Neuroplasticity Flashcards
What is neuroplasticity?
neuroplasticity is the brains ability to reorganize and restructure itself…
what are the 4 things that neuroplasticity can include?
- formations of new neurons or death of neurons
- formation of new neuronal connections or loss of connections
- strengthening or weakening of existing neuronal connections
- during the process of drug addiction/ dependence, the brain undergoes significant plasticity (involves learning)
What are some common changes to neurons at the cellular and molecular level thought to underlie addiction in chronic users?
- theres changes in neuronal structures, neuronal growth factors, and proteins that alter gene expression
drugs decrease neurogenesis in the hippocampus which is linked to memory issues in animal models
What are dendritic spines? where are they located?
dendritic arms are covered in spiny extensions, and their shape and number of those spiny extensions changes with learning, stress and drugs
spines in the nucleus accumbens are where synaptic contacts are made with other neurons
dendritic spines are the major site of mostly excitatory inputs from other neurons originating in diff brain regions mostly the PFC (because spines have receptors for glutamate) but also in the hippocampus and amygdala
What is the structure of the dendritic spine skeletons? what are they made from?
the dendritic spine heads are rich in a cytoskeleton protein called actin
the skeleton of dendritic arm, the spine and the connecting excitatory input
to change the shape and density of the spines, actin rearragenemnts is necessary
the tip of the projections contains glutamate receptors
drugs seem to modulate genes for the cytoskeleton cause by release in ERK protein pathway
what effects do opiates, and stimulants have on dendritic spines? what effect do they have on the VTA?
opiates like morphine and stimulatns like cocaine and amphetamines have opposite effects on dendritic spine formation, which means it has an effect on their number. Optiotes have less spine formation and stimulants have more
the size of the VTA cell body is also decrfeased by optiates
what is synaptic plasticity of dendritic spines though to be the basis of?
experience-dependent learning and memory
what kind of role does glutamate play in dendritic spines?
glutamate plays a role in mediating memory related processes by strengthening synaptic connections, and the spines where we find many of the glutamate receptors are on the medium-spiny neurons in the nucleus accumbens
how did a single dose of cocaine exposure lead to long-lasting receptor differences? what is the experiment? how did this show the changes in neuronal structure and glutamate receptors?
looking at the ratio of AMPA receptors to NMDA receptors tells us how much glutamate is released. In naive, less experienced drug users, the overal calcium flux is due to NMDA receptors working instead of AMPA receptors
in long term users, the calcium influx is from AMPA receptors than NMDA receptors.
AMPA allows more calcium entry that might trigger changes in the spine.
single injection of cocaine alters the density of spine sin speficic dopamine neuron populations in the VTA arae of rats
only neurons with increased spine density showed change in glutamate receptor ration
more spines means more potential for excitatory input from other neurons originating from other brian regions
this might underlie the learning associated with the acquisition of addictive behaviours
when comparing saline and cocaine results, the saline showed less spiny neuron amount vs. cocaine which had alot
how do cues associated with drug taking trigger increased spine density in nucleus accumbens?
- the experiment:
rats wer trained to press a lever to obtain cocaine.. each time they received cocaine, a light flashed, the behaviour was then extinguished, and they could still press the lever but get no reward, no light until they eventually rarely press the lever… the extinction of the behaviour lead to dendritic spine head diameter returning to normal
to trigger a relapse or reinstatement, rats randomly pressing the lever would also see the light stimulus again… this resulted in RAPID (15 minutes) increase in dendritic spine head size in the NA and increased lever pressing
it also elevated the AMPA/NMDA raito within 15 minutes
this was prevented by lesioning glutamate projections from PFC to nucleus accumbens which tells that us that the changes are due to other areas of the brain flooding nucleus accumbens with glutamate like PFC
what is the mechanism behind the change of density of dendritic spines when addicted? What is the role of BDNF?
it is said to be caused by differences in types of glutamate receptors which lead to increased calcium influx
BDNF (brain derived neurotrophic factor) plays a key role because calcium influx stimulates BDNF levels that persist during abstinence (more spines, increased cell body types).. whereas morphine reduces BDNF levels causing fewer spines, decrease in AMPA glutamate receptor levels
BDNF affects the ERK pathway along with several others involved in neuronal survive and growth
these pathways affect genes that code for cytoskeletal proteins involved in spine formation
so BDNF is involved in changing structure of dendritic spines and stimulants cause more BDNF to be released and depressants cause less.
What is the idea behind neurogensis now-a-days? can we build new neurons ? what was the view on this before?
until the 1990’s it was though that we couldnt grow new neurons
evidence recently accumulated suggesting some brain regions did produce new neurons in adult animals
new growth seems to be linked to a healthier brain
new neurons in the hippocampus is now thought to be essential for animals to tell the difference between cues that signal either pleasant or unpleasant experiences .., learning stops if u supress neurogensis
what are four things that inhibit neurogenesis?
- corticosteriods (cortisol) … long term stress
- anxiety
- depression
- addiction.. inhibits BDNF
what are four things that stimulate neurogenesis?
- enriched environment
- physical exercize
- antidepressants
- ECT
where are three main areas where new neurons grow in brains of adults?
