Lecture 5 Flashcards
The synapse
Presynaptic membrane: contains protein molecules that transmit chemical messages. Synaptic cleft: small space separating presynaptic terminal from postsynaptic dendritic spine. Postsynaptic membrane: contains protein molecules that receive chemical messages. Mitochondrion - provides cell with energy. Synaptic vesicle - round granule that provides the cell with energy. Storage granule: large compartment that holds synaptic vesicles. Postsynaptic receptor: site to which a neurotransmitter molecule binds.
Synaptic transmission
1) action potential propagated over presynaptic membrane 2) Depolarization of presynaptic terminal leads to influx of Ca2+ 3) Ca2+ causes vesicles to fuse with the presynaptic membrane and release transmitter into the synaptic cleft 4) The binding of transmitter to neurotransmitter receptors in the postsynaptic membrane opens channels, permitting ion flow and initiating an excitatory or inhibitory postsynaptic potential 5) these spread passively over the dendrites and cell body to the axon hillock 6a) Enzyme present in the extracellular space breaks down excess transmitter 6b) reuptake of transmitter slows synaptic action and recycles transmitter for subsequent transmission 7) Transmitters bind to autoreceptors in the presynaptic membrane (enzymes and precursors for synthesis of transmitter and vesicle wall are continually transported to the axon terminals), neurotransmitters are modulated quickly, drugs often work by modulating the amount of time neurotransmitters are in the space
Neurotransmitter Inactivation
Neurotransmitter action is brief and halted by three things: 1) enzymatic breakdown, rapid deactivation or breakdown of neurotransmitters by enzymes 2) reuptake, transporters, neurotransmitter is cleared from the synapse by being absorbed back into the presynaptic axon terminal by transporter proteins, target of psychotropic medications 3) autoreceptors that modulate amount of time and intensity in the cleft, modulates through influx of Ca2+. Caffeine modulates adenosine (autoreceptor) modulates catecholamine, higher energy with caffeine, modulation is not necessarily inactivation This happens quickly (neurons fire 1,200 per second maximally, most do 200-400 times)
Ionotropic receptors
Ionotropic vs metabotropic differ in how fast they open and how sustained their effects are. Ionotropic or ligand-gated ion channels, open when neurotransmitter binds. Fast-acting (a benefit) but transient effects. Ligands are molecules that fit into a receptor protein and activate or block it. Endogenous ligands: neurotransmitters or hormones made inside the body, typically cause opening. Exogenous ligands: drugs and toxins from outside the body, typically block. Agonists bind and open up the channel.
Metabotropic receptors
Or g-protein coupled receptors activate g proteins that trigger signaling cascades when a ligand binds. Slow acting but long lasting. Binds to receptor site contiguous with ion channel, facilitates G protein release (release from receptor), go over and either directly modulate ion channel (cause it to open) or can modulate through epigenetic changes. Bind on interior portion of the cell, results in opening of ion channel.
Additional terms for receptors
Receptor agonist: exogenous molecule (drug, toxin) that fits into a receptor and acts like a neurotransmitter. Receptor antagonist: exogenous molecule (drug, toxin) that fits into a receptor and blocks the action of a neurotransmitter. Nature of the postsynaptic receptors determines the action of a transmitter - ex: a particular type of neurotransmitter can be inhibitory or excitatory
at different synapse. Each subtype of receptor has unique distribution in brain. Same transmitter may bind to variety of receptor subtypes, triggering different responses. Neurotransmitters and receptors interact. Receptors are malleable (plastic) over life course (some fluctuate daily). Receptor up-regulation: increase in receptor number - Receptor down-regulation: decrease in receptor number (drugs, withdrawal). Neurons will generally be specifically responsive to one or two neurotransmitters. Agonists also don’t just ramp everything up, they can increase inhibition.
What is the EEG signal
postsynaptic potentials of cortical pyramidal neurons, also does not index presynaptic or subcortical
Neurotransmitters and Drugs
Neurons process information through electrical responses and release a chemical into a synapse to inform the next cell. Neurochemistry focuses on basic chemical composition and processes of the nervous system. The presynaptic neuron releases an endogenous (naturally produced in the body) ligand – a chemical neurotransmitter. Neuropharmacology is the study of chemical compounds that selectively
affect nervous system. Exogenous substances from external sources, such as drugs and toxins, have been used for ages to alter brain functioning.
