or they do not occur at all Firing of the gun analogy

28. Refractory periods Absolute refractory period During action potential, a 2nd stimulus, no matter how strong, will not produce a 2nd action potential Na+ channels undergo a closes and inactive state at the peak of the action potential Membrane must be repolarized to return Na+ channels to a state which they can be opened again Relative refractory period Interval followng the refractory period during which a 2nd action potential can be produced Stimulus must be greater than usual 10-15ms longer in neurons Coincides with the period of hyperpolarization Lingering inactivation of Na+ channels and increased number of potassium channels open Additional action potentials fired Depolarization exceeds the increased threshold Depolarization outlasr the refractory period

29. Action Potential Propagation The difference in potentials betwen active and resting regions causes ions to flow Local current depolarizes the membrane adjacent to the action potential site to its threshold potential producing another action potential action potential propagation Gunpowder trail analogy Action potentials are not conducted decrementally Direction of the propagation is away from a region of the membrane that has been recently active Due to refractory period

30. Action potential propagation Muscle cells Action potentials are initiated near the middle of these cylindrical cells and propagate towards the 2 ends Nerve cells Initiation at one end and propagate towards the other end Velocity of action potential propagation depends on Fiber diameter The larger, the faster Myelination Myelin is an insulator Action potential only in the nodes of ranvier Concentration of Na+ channels is high Saltatory conduction/ jumping of action potentials from one node to the other as they propagate Faster conduction

31. Initiation of action potential Afferent neurons Initial depolarization threshold achieved by a graded potential (receptor potential) generated by sensory receptors at the peripheral ends Efferent neurons/ interneurons Depolarization threshold due to Graded potential generated by synaptic input Spontaneous change in the neurons membrane potential (pacemaker potential) Occurs in absence of external stimuli e.g. Smooth muscle, cardiac muscles Contnuous change in membrane permeability no stable resting membrane potential Implicated in breathing, heart beat, GIT movements

33. Section C Synapses

34. Synapses Anatomically specialized junction between 2 neurons Electrical activity of a presynaptic neuron influences the elcetrical/metabolic activity of a postsynaptic neuron 100 quadrillion synapses in the CNS Excitatory synapse Membrane potential of postsynaptic neurons is brought closer to the threshold Inhibitory synapse Postsynaptic neuron membrane potential is brought further away from the threshold or stabilized Convergence Neural input from many neurons affect one neuron Divergence Neural input from one neuron affects many other neurons

35. Functional anatomy of synapses 2 types of synapses: Electrical synapses Pre and postsynaptic cells joined by gap junctions Numerous in cardiac and smooth muscle cells Rare in mammalian nervous system Chemical synapses Synaptic cleft Separates pre and post synaptic neurons Prevents direct propagation of electric current Signals transmitted by means of neurotransmitter Co-transmitters Additional neurotransmitter simultaneously released with another neurotransmitter Synaptic vesicles Store neurotransmitter in the terminals

36. Functional anatomy of synapses Presynaptic cell: Action potential axon terminal depolarization  voltage-gated Ca++ channels open Ca++ enters  fusion of synaptic vesicles to PM  release of transmitters by exocytosis Postsynaptic cell: Binding of neurotransmitters to receptors  opening or closing of specific ligand sensitive -ion channels One way conduction across synapses in general Brief synaptic delay (0.2 sec) from action potential at presynaptic neuron to membrane potential changes in post synaptic cell

37. Functional anatomy of synapses Fate of unbound neurotransmitters Are actively transported back to the axon terminal/glial cells Diffuse away from the receptor site Enzymatically transformed into ineffective substances 2 kinds of chemical synapse Excitatory Response is depolarization Open postsynaptic-membrane ion channels permeable to positvely charged ions Excitatatory postsynaptic potential (EPSP) Potential change wherien there is net movemnt of positively charge ions into the cell to slightly depolarize it Graded potential to bring the postsynaptic neuron closer to threshold Inhibitory Lessens likelihood for depolarization and action poterntial Opening of Cl- or sometimes K+ channels Inhibitory postsynaptic potential (IPSP) Hyperpolarizing graded potential

38. Activation of a postsynaptic cell In most neurons, one excitatory synaptic event by itself is not enough to cause threshold to be reached in the postsynaptic neuron Temporal summation: Axon stimulated before the 1st EPSP has died away The 2nd EPSP adds to the previous one and creates a greater input than from 1 input alone Input signals arrive at the same cell at different times The potentials summate because there is a greater number of open ion channels Spatial summation: 2 inputs occured at different locations on the same cell

