Midterm Review.docx

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Biological Sciences
Joanne Nash

Midterm Review Lecture 1 1. physiology a. how the body maintains homeostasis i. homeo 1. similar ii. stasis 1. condition b. pathology arises when homeostasis fails i. organism in homeostasis undergoes external change and internal change that results in a loss of homeostasis ii. organism attempts to compensate 1. failure to compensate results in pathology 2. success results in return to homeostasis c. understand human physiology by applying an integrated approach from different systems biology i. organism  genes 2. hypothesis building a. needs to be testable resulting in empirical data b. interpretation of data needs to account for i. variability between subjects 1. sex / race / lifestyle ii. psychological bias 1. from patient / subject / experimenter 2. placebo effect 3. need for double blinded studies iii. ethical considerations 1. potential risk to subjects / patients Lecture 2 1. action potentials a. explain animal behavior using anatomical connections and rules of cellular response i. excitation and inhibition of action potentials 2. 1902 membrane theory a. five considerations i. living cells are composed of an electrolytic interior surrounded by a thin membrane that is selectively permeable to ions ii. at rest, there is a pre-existing electrical difference of potential across the membrane iii. cell membrane is selectively permeable to potassium ions at rest iv. intracellular potassium concentration is high v. extracellular potassium concentration is low 3. the chemical gradient a. formed because of the properties of the plasma membrane i. water and small non-polar molecules diffuse easily ii. large and polar molecules are impermeable b. chemical gradient (concentration) influences direction of ion movement more than electrical gradient (charge / valency) FOR POTASSIUM i. i.e. at rest potassium is moving out along concentration gradient when the electrical gradient wants it to move in 4. electrophysiology a. voltmeter i. used to measure membrane potential difference of living cells between two points ii. difference in charge creates an electrical gradient (potential difference / driving force; measured in joules) between intracellular and extracellular compartments 1. E ion the voltage that has to be applied to the inside of the cell to prevent ion flux a. e.g. E ionof sodium is +60mV i. that means +60mV needs to be applied inside the cell to prevent sodium influx (since sodium is in greater concentration outside of the cell) b. e.g. E ionof potassium is -90mV i. this means -90mV needs to be applied inside the cell to prevent potassium efflux c. this only applies to one ion under the Nernst equation b. differential rheotome i. current slicer 5. resting membrane potential a. cell at rest has a negative charge (~70 mV) b. can be between -9 to -100 mV depending on the cell type (RBC / neurons of spinal cord at the extremes) c. three main factors that contribute to RMP (resting membrane potential) i. K+ leak channels 1. efflux of potassium resulting in negative interior ii. Na+/K+ ATPase (electrogenic) pump 1. 3 Na+ efflux 2. 2 K+ influx 3. electrogenic refers to net movement of positive charge out of the cell (efflux) 4. requires ATP  active transport iii. properties of the plasma membrane 1. impermeability 2. presence of voltage gated ion channels 6. ion channels a. allow for ions to pass through the membrane b. selective for specific ions and are voltage gated 7. Nernst equation a. calculates the individual equilibrium potentials of ions b. accounts for three properties i. ion concentration ii. valency iii. temperature 8. Goldman-Hodgkin-Katz equation (GHK equation) a. predicts membrane potential using multiple ions and membrane permeability properties i. accounts for two properties that Nernst equation doesnt 1. multiple ions 2. membrane permeability Lecture 3 1. voltage of membrane a. changes in response to voltage b. depolarization = more positive i. mainly duue to opening of Na+ channels ii. two gates 1. inactivation gate that closes at peak of action potential a. associated with absolute refractory period b. opens at RMP and stays open at firing 2. activation gate that a. opens at firing b. closes at RMP c. hyperpolarization = more negative d. repolarization = towards RMP 2. types of K+ channels a. leak channels i. always open ii. contribute to RMP b. voltage gated channels i. respond to changes in voltage ii. open in response to depolarization (AP firing) iii. slow to open and slow to close 1. closed at RMP 2. slowly opening at firing 3. fully open at repolarization 4. slowly closing at hyperpolarization iv. contribute to repolarization and hyperpolarization 3. the neuron a. presynaptic axon terminal releases neurotransmitter b. neurotransmitter