Criteria for a neurotransmitter
1. Substance is synthesized in
presynaptic neurons and stored
in axon terminals
2. Is released when action potentials
reach axon terminals, recognized
by receptors on postsynaptic
membrane, and causes changes
(responses) in the postsynaptic cell
3. When experimentally applied to
target, produces same receptor
action; blocking its release
interferes with its effects on the
postsynaptic cell
4. Mechanisms for removal
These are endogenous, all of those ions that facilitate neurotransmission are not neurotransmitters.Neurotransmitter life cycle
- Synthesis and storage. Some transmitters are transported from the nucleus to the terminal buttons. Others are made from building blocks imported into the terminal and are packaged into vesicles there.
- Release of neurotransmitter. In response to an action potential, the neurotransmitter is released through exocytosis. Arrival of action potential opens voltage gated Ca2+ channels. CA2+ influx leads to NT release (exocytosis). 3. Interaction with receptor- Ionotropic- Metabotropic. The transmitter crosses the synaptic cleft and binds to the receptor. 4. Deactivation of NT signal - Enzymatic inactivation or degradation in synaptic cleft. Reuptake by presynaptic membrane (transported proteins). The transmitter is either taken back into the terminal or inactivated in the synaptic cleft.
The table of neurotransmitters that you need to know
Amines - - quaternary amines: Acetylcholine.
monamines: catecholamines - norepinephrine, epinephrine, dopamine. indoleamines - seratonin, melatonin. Amino Acids - GABA, glutamate, glycine, histamine. Neuropeptides - opiod peptides: enkephalins - met-enkephalin and leu-enkephalin, endorphins: beta-endorphin, dynorphins: dynoprhin A. other neuropeptides: oxytocin, substance P, cholecystokinin (CKK), vasopressin, neuropeptide Y (NPY), hypothalamic-releasing hormones. Gases: nitric oxide, carbon monoxide.
Neurotransmitter systems
Neurotransmitter vs neuropeptide – size of molecule, peptides are larger. Tend to have neural circuits in the brain that correspond to certain neurotransmitter systems. Different neurotransmitters have different effects, not all areas have equal distribution of receptors and things. Different types of receptors e.g. 5 types of dopamine receptors, each one may have a different distribution in the brain and serve different purposes. Function of neurotransmitter contingent on receptor to which it is binding. Different receptors in diff areas corresponding to diff psychological properties. Different circuits in the brain, different nuclei produce different neurotransmitters. GABA and glutamate are most common.
Some neurons release more than one neurotransmitter
- Certain neurons can release more than
one neurotransmitter from axon terminal (e.g., neurotransmitters, neuropeptide) - Firing rate of action potential affects which
NTs are released - Low frequency stimulation generates more
localized increase in Ca2+ resulting in
preferential release of small molecule
neurotransmitters (get vesicles lower down by synapse) - High frequency stimulation generates
more diffuse increase in Ca2+ resulting in
release of multiple NTs (get vesicles higher up)
They typically release a transmitter and neuropeptide, rare that you get two neurotransmitters.
ACh
Amine, quaternary amine. ACh was first neurotransmitter discovered. Referred to as cholinergic. In central nervous system, cholinergic cells in basal forebrain project to hippocampus, amygdala, and broadly throughout cortex. Loss of basal forebrain ACh associated with Alzheimer’s disease and disruption of these pathways interferes w/ memory. In peripheral nervous system, ACh is central to autonomic nervous system. In peripheral nervous system, ACh is used at neuromuscular junction – activates muscles. Nicotine affects ACh
Dopamine
Amine, monamine, catecholamine. - Dopamine (DA) is important for many aspects of behavior. Five primary receptors (D1-D5) that subserve different functions. Two primary dopaminergic pathways originate in midbrain nuclei. 1) Mesostriatal dopamine pathway projects from substantia nigra to striatum/basal ganglia (?) (caudate, putamen). Involved in motor control. Parkinson’s disorder is loss of DA neurons in substantia nigra. - Parkinson’s – probably treatable in 10 years with optogenetics and directly turn on/off dopamine cells, can do electrode, deep brain stimulation (get a lot of side effects), optogenetics is more precise – pathophysiology of Parkinson’s is very well known and specific, things like depression are harder to treat2) Mesolimbocortical dopamine pathway projects from ventral tegmental area (VTA) to the limbic system (amygdala, nucleus accumbens - also called ventral striatum, hippocampus - reward signaling has a big effect on memory through this pathway), to the cortex. Implicated, especially via D2 receptor subtype, in reward processing, and reinforcement. This path is hijacked in all addictions. D2 receptors are important for reward processing. This circuit is critical for wanting things in life but not for enjoying it once you get it, wanting = dopamine, savoring = opiod, cannabinoid. Addicts – they don’t even enjoy it after a certain part, need substance just to be at homeostasis, minimal pleasure while having it, all of this part of the basal ganglia – motivational and motor circuit, the two are coupled, contentment is not necessarily a dopamine state. Ventral striatum, nucleus accumbens, caudate, putamen, all part of the basal ganglia.
