Neurobiology PDF

Neurons – effector cells: receive, process, convey information (sensory, motor, etc.) - Polar cells, have directionality - Some are multipolar – have many dendrites (= many poles) - Dendrites have mitochondria, rough endoplasmic reticulum (RER) and ribosomes, Golgi...

Neurons – effector cells: receive, process, convey information (sensory, motor, etc.) - Polar cells, have directionality - Some are multipolar – have many dendrites (= many poles) - Dendrites have mitochondria, rough endoplasmic reticulum (RER) and ribosomes, Golgi outputs - Synaptic terminals have same organelle as above - And in somas ^^ o Mitochondria will be transported btwn d and st (back and forth – back to axon when mitochondria is dead) Resting membrane potential – created by electrochemical gradients, one of main ions: NA+, K+, Cl-, A- (anions that can’t cross lipid barrier – usually inside cell) - Outside = 0 mV; inside -70 mV o This diff results from an uneven distribution of ions btwn inside and outside of cell o Higher concentration of Na+ and Cl- outside, higher of K+ and A- inside o The membrane potential is relative – we’re always comparing the inside to the outside - Maintained by sodium and potassium 1. Simple diffusion (concentration gradient) – forces Na+ and Cl- inside, K+ and A- outside 2. Electrostatic change (similar electrical charges repel and opposite attract) K+ and Na+ are repelled by net positive charge outside and attracted to neg inside, vice versa for Cl- and A- 3. Differential permeability – moving through ion channels/ionophores o Nongated ion channels – always open but only certain ions can pass (K+ and Cl- pass easily, but tend to remain in their og spot bc 1 and 2 offset each other § A- too large to cross, trapped inside § Na+ forced into by 1 and 2 4. Transporters/ion pumps – selectively move ions through/out membrane o Sodium-potassium pumps move 3 Na+ out for every 2 K+ in (excess positive ions outside) o Na+ can’t pass through channels easily Action potential – all or nothing, don’t lose strength during axon hillock to terminal (i.e., non-decremental) - Stimulus strength/rate of firing – strength of AP will always be the same, but the cell may fire more/less - -50 ish is when an AP is triggered PSP (post-synaptic potential): o IPSPs – hyperpolarized neuron, harder to produce APs o EPSPs – depolarized neuron, easier to produce APs (it’ll fire faster the more it’s depolarized past the threshold) o … summates together  o If it reaches -50, that triggers AP at hillock o Temporal integration – based on when PSPs reach neuron o Spatial integration – depending on where PSPs are on the neuron - Na+/K+ ATPase (pump) maintains resting membrane potential o Through active transport § Takes three sodium inside and carries outside; takes two potassium from outside and brings in § Uses ATP to complete this process - Voltage-gated channels open/close depending on voltage of cell - Depolarization membrane potentials becomes less neg (towards 0 and positive numbers) - Repolarization - Hyperpolarization potential becomes more negative AP process - When the potential passes the threshold, the voltage-gated ion channels open and allow free flow of ions across membrane o Sodium channels open and Na+ ions rush into cell bc of concentration gradient and electrostatic charge (otherwise they have diffs crossing cell membrane during RP) o Potassium channels require more depolarization to open § Triggered by influx of Na+ ions, potassium channels open and K+ rushes out of neuron driven by concentration gradient and now positive charge inside created by Na+ influx - Once the polarity is reversed and the inside of the neuron reaches ab +40mV, Na+ channels close, but K+ remain open and the efflux of K+ continues o K+ channels close gradually, allowing just too many K+ ions to leave = hyperpolarization of cell membrane o Sodium-potassium pumps restore the RP over time Actions at synapse – chemicals and receptors - Course is esp concerned w actions influenced by drugs - NTs: o Usually synthesized in presynaptic cells, undergo exocytosis (release from vesicles into synaptic cleft), stored in vesicles, released in response to an AP o When AP reaches neuron, voltage gated Ca2+ channels (VGCC) open – influx of calcium into terminal button – calcium influx triggers the movement/fusion of synaptic vesicles w presynaptic membrane and release of NT; NTs then diffuse across cleft where they reach the membrane of postsynaptic cleft o Three options for ending synaptic action/controlling amount of NT in synapse: § Broken down in synaptic cleft § Reuptake – repackaged by vesicles, uses a transporter protein in the membrane of synaptic cleft  § Broken down in cell (by an enzyme in mitochondria) – these parts may also be taken back into presynaptic cell to be remanufactured o Autoreceptor (metabotropic) – binds to NT w same name; heteroreceptor (metabotropic) – binds to another § Always on presynaptic cell § Auto – provides feedback on amount of NT released in synaptic cleft to regulate its levels through G proteins and 2nd messengers · This may cause the delay in effectiveness of some drugs – ex: antidepressants produce buildup of NTs, but auto receptors detect this and reduce production (blocking effectiveness of drug) § Hetero – respond to the release of NT and also to chemicals released by postsynaptic cell/other nearby cells when they’re depolarized · This is called retrograde signaling – how a postsynaptic neuron can control its level of stimulation (either suppressing excitation or inhibition) by controlling NT synthesis and release at presynapse o Criteria for a NT: § Synthesized w/in neuron § Released in response to cell depolarization § Binds to receptors to alter postsyn cell § Removed/deactivated w/in synaptic cleft o Steps in NT action 1. They’re synthesized from precursors under influence of enzymes 2. NT Molecules stored in vesicles 3. Those that leak from vesicles are destroyed by enzymes 4. APs cause vesicles to fuse w presyn membrane and release NT into synapse 5. Released NT binds w auto receptors and inhibits subsequent NT release 6. Released ones bind to postsyn receptors 7. Released ones are deactivated (reuptake or by enzymes) - Neuromodulators (NMs): o Diffusing chemicals, modulate activity