causes depolarization of postsynaptic membrane c. changes in membrane potential of postsynaptic neuron results in opening and closing of ion channels 4. graded potentials a. amplitude (size) of GP proportional to strength of triggering signal b. decrease in amplitude as you move away from the stimulus i. i.e. potential is much lower at the axon hillock than it is at the synaptic membrane ii. if GP summates to threshold, action potential is fired 5. action potential a. generally the same size b. larger current does not result in larger action potential i. but increases in frequency of firing instead c. generated at the axon hillock (trigger zone) d. reaching threshold means action potential reached all-or-none response i. i.e. no longer directly proportional to the signal Lecture 4 1. discovery of action potential a. galvani i. electrical signals stimulating dead frog muscles ii. studies on bringing back dead b. differential rheotome i. berstein describes action potential as negative variation ii. negative variation 1. great difference in membrane potential 2. attributed to the resting membrane potential c. hodgkin and katz i. rediscovers negative variation / overshoot ii. formulation of sodium hypothesis 1. which explained transient reversal in RMP by influx of Na+ d. hodgkin and huxley i. ionic basis of action potential ii. develop mathematical model that predicted speed of propagation in squid giant axon 1. on unmyelinated axons a. broad axons allowed for better conduction b. more leaky compared to myelinated iii. action potential described as positive variation 1. positive inside the cell 2. negative outside the cell 3. attributed to overshoot / peak period iv. method 1. silver wire inside axon to measure electrical potential inside cell 2. maintained a delivered current inside the cell using voltage clamp 3. determined which ions were responsible for which currents 2. location of ion channels a. in dendrites and cell body b. high concentration of Na+ channels in trigger zone and nodes of ranvier c. no ion channels on myelin sheaths 3. positive feedback loop a. Na+ entry creates feedback loop b. depolarization of one Na+ channel activates more Na+ and K+ channels which adds up to an action potential 4. refractory periods a. absolute refractory period i. attributed to closing of inactivation gate b. relative refractory period i. any action potential induced is smaller than normal 1. attributed to slowly closing K+ channels 2. attributed to slowly de-inactivating Na channels 5. coding of stimulus intensity a. graded potentials are additive and summate b. action potentials do not summate i. always the same amplitude ii. stimulus intensity of action potentials is transmitted by frequency firing c. frequency of action potentials governs the amount of neurotransmitter release i. however, sustained action potential firing results in decreased neurotransmitter release because the axon terminal cannot replenish its supply quick enough d. the flow of action potentials down the axon is known as current flow 6. local current flow a. conduction down a non myelinated axon b. positive flow charge flows into the adjacent sections of the axon c. causes new sections (downstream) to be depolarize d. refractory period prevents backward conduction (upstream) e. loss of K+ from cytoplasm repolarizes the membrane (more negative) f. why doesn't the current flow back upstream? i. because sodium channels are not in default configuration (RMP) g. three phases in local current flow and saltatory conduction i. active phase 1. currently depolarized ii. inactive phase 1. not yet depolarized iii. refractory period 1. no longer depolarized / inactive 7. saltatory conduction and myelinated neurons a. leaping of current from nodes of ranvier through myelin sheaths devoid of ion channels i. myelin sheaths act as an insulator ii. conduction of action potential only occurs at nodes of ranvier 1. each node has a high concentration of sodium channels which open with depolarization b. why is conduction of action potentials faster in myelinated axons? i. insulation against current leak ii. concentrated Na channels at nodes of ranvier to reinforce depolarization 8. multiple sclerosis a. demyelinating disease which prevents the proper transmission of action potentials b. scarred myelin sheath results in leakage of action potential outside of the axon i. slows down signal propagation Lecture 5 1. neuronal signalling involves three signalling mechanisms a. graded potential b. action potential c. chemical neurotransmission 2. neurotransmission a. is the conversion of the action potential into a chemical signal which is released from the presynaptic axon terminal (neurotransmitter) b. this causes a response (graded potential in the dendrites / cell body of the target neuron at the post synaptic junction 