Mesolimbocortical dopamine pathway
Central to reward processing, hedonic emotion, and goal-directed behavior. Implicated in incentive salience (part of reward processing), reward prediction error, and reinforcement learning. Incentive salience: pursuit or anticipation of rewards (as opposed to reward consumption). Wanting vs liking. Reward prediction error: discrepancy between predicted and currently experienced reward of particular event. Reinforcement learning: learning association between stimuli and reward receipt. - reward predicton – dopamine critical for learning, positive things in your environment, discrepancy between what you want and what happened, dopamine is critical (telling hippocampus to remember, it’s important, you learn more from discrepancy in expectation than everything running smoothly)
- depressed – reduced reward prediction, less reward-related learning, certain people have more or less response to the prediction
- reinforcement learning – dopamine is involved, mediated by dopamine, also about learning what you want and what is associated with it
- Example: single-unit recordings of dopamine neurons in nucleus accumbens, dopamine fires when you get food out of the blue (do it a lot, the neurons don’t fire to receipt, fire to signal that juice is coming, they transfer from initial learning to actual cue that reward will come – do not react to actual reward though now)
- Learning what predicts what you want
- Won’t have craving for food if inactive dopamine
- If reward is guaranteed, don’t really need the dopamine, a bit of uncertainty
Impulsivity and mesolimbocortical
Elevated dopamine signaling implicated in risky and impulsive behavior. Parkinson patients receiving dopamine agonists (L-Dopa) treatment is L-Dopa (precursor of dopamine), those that take this can be risky – brain gets into gambling or something. Rats injected with dopamine agonist (Pramipexole, PPX). PET in humans. Human PET study assessing dopamine receptor availability and dopamine neurotransmission in the striatum during amphetamine use. Elevated dopamine release in striatum important for understanding trait impulsivity. Dopamine centrally involved in psychopathology (depression, bipolar disorder, schizophrenia) and the chemical most implicated in addiction.
Norepinephrine
Amine, monamine, catecholamine. Norepinephrine functions in brain and body as a neurotransmitter and hormone. General function is to mobilize brain/body for action, stress, and fight-or-flight response. Referred to as noradrenergic. In CNS acts as a neurotransmitter. Released in locus coeruleus and lateral tegmental area in the CNS. Increases arousal, alertness, attention, promotes vigilance and enhances memory formation (binds to hippocampus, up-regulates consolidation). In PNS, norepinephrine is main neurotransmitter used by the sympathetic nervous system of the autonomic nervous system. Noradrenergic activation of sympathetic
nervous system prepares body for action and fight-or-flight response – increases heart rate, blood pressure, dilates pupils, etc. As a hormone, norepinephrine is secreted by the adrenal glands (alongside the kidneys) where it further mobilizes body for action. Norepinephrine functions as both a neurotransmitter and hormone, where epinephrine only functions as hormone. About vigilance, threat, anxiety, depression (general distress symptoms of it). Neurotransmission effects are focal/local – synaptic cleft. Hormones: released into your bloodstream, distributed and move throughout the bloodstream. Much less precise, much more diffuse with hormones, also longer lasting. Epinephrine is only a hormone, just a hormone. Norepinephrine – time, fast immediate with transmitter, hormone – slow, takes time (need both the fast and slow part to address stressful thing)
