Cellular Physiology of the The Central Nervous System

1. Cellular Physiology of the The Central Nervous System Metro Anatomy & Physiology Spring 2017 Stan Misler <latrotox@gmail.com>

2. A. Two types of nerve to nerve communication: chemical vs. electrical synapse Neuron –neuron communication across synapse “E pluribus unum” (half channels link up between adjacent cells; spread of current synchronizes voltage in these cells) most often used in epithelial cells “Action at a distance”; temporal sequence neurotransmitter: works in ms to s over < 1 um gap Conventional ionized neurotransmitters stored in vesicles while lipid soluble transmitters (CO, NO, cannabinoids) are manufactured and quickly diffuse out of cell

3. 1. The use of the action potential for each mode of transmission

4. 2. The chemical synapse: a. Presynaptic Depolarization-secretion coupling (a) Ca hypothesis: depolarization of nerve terminal by AP -> opening of voltage sensitive Ca channels and a measurable Ca current that raises local intracellular Ca just under membrane from 100 nanomolar to 10s of micromolar) b. Quantal Hypothesis: Transmitter release, monitored as the post-synaptic potential (psp) or endplate potential (epp), occurs as unitary packets containing ~50,000 transmitter molecules of which 10,000 molecules are enough to give a unitary psp c. Vesicle Hypothesis: Synaptic vesicles of 10s nm diameter contain the packet, or quantum, of transmitter; release of contents is by exocytosis (fusion of vesicle membrane with plasma membrane) allowing soluble contents to locally ooze out and diffuse across the synaptic cleft to excite the post-synaptic cell. The vesicle, retrieved by endocytosis, refills with transmitter and is attracted to the nerve terminal membrane where the it is pulled close to the plasma membrane and primed for another round of exocytosis.

5. The central miracle of exocytosis: how granules get to, dock at, get “primed” and then fuse with the plasma membrane (an “exocyst complex”) for fusion pore formation Diffusion of vesicles from microtubule to membrane; vesicles then become ensnared to plasma membrane by intertwinement of vesicle and plasma membrane SNARE proteins • Protein components of vesicle membrane • Attachment devices for vesicle transport • Vesicle or v-SNAREs to intertwine with plasma membrane target or T-SNARES (docking and priming • Ca sensors (synaptotagmins)

6. b. Post-synaptic reception -> excitation : Details of nicotinic Ach post-synaptic receptor (= nAchR) -> depolarization of skeletal muscle (i) subunits, electron microscopy of membrane vesicles containing nAch R(top) -> 5 subunits with 4 transmembrane domains contribute to transmembrane pore (bottom left)(ii) agonist-bound sites in alpha subunits -> conformational change of receptor complex and opening of constriction near pore (bottom right)

7. c. Excitatory (epsp) vs. Inhibitory (ipsp) Post-synaptic potentials Both result from increase membrane conductance but epsps result from opening of non-selective cation channels that bring Vm positive to threshold for firing an AP. Ipsps result from opening of K or Cl channels that fix Vm at Vrest or else bring Vm positive to Vrest but negative to the threshold for firing an AP

8. d. Two types of Cell surface receptors and “sensing” of released transmitter (fast working & direct vs. slow & indirect) Direct response: ion channel is transmitter receptor -> nearly instantaneous (< 100 us) response Indirect response: transmitter receptor coupled at a distance to ion channel via G-protein cascade; response after 100s of msec delay

9. e Fast acting, low molecular weight neurotransmitters: actions and sites of action

10. f. Synaptic plasticity = Use dependence of increased efficiency of complex synapses • Learning = modification of behavior by experience. Represents changes in strength of synaptic throughput between precisely interconnected neurons. • Memory = retention of behavior modification over time. While the development of nervous system specifies connections, experience alters the effectiveness of connections which over the long term requires new protein synthesis due to activation of genes in nucleus = “A dialogue between genes and synapses” • Learning + Memory = Enlargement of presynaptic terminal + enlargement of neighboring dendritic spine. Larger post-synaptic potential makes it easier to trigger and AP • Forgetting = reversal of learning, but by which of these processes? However even if forgotten fact or concept is easier to relearn