3. neurons make 1000  150,000 synapses on dendrites and cell bodies 4. components of a synapse a. axon b. axon terminal i. mitochondrion ii. synaptic vesicles iii. synaptic cleft c. post-synaptic neuron i. ion channels ii. receptors 5. information transfer at the synapse a. AP depolarizes axon terminal b. depolarization opens voltage gated Ca2+ channels c. calcium entry triggers exocytosis where vesicles fuse with the membrane at the active zone i. subsequent release of NT into synapse d. binding of NT with postsynaptic cleft e. causing a cellular response in postsynaptic cell 6. receptor activation initiates a downstream signalling cascade a. signal transduction i. signal amplification b. different receptor types activate different signalling cascades c. general mechanism i. neurotransmitter binds to receptor ii. receptor activates G protein iii. G protein activates amplifying enzyme iv. amplifying enzyme activates second messengers v. second messengers stimulate the cellular response 7. types of receptors a. ionotropic i. chemical / ligand gated ion channels ii. activated by NT iii. coupled to ion channels iv. fast postsynaptic response b. G-protein coupled receptors (GPCR) i. NR binds to GPCR ii. receptor activates G protein iii. G protein activates downstream signalling cascades iv. slow but sustained postsynaptic response v. mechanism 8. types of postsynaptic responses a. ionotropic i. NT binds to receptor ii. ion channels open iii. two effects depending on which ion channels are opened 1. depolarization  EPSP a. more Na+ into postsynaptic neuron 2. hyperpolarization  IPSP a. more K+ out of postsynaptic neuron b. more Cl- into postsynaptic neuron b. GPCR i. NT binds to GPCR ii. GPCR activates G protein iii. G protein activates amplifying enzymes iv. amplifying enzyme action is twofold 1. can cause changes in voltage gated ion channels through modification of membrane potential and structural changes 2. can activate second messengers to activate responses further downstream c. GPCR modulation of ion channels i. change in membrane potential or structural change in the receptor ii. there is an alteration of the voltage gated ion channels 1. causing more ion movement 2. causing less ion movement iii. opening and closing can result in excitatory or inhibitory action depending on the channel type d. GPCR mediated alteration in synaptic potential via ion channels i. two types of receptors are being modified 1. ionotropic receptors 2. GPCR ii. both modify the voltage gated ion channel iii. triggers caused by 1. activation of the ionotropic receptors 2. activation of GPCR iv. result in downstream response in postsynaptic cells e. GPCR mediated alterations in cell function i. activation of amplifying enzymes ii. modification of existing proteins and synthesis of new proteins iii. coordinated cellular response iv. evocation of chemical response at the level of the GPCR 1.  amplifying enzyme  second messenger  cellular response 2. causes long term changes in a. protein synthesis b. learning and memory c. neuronal signalling 9. cycling of neurotransmitter in the presynaptic terminal a. once NT released from presynaptic terminal, it undergoes re-uptake via the ATP dependent uptake transporter i. the uptake transporter is similar in structure to Na/K ATPase pump 10. neurotransmitter classification a. amines i. synthesized in body ii. derived from amino acids 1. derived from tyrosine (CATECHOLAMINE) a. dopamine b. adrenaline c. noradrenaline 2. derived from tryptophan a. serotonin / 5HT b. amino acids i. derived from glutamine 1. glutamate ii. derived from glutamate 1. GABA c. acetylcholine i. synthesized in body ii. derived from acetate and choline 11. biosynthesis / release / catabolism of catecholamines a. tyrosine is transported into axon terminals b. enzymes converts tyrosine into neurotransmitter c. DOPA is the precursor for dopamine d. dopamine is the precursor for noradrenaline e. enzyme content of presynaptic terminals determine which neurotransmitter is formed f. NT undergoes reuptake by active transport g. excess NT is broken down 12. biosynthesis / recycling of acetylcholine a. acetylcholine made from choline and acetyl CoA b. ACh is broken down in the synaptic cleft i. by acetylcholinesterase c. choline is transported back into axon terminal and used to make more ACh 13. biosynthesis / release / breakdown of other NT a. glutamate / GABA i. Glutamine  a-ketoglutarate  glutamate  GABA ii. taken up by active reuptake iii. broken down in terminal b. 5HT (serotonin) i. tryptophan  5HT ii. taken up by active reuptake iii. broken down or repackaged into synaptic vesicles 14. neurotransmitter binding to receptor a. finite number of receptors i. at low concentrations 1. linear relationship with concentration and amount of NT bound ii. at high concentrations 