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BIOC14H3 (51)
Lecture 2

BIOC14Winter2013 Lecture 2 Notes.docx

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Department
Biological Sciences
Course Code
BIOC14H3
Professor
Patrick Mc Gowan

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BIOC14Winter2013 Lecture 2 Notes CHAPTER 3: NEUROGENETICS AND NEUROPHARMACOLOGY Gene shapes behavior at multiple levels Genes shape behavior at multiple levels - the environment can affect each step DNA genome - the way you are raised can also (gene) affect gene expression and the way you behave RNA transcriptome Protein proteome Environments (physical, chemical, biological, social, economical, etc.) Cells (Neurons) connectome Brain (Gr oup of neurons and their interconnections) Behaviors Behavioral repertoire (actions, responses, emotion, personality, etc) o o the environment can affect each step 3 o the way you are raised can also affect gene expression and the way we behave Neuron o o the axon is myelinated to increase signal transduction Synaptic Transmission o signal starts at the soma (the cell body of the neuron) o the resting membrane potential is of -70mV o voltage gated Na channels open, allowing Na to come in so the inside of the neuron depolarized (becomes more positive) o this starts a chain reaction so depolarization continus along the membrane (propagates down the neuron as the positive charge reaches and causes other voltage gated channels to open) o eventually they reach the Ca channels and Ca comes in o Calcium influc causes the vesicles to move to the membrane and fuse, releasing neurotransmitters into the synaptic cleft o The neurotransmitters bind to receptors on the post synaptic neuron o o both in CNS and PNS 1 o After a period of time they can diffuse away or they can be reuptaken by the presynaptic neuron Synaptic Transmission o Amino acids: o Acetylcholine  stimulatory at the neuromusculatory junction and inhibitory in the heart o Gamma aminobutyric acid (GABA)  inhibits 90% of all synapses o Glycine, Glutamate (activator), Aspartate o Biogenic amines  organic compounds with multiple amine groups o Dopamine, Noradrenaline, Serotonin, Histamine Synaptic Reception o Neurotransmitter receptors in postsynaptic neuron memebrane bind NTs that are released from pre-synaptic neurons o NT receptors influence the opening and closing of ion channels o NT receptors can be divided into 2 classes depending on how they influence the ion channels Ionotropic Receptors o Ionotropic receptors function both as receptors and ion channels o Upon binding of NT, the receptor undergoes conformation change that results in the opening of the channel  ions of appropriate size and charge can come in the cell o The cell memebrane potential then changes  when Na comes in membrane potential increases, while when Cl ions come in the memebrane potential further decreases (more difficult for an action potential to be created) o Metabotropic Receptors o metabotropic receptors influence ion channels indirectly o upon binding, metabotropic receptors activate cascade of signaling events involving G –protein signaling and second messeneges (cAM and DAG) o activation of second messengers in turn activate protein kinases that phosphorylate different substrate proteins including ion channels o also affect cell function over longer term by changing the synthesis of new proteins 2 o o the receptor is bound to G protein o conformation change in G protein occurs  activates adenylyl cyclase cAMP  protein kinase A is activated which phosphorylates channels and causes opening or closing of ion channels Synaptic Integrationptic potentials can piggy back on each other. o multiple synaptic potentials can piggy back on each other Synaptic integration o• Excitatory and inhibitory synaptic signals are integrated into a single response. o one signal from• Multiple synaptic potentials can piggy back on each other.re mey be contradictory messeges o temporal summation  when more than one neuron transmit the same signal one after the other so the neuron has no time • Excitatory and inhibitory synaptic signals are integrated into a single response. to recover, adding up the signal and causing the firing of an action potential Temporal summation - one signal from a neuron to another is not enough to fire an AP because there may be contradictory messeges o one neuron transmit the same signal at the 12 o Spatial summationone after the other so the neu- all signals come in at once, some mayxcitatory, but added up they may to recover, adding up the signbe inhibitory and some may be or mayTemporal suthe firing of an action potentiexcitatory Influence of Genes on Neuronal Functions and Behaviors enough to fire an AP because there may be contradictory messeges - temporal summation --> when more than one neuron transmit the same signal at the 12 Spatial summation one after the other so the neuron has no time - all signals come in at once, some may to recover, adding up the signal and causing be inhibitory and some may be the firing