human physiology part 4

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 negative than resting membrane potential • 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 with magnitude more than the threshold magnitude elicit action potentials with 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 absolute 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 K+ 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 either: 1. Graded potential generated by synaptic input 2. 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

49. Section D Structure of the nervous system

50. Structure of the nervous system • Definition of terms • Axon/nerve • Long extension from a single neuron • Nerve • Group of many nerve fibers that are travelling together to the same general location in the PNS • Pathway/tract • A group of nerve fibers travelling together in the CNS • Commisure • Pathway/tract that links the right and left halves the CNS • 2 types of pathways in the CNS • Long neural pathways • Neurons with long axons carry information directly between the brain and the spinal cord or between large regions of the brain • Little opportunity for alteration in the information transmitted • Multineural/multisynaptic pathways • Made up of many neurons and many synaptic connections • Many opportunities for neural processing along the pathway • Ganglia • Group of neuron cell bodies in the PNS • Nuclei • Group of neuron cell bodies in the CNS