1. receptors saturated 2. no more NT binding as often iii. maximum binding to receptors 1. maximum downstream effect caused by NT b. rate of binding decreases as neurotransmitter increases over time 15. neurotransmitters bind to different subtypes of receptor a. receptor subtypes defined by ligand (NT) that binds i. adrenergic receptors 1. NT = noradrenaline / adrenaline 2. GPCR a. subtypes i. a1 ii. a2 iii. b1 iv. b2 v. b3 ii. dopaminergic receptors 1. NT = dopamine 2. GPCR a. subtypes i. D1 ii. D2 iii. acetylcholine receptors 1. NT = acetylcholine 2. ionotropic a. nicotinic receptor 3. GPCR a. muscarinic receptor iv. glutamate receptors 1. NT = glutamate 2. ionotropic a. NMDA b. AMPA 3. GPCR a. glutamate receptor 16. neurotransmitters a. type of NT release defines the neuron i. e.g. dopaminergic  release dopamine 1. dopaminergic neurons found in areas of brain that control mood and personality ii. noradrenergic neurons controls movement and stress response b. acetylcholine is only NT that can be released into blood stream c. receptors i. cholinergic receptors found in skeletal muscle ii. adrenergic receptors found in heart / blood vessels 17. signalling molecules downstream of GPCR a. Gs i. activates adenylyl cyclase (amplifying enzyme) ii. adenylyl cyclase activates cAMP (secondary messenger) iii. cAMP activates pkA (excitatory cellular response) b. Gi i. inhibits adenylyl cyclase ii. no activation of cAMP or pkA c. Gq i. activates PLC (amplifying enzyme) ii. PLC activates two secondary messengers 1. IP3 a. located within the cell b. increases calcium levels i. calcium is important for postsynaptic cell ii. often referred to as intracellular NT 2. DAG a. located in the membrane 18. receptor coupling to signalling molecules a. adrenergic receptors i. a1  Gq ii. a2  Gi iii. B1/B2/B3  Gs b. dopaminergic receptors i. D1  Gs 19. functions of amine neurotransmitters a. dopamine i. physiological 1. motor control 2. mood control 3. motivation / reward 4. vomiting ii. pathological 1. parkinsons a. reduced dopamine 2. depression a. decreased dopamine 3. schizophrenia a. increased dopamine 4. stress and insomnia a. decreased dopamine 5. drug addiction a. increased dopamine b. 5HT i. physiological 1. mood control ii. pathological 1. depression a. decreased serotonin 2. anxiety a. decreased serotonin 20. functions of amino acid NT a. glutamate i. physiological 1. motor control 2. learning and memory ii. pathological 1. parkinsons a. increased glutamate 2. alzheimers a. increased glutamate b. GABA i. physiological 1. motor control ii. pathological 1. huntingtons a. decreased GABA 2. epilepsy a. decreased GABA 21. functions of acetylcholine a. acetylcholine i. physiological 1. muscle contraction 2. motor control 3. memory formation ii. pathological 1. parkinsons a. increased 2. alzheimers a. decreased 3. addiction to cigarettes a. increased 22. neurotransmitters and treatment a. GABA agonists i. epilepsy ii. bipolar disorder iii. anti anxiety iv. sleeping tablets v. panic attacks b. 5HT agonists i. anti depressant ii. anti anxiety iii. ecstacy c. b adrenergic agonists i. blocked sinuses ii. stimulants d. b adrenergic antagonists i. heart disease ii. anti anxiety e. dopamine agonists i. parkinsons ii. anti depressants f. block dopamine uptake i. cocaine ii. amphetamine g. dopamine antagonists i. schizophrenia Lecture 6 1. receptor binding assays a. used to determine what types of receptors are expressed in different parts of the body b. important in developing new drugs c. endogenous ligand is the ligand / neurotransmitter found in our bodies d. radioactive ligand is what competes for the receptor i. when radioactive is bound, it creates a signal that exposes it to photographic film e. the endogenous ligand is usually the potential drug  want to find a new drug that mimics the mode of action of the endogenous ligand i. if the drug works, it will decrease the signal of radioactive ligand because it will competitively bind to the receptor 2. immunohistochemistry a. antibodies for receptors b. antibodies are activated as an immune response i. antibodies specifically binds to immune regions c. overlapping expression of different receptors or proteins to find their relationship i. points of overlap where they are related 3. flotation assays a. biochemistry b. assays allow separation of vesicular and synaptic membranes i. homogenized and centrifuged at different speeds ii. isolating substances by relative densities 1. most dense substances at the bottom (usually the targeted proteins) Lecture 8 1. development of antibodies to study neuronal and synaptic function a. how antibodies are made b. take sequence of a receptor and inject it into a mouse c. mouse sees it as a foreign body (antigen) d. mouse makes antibodies against the antigen e. immune response f. antibodies generated