39. Activation of a postsynaptic cell

40. Synaptic effectiveness A presynaptic terminal does not release a constant amount of neurotransmitters everytime it is activated Presynaptic synapse (axon-axon synapse) Axon terminal of one ends on an axon terminal of another Effects: Presynaptic inhibition Decrease the amount of neurotransmitter secreted Presynaptic facilitation Increase the amount of neurotransmitter secreted

41. Modification of Synaptic transmission by Drugs and Disease All synaptic mechanisms are vulnerable to drugs Agonist: Drugs that bind to a receptor and produces a response similar to normal activation of a receptor Antagonis: Drugs that bind to the receptor but aren’t able to activate it Diseases: Tetanus toxin Protease that destroys certain proteins in the synaptic-vesicle docking mechanism of inhibitory neurons to neurons supplying the skeletal muscle Botulinum toxin and spider venom Affect neurotransmitter release from synaptic vesicles Interfere with docking proteins Act on axons different from those acted upon by tetanus toxin

42. Synaptic effectiveness

43. Neurotransmitters and Neuromodulators Neuromodulators Messengers that cause complex responses/modulation Alter effectiveness of synapse Modify postsynaptic cell’s response to neurotransmitters Change the presynaptic cell’s release, release, re-uptake, or metabolism of a transmitter Receptors for neuromodulators bring about changes in the metabolic processes in neurons via G-proteins Changes occur within minutes, hours, or days enzyme activity Protein synthesis Associated with slower events Learning Development Motivational states Sensory/motor activities

44. Neurotransmitters and neuromodulators Acetylcholine (ACh) Synthesized from choline and acetyl coenzyme A Reducing enzyme: acetylcholinesterase Mostly in the PNS, also in CNS Nerve fibers: cholinergic Receptors: nicotinic, muscarinic Function: attention, learning, memory Pathology: Alzheimers Biogenic amines Synthesized from AA and contain an amino group MC: dopamine, norepinphrine, serotonin, histamine Epinephrine: biogenic amine hormone secreted by adrenal medulla Norepinephrine: important neurotransmitter in CNS and PNS

45. Neurotransmitters and neuromodulators Catecholamines Dopamine, norepinephrine, epinephrine Contain a catechol ring and an amine group Synthesized from tyrosine Reducing enzyme: Monoamine oxidase Catecholamine releasing neurons mostly in brainstem and hypothalamus but axons go to all parts of the CNS Function: state of consciousness, mood, motivation, directed attention, movement, blood-pressure regulation, and hormone release Catecholamines Fibers: adrenergic, noradrenergic Receptors: Alpha, Beta Further divide in Alpha1, alpha2, Beta1 and Beta2 receptors

46. Neurotransmitters and neuromodulators

47. Neurotransmitters and neuromodulators Serotonin Biogenic amine synthesized from trytophan Effects have slow onset and innervate virtually every structure of the brain and spinal cord. Has 16 different receptor types Function: Motor: excitatory Sensation: inhibitory Lowest activity during sleep and highest during alert wakefulness Motor activity, sleep, food intake, reproductive behavior, mood and anxiety Present in non-neural cells (e.g. Platelets, GI tract, immune system) Amino Acid Neurotransmitters Amino acids that function as neurotransmitters Most prevalent neurotransmitter in the CNS and affect virtually all neurons there Excitatory Amino Acids Glutamate Aspartate Function: learning, memory, neural development Pathology: epilepsy, alzheimers, parkinsons disease, Neural damage after stroke, brain trauma Drugs: phencylidine (angel dust) Inhibitory Amino Acids GABA (gamma-aminobutyric acid) Glycine Drugs: valium

48. Neurotransmitters and neuromodulators Neuropeptides Composed of 2 or more AA linked together by peptide bonds Function as hormones or paracrine agents Synthesis: from large proteins produced by ribosomes Fibers: peptidergic Endogenous opioids B-endorphin, dynorphins, enkephalins Receptors are site of action of opiate drugs (morphine, codeine) Function: analgesia, “jogger’s high”, eating and drinking behavior, CVS regulation, mood and behavior Substance P Released by afferent neurons Relay sensory information into the CNS Nitric Oxide Diffuse into the intracellular fluid of nearby cells from cells of origin Messenger between neurons and effector cells Activate cGMP Function: learning, development, drug tolerance, penile erection, sensory and motor modulation ATP Very fast acting excitatory transmitter Adenine