Brain And Behavior 1: Molecular Basis Of Cognition Flashcards
How are neurons classified?
By their output/ what neurotransmitters they release
Differences between inotropic and GPCRs
Inotropic:
- ion channels
- rapid intracellular changes (seconds)
- ACh/GABA/glutamate neurons are most common
GPCRs (metabotropic):
- protein channels
- longer intracellular changes (minutes)
- catecholamines and muscarinic are most common
What is the most common neurotransmitter?
Glutamate
Glutamate and GABA neurons
Are seen in hierarchical neuron systems
- functions in sensory perception, motor control and some cognitive function
Are seen in myelinated neurons w/ long axons and interneurons
GABA = inhibitory Glutamate = excitatory
Monoamine neurons
Are used in diffuse neuronal pathways that regulate global functions
- disruption has complex effects that are widespread
Histamine receptor subtypes and clincial relevance
H1 = allergic responses and inflammation
- increases Phosphatidyl inositol turnover
- antagonists = anti these effects and weight gain
- increases phosphoinositide degradation
H2 = Promote GI reflux/bleeding
- increases local adenylate Cyclase production
- antagonists = treat peptic ulcers and these conditions
H3 = Sleep disorders, obesity and dementia
- antagonists = anti these effects
- decreased local adenylate Cyclase levels
NE receptor subtypes and clinical relevances
a2=
- decreases Adenylate Cyclase
- agonists for sedation and treat hypertension by vasodilation
A1 = agonists for “fight/flight”
- increases adenylate Cyclase
- vasoconstriction, increased BP/HR
B1 = agonists increase cardiac function
- increases adenylate Cyclase levels
- antagonists decrease anxiety (anxiolytic)
B2 = agonists used as bronchodilators
- increases adenylate Cyclase levels
Serotonin sub receptor types and clinical relevance
5HT1A-F
- activation decreases adenylate Cyclase and activated GIRK currents
- partial agonist = anxiolytic
- antagonists 5HT1B/D = triptans for migraines
5HT2A
- increases phsophatidylinositol turn over
- antagonist = antipsychotic effects
- agonist = induces hallucinations
Autoreceptors
Receptors that lie inside the cell body or terminal of the presynaptic neuron
- self-regulates the release/synthesis of the neuronal neurotransmitter
Neuropeptides (ACTH, GH, etc.)
Can act as transmitters, modulators or hormones
- MUST use axonal transport to get to the source of packaging (slower actions)
- do not always evoke an action potential
- most commonly used to modulate neurotransmitter actions
most commonly seen in conjunction with serotonin, NE and dopamine neurons
What factors does individual neuron growth depend on?
Genetic identity of the cell type
Neuronal migration to the appropriate region
Neuronal growth factors for cell survival
Functional activity of surrounding neurons
Arborization and synaptic pruning of the dendrites
general morphological of a neuron is help constant due to genetics, however the environment and epigenetic cues and alter the structure of the neuron to make it slightly different
Neuronal migration
Is responsible for the layered organization of neurons as seen in a cross section of the brain
- neurons when first developed use radial glial cells as a “scaffold” to migrate to where they are suppose to be, normally resulting in six neuronal layers in the mature cerebral cortex
disruption of cortical layers (looks disorganized) can be seen in autism (ASD)
Astrocytes functions
1) insulate groups and synaptic connections
2) regulate potassium concentrations
3) reuptake and recycle neurotransmitters
- very important in glutamate neurons
4) release of growth factors to surrounding neurons
Neurotrophic factor hypothesis
1) Neurons extend their axons to target cells based on the levels of neurotrophic factors being released.
- more growth factor/neuropeptide = grows well
- less growth factor/neuropeptide = apoptosis
2) Neurotrophic factors will only bind to specific receptors they are meant to bind to within the proximity of target cell producing them.
3) activated receptors on target cell (axon has connected to the receptor) generates retrograde transport of growth factors towards the cell body
- this ensures survival for the neuron and prevents apoptosis
4) astrocytes can release small amounts of neurotrophic factors to support crucial neuronal survival
5) when in stages of depression of isolation, can decrease levels of BDNF which results in decreased adult neurogenesis as well as regression or loss of function
- successful treatment can reverse this though
What are the three major neurotrophins?
Nerve growth factor
Brain derived neurotrophic factor
Neurotrophin-3
all neurotrophins interact with the transmembrane tyrosine kinase receptor (Trk) and induce dimerization and phosphorylation of these receptors
What subtypes of Trks bind to which neurotrophins
Trks = tyrosine kinase receptors that are transmembrane bound and are phosphorylated/dimerized when activated
Trk(a) = NGF
Trk(b) = BDNF
Trk(c) = NT-3
P75 = all 3 neurotrophins
What is the end effects of activating Trk receptors via neurotrophin interactions?
Novel neuron: has FRS2 protein
- increases MAPK transcription which leads to neuronal differentiation and novel neuron survival (multipolar/unipolar/etc.)
Mature neuron: does not have FRS2 protein
- increases PKB and Akt levels which leads to neuronal survival
- also inhibits caspase proteins which again leads to neuronal survival by preserving DNA stability
How due neurotrophins inhibit apoptosis?
Activation of Trk receptors increase PI3/Akt signaling which inhibits caspase enzymes (usually caspase 9, but can be any)
- caspase pathway results in DNA fragmentation and chromatin condensation -> cell death
Dendritic pruning
A whole bunch of dendritic branches are developed, but as stimulation is decreased on certain spines and increased on others (depending on usage), these are “pruned”
- pathways that are used often are kept around, where as seldom/never used pathways are signaled for apoptosis
- believed to be mediated by glial cells
this process once complete is call “mature dendrite arborization”
What is the time line for general dendritic pruning?
Synaptic density increases until at its peak around 7 years
- visual = 1 yr
- prefrontal = 5 yrs
- frontal = 7-8 yrs
Synaptic pruning occurs in adolescence generally, but all brain regions experience this at different times
Most of it (80%) is done by age 15
** schizophrenia is believed to be due in part from excessive synaptic pruning. This cause is unknown for sure but believed to be due to abnormalities in microglia.**
Minocycline
A tetracycline antibiotic that cannot be used in young-children or pregnant mothers because it is known to reduce synaptic pruning
- is hypothesized to help schizophrenia and ASD patients due to their natural deficiencies in synaptic pruning.
Can excessive experiences increase cortical representation in previously atrophied areas ?
Yes, it is challenging and takes time but previously atrophy or pruned areas can be regenerated slowly
Are density of cortical synapses and function directly correlated?
Yes but a decrease in cortical synapse numbers does NOT guarantee a loss of function
- instead can heighten one pathway greatly and decrease other small pathways.
What aspect of the brain is directly correlated with social and cognition in children?
Uncinate Fasciculus
- in normal children = well developed
- in socially deprived children = poorly developed and organized
How is neurogenesis affected by depression and depressed states?
Is decreased as well as BDNF release
- implies depressed patients also have less synaptic density available
Treatment of depression increases synaptic density and BDNF release
Dopamine receptor subtypes
D1,D5:
- increase adenylate Cyclase
- D1 agonists = treat Parkinson’s
D2,3,4:
- decrease adenylate Cyclase
- D2 antagonists = antipsychotics
- D3 agonists = treat Parkinson’s