and purified g. antibodies then used as scientific tools h. to detect the antibodies  radioactively tag them with colors i. use different colors of antibodies to test for multiple antigens 2. western blotting a. used to identify proteins b. tissues are removed and prepared to be added to gel electrophoresis c. allows proteins of interest to be separated by size d. transferred to a nitrocellulose membrane i. nitrocellulose membrane is incubated with antibodies that target proteins of interest e. western blotting performed i. to see which proteins bind to the antibodies 3. johnson parkinsonian study a. MDMA analogue (UWA-101 / ATK-101) enhances L-DOPA benefit in parkinsonian primates b. same effects on parkinsons as MDMA but does not have the accompanying psychoactive and cytotoxic activity that follows with ecstasy c. is there a role for ecstasy in the treatment of parkinsons? i. no 1. changes mood 2. reduces ability to learn 3. reduces ability to remember 4. affects sleep 5. kills brain cells 6. affects heart function ii. however 1. ecstasy illustrates the potential of manipulating 5HT transmission in parkinsons disease d. results i. MDMA and MDMA analogues decrease dyskinesia in primate model of parkinson's disease ii. y-axis represents on time 1. i.e. the time patient is able to move 2. i.e. the time L-DOPA starts working a. good on-time i. parkinsons symptoms abolished b. bad on-time i. dyskinesia present iii. UWA-101 1. seems to be the most optimal analogue at mimicking MDMA effects without its associated side effects 2. extends duration of action (overall) as well as extending period of good ontime 3. is not toxic to dopaminergic or serotinergic cells a. no psychotropic effect 4. no effect in terms of food intake 5. UWA-101 has a higher affinity to the receptors (5HT) than MDMA 6. how does UWA-101 cause these effects? a. refer to binding assays (lecture 6) i. have drug, dont know what it does or how it is working ii. random binding assays using different binding systems to see where it binds iii. different 5HT receptor subtypes iv. screened against receptors and reuptake systems v. radioactive ligand is selective for 1. receptor of interest 2. transporters of interest vi. results 1. MDMA prevents reuptake of serotonin a. creates mood elevation due to longer serotonin release at synapse iv. MDMA 1. is toxic to dopamine and serotinergic neurons 2. as dosage increases the toxicity to serotonergic and dopaminergic neurons increase e. conclusions of the study i. UWA-101 1. enhances the anti-parkinsonian actions of L-DOPA 2. reduces L-DOPA induced 3. is not toxic 4. is not psychotropic 5. useful as an 'add on' treatment to L-DOPA in the treatment of parkinsons disease ii. future studies 1. focused on finding ways to make UWA-101 druggable 2. human trials 3. administration of drug 4. absorption of drug 5. how it is metabolized Lecture 9 1. the central nervous system 2. the nervous system a. the central nervous system i. brain ii. spinal cord b. the peripheral nervous system i. autonomic nervous system 1. cardiac 2. smooth muscle 3. adipose tissue 4. endocrine system ii. enteric nervous system iii. somatic motor division 3. evolution of the brain a. as brain evolved, noticeable changes occurred i. increase in cortical width ii. increase in forebrain size iii. increase in convolutions of the brain b. nerve net  CNS - simple brain  development of the brain  development of cortical areas 4. anatomy of the brain a. dorsal (above) b. ventral (below) c. caudal (tail) d. rostral (beak) e. anterior (forward) f. posterior (back) 5. development of the nervous system a. neural plate i. region in the embryo that forms the CNS b. day 20 i. neural plate cells migrate to midline resulting in elevation of neural crest and deepening of the neural groove c. day 23 i. neural tube formation becoming the CNS ii. formation of the central cavity of the CNS by the lumen iii. differentiation into epithelial cells iv. outer layers of lumen become neurons and glia v. neural crest becomes sensory and motor neurons of PNS d. week 4 i. 3 major regions of the CNS formed ii. anterior portion of neural tube specializes into regions of the brain 1. forebrain 2. midbrain 3. hindbrain e. week 6 i. 7 major regions formed 1. growth of cerebrum outpaces other regions 2. ventricles (1-4) a. lateral ventricles b. descending ventricles 3. forebrain a. diencephalon b. cerebrum 4. midbrain 5. hindbrain a. medulla b. cerebellum c. pons f. week 11 i. cerebrum is the largest component of the brain 1. surrounds diencephalon, midbrain and pons ii. birth 1. rapid growth of the cerebrum and restraints of the cranium results in folding of the brain a. i.e. formation of convolutions i. gyri ii. sulci 6. three protective layers surround the CNS a. bone i. irregu
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