11. g. cAMP hypothesis of memory : Enhanced synaptic transmission to follower neuron by two different effects of cyclic AMP (cAMP) over two different timescales. Short term sensitization (over seconds) = covalent modification of already extant proteins: Binding of catecholamines to surface receptors -> activation of adenylate cyclase -> cAMP -> stimulation of PKA -> channel phosphorylation -> altered channel gating Long term sensitization (over minutes to hours) = gene activation by transfer of PKA catalytic subunit to nucleus to activate cAMP responsive element on chromatin (CREB) -> gene expression, protein synthesis and synapse remodeling (sprouting of new branches of presynaptic terminal)

12. B. Simplest CNS neuronal circuit and its modulation (i) stretch of limb -> withdrawal = stereotypic limb movements. Ex. patellar ligament -> knee jerk) (i) Reflex arc: stretch of muscle -> activation of stretch receptor fibers in muscle -> activation of 1A afferent sensory nerve to spinal cord -> synaptic transmission (pre-synaptic release and post-synaptic reception of glutamate) -> activation of a motor neuron to muscle -> conduction of AP down motor neuron and release of Ach at neuromuscular junction -> muscle contraction to restore length (ii) Voluntary contraction: Impulse generated in cerebral cortex of brain travels down upper motor neuron to activate a motor neuron synapsing on muscle 1A sensory fiber a

13. 2. Adding synaptic inhibition to the spinal reflex= synaptic potential produced by the interneuron excited by sensory afferent opens chloride channels and brings Vm of flexor motor neuron to near Vrest thus transiently abolishing any AP activity occurring in flexor motor and relaxing flexor muscle Quadriceps femoris Spinal cord Hamstrings inhibitory Central excitatory transmitter = glutamate; Central inhibitory transmitter = GABA

14. 3. Extending Spinal Reflex to brain: 1A afferent fibers project to the sensory cortex while aMNs receive info from motor cortex Projection of branches of sensory afferent (1A) fibers to CNS through several synapses in medulla, thalamus and finally somatic sensory cortex Fibers project from sensory cortex to motor cortex whose axons activate alpha motor neurons to muscle. 1A Without functional supraspinal innervation, such as after acute stroke, there is not enough background excitation of alpha motor neurons to sustain a reflex = flaccid paresis. Ultimately the 1A fibers sprout more synaptic knobs so alpha motor neurons are excited by even by small stretch and muscle tone is increased = spastic paresis a Note crossing of motor and sensory pathways from left to right

15. 3. Approaches to nervous system:Big and Basic Questions now being studied a. How does the brain regulate thoughts and emotions to make us unique individuals? b. How is the brain is regulated ? (1) sculpted by evolution (natural selection) (2) constrained by genes (3) modulated by hormones (4) shaped by early experience (5) altered by continuous activity in changing environment (fetal -> perinatal -> infant -> child -> adolescent) c. How does knowledge of the biology of behavior shape public policy? How to deal with aggression; addiction; child rearing; aging and declining brain function

16. a. Modern synthesis: Central nervous system (brain + spinal cord) underlies the following (1) sensation: output of vision, hearing, touch, smell, taste, pain and heat receptors cells at periphery project to the brain and underlie perception, the interpretation of sensory output (2) body movement + gait (pattern of walking), station (ability to maintain posture while standing) and balance: body movement may be fixed as in a reflex in response to stimulus (e.g., muscle or tendon stretch) or voluntary = formulated by brain (3) modulation of involuntary (autonomic or vegetative) functions for homeostasis: changes in contraction of gut or heart muscle and stimulation or inhibition of fluid secretion by exocrine glands (salivary) and hormone secretion by endocrine glands (insulin secreting b cells of the pancreas)

17. (4) memory and learning + forgetting = plasticity of brain function : proliferation or withdrawal of synaptic contacts between nerve cells (5) cognition : (i) brain processes of acquiring knowledge and understanding through thought, experiences and the senses and (ii) how innately the brain looks for and concentrates on specific sensory inputs (e.g., visual forms) that are most significant for it to realize (first proposed by Kant) (6) behavior: whole body output that emerges from coordinated and sequential activation of multiple systems of neural circuitry. e.g. external stimulus (= food) + internal driving state (= hunger) -> excitement of behavioral motivation system (= feeding) coupled to recruitment of mood related systems and emotions, and arousal of endocrine and nervous responses (autonomic) for stimulation of digestion of complex foodstuffs, absorption of simple nutrients into circulation and uptake and storage in cells (muscle, liver, fat cells). (7) personality (the unique and stable way of thinking, feeling and behaving) = at least character (value judgments) + temperament (inborn features such as irritability or adaptability)