of groups of neurons, act over fast and slow timescales o Can either influence pre (to influence the release of a NT) or post synaptic cleft o Usually are released more and travel further than NTs o Change rates of depression and facilitation at synapses o Regulate switching/brain states – switching attention/arousal level § Ex: ECBs - ** a substance can be a NT in one location and a NM in another Receptors & second messengers - Ionotropic – binding sites are directly connected to ion-gated channels o Protein reconfigures to allow channels open when NT binds (influx/efflux of ions); changes membrane potential (-/+)  o Can cause second messenger signalling - Metabotropic – indirect cascade of events o G-protein coupled receptors – when a NT binds to a receptor, a subunit/portion of the G protein breaks away – it moves inside the membrane to activate a nearby ion channel = yields an EPSP/IPSP § OR the subunit initiates a biochemical/enzymatic reaction that leads to the synthesis of a second messenger nd § 2 messenger often interacts w gated ion channels from w/in cell, or alters the operation of nongated channels that changes the RP o G-proteins have subunits (alpha and beta-gamma) o Two possibilities: § Activate/inhibit nearby ion channels § Initiate second messenger cascades · GPCRs – cannabinoid receptor 1 (CB1R) o Decreases (cAMP) and inhibits PKA phosphorylation pathway § cAMP activates protein kinase A – kinase is more persistent than a 2nd messenger and can remain active for mins-hrs (they also alter functioning of ion channels and receptors) o Decreases synaptic vesicle release o Results in membrane hyperpolarization o … suppression of neurotransmission Circuits: - Dopamine o Nigro-striatal pathway – movement (in BG) § In schizophrenia, yields extrapyramidal symptoms § From SN to striatum o Meso-limbic – reward, involved in most drug taking (from VTA to NAC and VTA to cortex including PFC) o Meso-cortical – motivation and emotions, to cortex (including PFC) o Tubero-infundibular – posterior pituitary – hypothalamus to pituitary (gland that secretes hormones into blood) Establishing circuits: - Cytokines can pass through placental barrier o Viruses/infections/drugs can cross  - Alcohol can pass through – fetus doesn’t have the enzymes to break it down, influences their brain dev - Drugs that modify the brain/body of fetus = teratogen - Proliferation of stem cells (create neurons and glial) – cells have to migrate and create physical brain – then have to connect (dendrites, terminal) – then myelination o Depending on when drug comes in, it disrupts diff processes o Early = might be affecting migration – incorrectly formed brain regions o Later on = myelination/arborization – connectivity issues, diff behavioural effects Two spots in adult brain that produce new neurons (neurogenesis) - Hippocampus – these new neurons esp implicated in encoding neurons in space and time - Subventricular zone – striatum o In rodents and monkeys – these neurons migrate to and replace olfactory neurons (they have a v good sense of smell) o In humans, they stay in the striatum Neuroplasticity - Some connections in brain don’t move, like the trunk of a tree – some connections are malleable, new ones form (like leaves in smaller branches) o I.e., our everyday learning processes when learning new things, activating new things o We can learn small things, but larger things like changing a whole personality shows much more physical constraint - We have physical constraints – can’t change circuits too much (finite space) - Most of the stable patterns of connectivity and architectural constraints (i.e., ones that are more diff to change) dev during sensitive or critical periods – so these connections are harder to establish later on after these periods Brain imaging: Looking at brain activity – use of oxygen and glucose, blood flow, water flow (theory is that more oxygen and sugars going to one region = indicates activity) - Magnetic resonance imaging/MRI o Non-invasive o Uses magnets and radio waves, not x-rays o Relies on movement of hydrogen atoms – esp that found in water, the movement of those atoms in a magnetic field o Good contrast (differentiating tissues) and spatial (actual size of the brain) resolution[IG1] § Contrast = inject substance that gives more resolution o Less dangerous bc doesn’t use radioactive materials and no x-rays - Functional MRI/fMRI  o Real-time looking at brain function o Dynamic view of metabolic chances in an active brain § Slower (s) vs NTs that are ms o Good spatial resolution, mostly non-contrast o Looking at changes in blood flow o Only moderate level of temporal resolution o Most ppl use BOLD imaging (relies on measuring blood-0xygen levels) o Is the activity we’re seeing actually due to manipulation or bc of boredom, anxiety, etc. o DTI (diffusor tensor imaging) – measures water diffusion, it’s faster in the direction of white matter fiber bundles (3-6x faster) § How we study white matter – myelin § V important for speed – as we age, white matter deteriorates = slower processing/transmission § DTI can look at white matter damage - Positron emission tomography/PET o Tomography (CT scan) and radioisotope imaging o Radioactive ligands are injected o Allows study of § Receptor distribution/density § Metabolic activity § Changes in receptors over time o Indirect measure of brain function, less temporal resolution o Lower spatial resolution compared to MRI, diff to distinguish btwn close structures - IRL ex of PET: dopamine hypothesis of schizophrenia o Dopamine is involved in psychosis symptoms bc… § Many abused drugs can cause psychosis symptoms in healthy ppl and worsen psychosis in schizophrenic patients § Antipsychotic drugs target dopamine system (are D2R antagonists or partial antagonists) o Raclopride is a competitive antagonist of the D2/D3 R (binds to either); emits radiation (a signal); lights up on scanner § Then give amphetamine (AMPH) – causes DA release in striatum; DA kicks of raclopride, DA emits no signal o 2 groups: control and schizophrenia subjects § *higher displacement indicates higher DA release into striatum § Bigger drop in signal intensity of schizo patients – i.e., more DA was being released into striatum § Provided direct support for dopaminergic hypothesis