- thin layer of stiatal tissue called subventricular zone that lines the lateral ventrcile
- a section of cells in the hippocampus called the subgranular layer of the hippocampal dentate gyrus
- olfactory bulb
which area of the brain shows altered neurogenesis in response to drugs?
hippocampus
How do you measure new growth in the hippocampal area?
you introduce a compound called brdU - bromodeoxyuridine which will only interact with DNA that is being activetly replicated
brDU mimics the natural constituents of DNA (thymidine) and gets incorperated int onew DNA strands as neurons divide
an antibody to brdU will produce a singla to identif the cells that have brdU in their DNA
what is an example of diving neurons incorporating brDU?
in the SGZ (subgranular zone) progenitor cells arise, and once they are born, they migrate to the granular cell layer (GCL) where they mature and establish contacts with other neurons
the brdU shows bright green areas showing this movement of new cells into the GCL after birth
approx how many thousands of neurons are generated daily from stem cells in the adult rat hippocampus? and what is happening to the other cells in hippocampus?
on thousands neurons are generated daily
there are also ten thousand immature cells migrating into dentate gyrus granule layer which has a mature cell population of approx one
what conditions are linked with hippocampal dysfunction that could be most likely due to imapirement of neurogenesis in hippocampus?
conditions such as schizophrenia, major depressive disorders, mild cog disorders linked to short and long term memory storage and spatial memory occur
How does chronic cocaine use affect neurogenesis?
chronic cocaine causes significant decrease in BrdU incorporation due to decreased proliferation
similar results with single exposure
cocaine prevents new neurons from being formed
how does binge ecstasy use affect neurogenesis?
ecstacy is MDMA which is a stimulant
short term heavy dosing did not decrease neurogenesis but decreased the survival rate of newly formed cells … which means that overall neurogenesis was decreased
it likely has a toxic effect on vulnerable new neurons
How do methamphetamines affect neurogenesis? (a stimulant)
impairs both proliferation of cells and their survival
How do caffeine affect neurogenesis? (a stimulant)
also inhibits neurogenesis and results in memory deficits in certain types of test
How do nicotine affect neurogenesis? (a stimulant)
impairs neurogenesis and certain types of memory
how do chronic optiates affect neurogenesis? (an opiod)
acute morphine had no effect on neurogenesis but chronic morphine (5 days of exoposure) did have an effect
self administration of heroin seems to be linked to decrease neurogenesis
narcots had no effect initially but did after 5 days
What happens when neurogenesis is experimentally inhibited?
looking at how animals react to drugs when neurogenesis is inhibited by using targeted x-ray irradiation of hippocampus of rats and then see how they are affected by cocaine
in terms of dose response –> they needed more to reach optimal
in terms of dose intake –> they took higher doses
in terms of progressive ratio –> they work harder for it so they find it more rewarding
together this shows that animals are more vulnerable to addiction when theres decreased neurogenesis
what kind of behaviours does inhibiting neurogenesis impair?
it impaires stopping a behaviour (aka extinction)
experiment:
rats were told to press a lever to get cocaine, and then they were weened off of it so that when they pressed it they got no cocaine
in irradiated animals, it was harder to stop a behaviour that previously rewarded them with drugs when they were placed in a chamber in which they previously received drugs…
normal rats gave up easier at about 2 sessions but irradiated rats took 4 sessions
this behaviour might be associated with drug use bc lack of association with environment and memory formation
what is the role of hippocampal neurogenesis in addiction and dependence
it plays a role in learning and memory especially associating place with events (contextual memory)
a dysfunction can lead to deficits in memory processing of drug associated cues and context and ehancement of drug reinforcement learning
new neurons have been shown to be important in determinign difference between safe and aversive dangerous cues so thats why when u dont have them u have less inhibition of stopping the drug
there is also evidence that the lack new hippocampal neurons results in excessive glutamate release form the hippocampus onto PFC and NA, int he presence of drugs and cues
excessive glutamate in PFC is correlated with loss of neuronal mass and dysfunction which can lead to poor decision making
excessive glut release at NA may lead to excessive stimulation ad general dysfunction (ERK protein)
what are 4 possible factors for impaired neurogenesis?
- some drugs have been shown to affect the hypothalamus-pituitary-adrenal (HPA) system that governs the corticosteriod levels (cortisol) but that doesnt seem to play a major role in inhbiting neurogenesis during drug taking
- dopamine receptors are present in the hippocampus and drugs that active these receptors can inhibit neurogenesis
- some drugs cause oxidative stress that damages the mitochondria in developing neurons (makes oxygen free radiacals and causes apoptosis)
- some addictive drugs influence levels of growth factors such as brain-derived nedurotrophic factor (BDNF) or endothelial growth factor (VEGF)
What is the exception to the neurogensis and drug rule?
cannabidiol is the component of cannabis plants but not THC
it appears to increase adult neurogenesis and has no effect on learning ability in mice
it increases cell survival and maturation
THC on the other hand… reduces learning ability in mice and has no effect on neurogenesis
the dentate gyrus contains cannabinoid type (CB1) receptors