of an action potential excitatory o o Depression: serotonin is taken out of the cleft and is repackaged so that amount of serotonin in the cleft differs than a “normal” person o Schizophrenia: overstimulation of dopaminergin neurons = too much dopamine o A deficit of dopamine can also cause ADHD o * Neuropharmacology  the branch of research concerned with drugs affecting the nervous system SSRI o selective serotonin reuptake inhibitor o a class of drugs used as antidepressents  fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa) 3 o increase the extracellular level or serotonin o drug responses vary between individuals o major depression is caused by a deificit of serotonin in the cleft  drug prevents the reuptake of serotonin o these drugs tend to not be usefull for major depression because the neuron can detect levels of serotonin and it will continue to just reuptake o in less sever depression, the drugs can work o o in acute depression (A) the uptake of serotonin is increased o the drugs, block the transporters so that serotonin in the cleft increases  person gets worse (symptoms increase) at first beAntipsychotics time for the transporters to adapt (B) o (C) – fewer receptors because there is less serotonin in the cleft eventually results in less symptoms • A class of drugs used in the treatment of schizophrenia, e.g. Haloperidol Antipsychotics - Dopamine receptor antagonist o a class of drugs used in treatment of schizophrenia  Haloperidol - Suppress toe odopamine receptor antagonist  suppresses the overactivation of dopamine system - atypical drugs now have lowor atypical drugs now have lower side effects so they side effects so they are favoured are more favoured than typical psycotics - if you take typical psychotics typical psychotics, if you take them for a long time for a long time you can develop can result in symptoms like parkinson’s symptoms like parkinson's - inverse agonist not antagonist acts like an inverse agonist not antagonist  binds --> binds receptor and causes receptor and causes the opposite effect of what the th opposite effect of what the receptor is doing receptor is doing - when there is no dopamine o when there is no dopamine bound, Na is still allowed bound, Na is still allowed to to pass through  when dopamine is bound even pass through --> when more Na passes through dopamine is bound even more Na is allowed through o with inverse agonist, receptor is shut down so that - with the inverse agonist, no Na is allowed in which decreases the AP receptor is shut down, so no Na transmitted from neuron to neuron, and the is allowed in, which decreases symptoms of schizophrenia symptoms of schizophrenia 17 o Benzodiazepine o a class of drugs used in treatment of panic and anxiety disorder o diazepam (Valium), Iorazepam (Ativan) o GABA receptor agonist: binds to GABA Aeceptor and decreases neuron excitability o Also used to treat insomnia and seizures o Highly addictive drugs 4 • A class of drugs used in the treatment of panic and anxiety disorder - diazepam (Valium), lorazepam (Ativan) - GABA receptor agonist: binds to GABA receptor and decreases neuron excitability A o GABA is released from the presynaptic neuron - Also used to treat insomnia o Binds receptor and opens them allowing Cl to come and seizure in  causes membrane to become even more - highly addictive negative so no AP can be fired = causes relaxation - GABA is released from presynaptic o If GABA binds more frequently, the channel open neuron more frequently so more CL comes into the cell = - binds receptor and opens them allowing Cl to come in more reduction of anxiety = more relaxation - causes membrane to be more negative so no AP can be fired --> causes relaxation - if GABA binds more frequently the channel opens more frequently, so more CL comes into the cell = more reduction of anxiety = more relaxation 18 o CHAPTER 4: THE HUMAN GENOME PROJECT The birth of the Human Genome Project o 1985 – first meeting to discuss the feasibility of sequencing the human genome was organized by Robert Sinsheimer at the University of California Santa Cruz o 1988 – US government provided funding to the NIG and the Department of Energy office to study human genome o 1990 – the human genome project was launched o 1993 – Francis Collins was named as director after James Watson o as an international collaboration, scientists involved in the human genome projects made the sequence databases freely available to all scientists as well as the public Goals of the Human Genome Project o identify all genes in human DNA (one haploid reference) o Determine the sequence of the 3 billion chemical base pairs that make up human DNA o Store this information in databases o Improve tools for data analysis o Transfer related technologies to the private sector, and address ethical, legal and social issues that may arise from this project Human Genome Sequencing o Clone by clone technique  chop DNA with Res, purify then insert into vector  sequence the ends and develop seque
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