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neuro
11/21
hand

neuroplasticity

plasticity: the ability 
of the nervous system to adapt or adjust functionally/physiologically 
(that you can't see) and/or anatomically (you can see the change) to 
changes in the external or internal environment, or to PNS/CNS damage, or 
changes in its activation.

much of our remaining study in neuro will 
involve how nuclei interact with eachother in pathways, and how these 
connections permit the organism to exist in the environment, to record 
sounds and visual input, to navigate the environemnt, pathways dealing 
with touch, chemosensory (taste and smell) and how organism uses info to 
locomote in environment and regulate behavior. so we're studying hard 
wiring, static properties of CNS. 

this hard wiring is specified by 
genetic and normal developmental processes, but nerve cells aren't just 
static, they have dynamic properties that can change - structure and 
function - based on amount and type of info being recieved. the ability 
of the NS to change like this, functionally and anatomically, is called 
neuroplasticity.

some of the conditions which produce the change are 
damages to PNS, trauma to CNS, neoplasms that are growing in CNS that 
interrupt or change input, strokes, which produce alterations of 
remaining fiber systems, hopefully allowing for some recovery of 
function. 

however, those are rather severe changes going on in the NS 
following trauma and neoplasia, but the NS can also change by more subtle 
things, in a day to day way, with learning, memory, etc. these are more 
physiological. this is important b/c it allows organism to change 
behavior, giving characteristics of individuals. this latter type of 
neuronal change is more physiological, and is called activity dependent 
plasticity. it's one of those types that results from "use it or lose it" 
situation. if you use a certain feature - if you type every day the 
typing center will be well represented. if you stop doing it, that area 
of the brain will be reduced. there is a competition in your NS for 
territory and function - a waxing and waning of various types of sensory 
sytems and motor systems. it involves our daily experiences. again, those 
changes are more subtle than those following trauma or neoplasia.
they 
are occuring at a molecular level and you can't detect them visually.


this plasticity allows NS to adjust to changes in the world, allows 
animal to adapt, change behavior, etc. not all these adjustments are 
positive. there are maladaptive types of plasticity eg wrt chronic pain, 
a CNS plasticity that is maladaptive or destructive - can be devastating 
- eg, a leg is removed and someone can have phantom pain, due to a CNS 
plasticity phenomenon. it's not useful and it is a big problem. so not 
all plasticity is positve. 

plasticity as you might think is most robust 
in the young animal, where the hard wiring isn't fully developed yet. 
then, changes that occur in certain critical developmental periods are 
very important. so animals deprived of sensory input at an early age 
don't develop robust connections. there is hope for some of us as adults, 
plasticity also occurs in the adult NS that is hard wired, based on 
activity dependent changes - but this is less robust than in young 
animal.

continuing with intro - there seem to be three changes of 
synaptic modification or plasticity in CNS

first stage: synapse 
formation stage. occurs mainly in developing animal. this is under direct 
genetic and developmental control. GCN with VPL to somatosensory area I - 
this happens regardless of animal getting sensory input. it's genetic. 


second stage: fine tuning - validation stage. this occurs at certain 
"sensitive or critical period" when synaptic connections are established 
but immature and sensitive. here, the amount of sensory activity has an 
important influence on the connections. here it is important to have 
normal input - if young animal is deprived of normal input it will not 
develop robustly in this stage. this may be irreversible. this is 
activity dependent

third or final stage: adult. this is the stage that 
regulates in a transient and long term way the synaptic connectivity in 
the NS. based on day to day experiences. while we exist in environment, 
you might start to play the guitar - won't be as easy as if you started 
in childhood, but the areas involved can become fine tuned and enriched 
in the brain, you can increase synaptic contacts and give those areas 
greater representation - but these changes aren't as robust as they would 
have been in second stage. 

all this is adding up to the implication 
that behavioral potentials are laid down genetically but must be 
developed through environmental and behavioral factors, and use. they are 
activity dependent.

in the lecture we will get results of a few seminal 
studies on some mechanisms of neuroplasticity based on snails, and some 
studies that illustrate mammalian NS plasticity - based on the rat and 
the whisker system, which is elegantly organized. also some monkey 
studies. again, b/c mammalian NS is so complex, PIs often try to use 
simply organized animals - the snail which has 20,000 neurons is a lot 
easier than a mammal. there are also very simple defensive reflexes in 
the snail. we're looking at reflexive learning in the snail. (Aplysia is 
the type of snail). another type of learning is sensitisation, which 
sensitizes your NS so a light stimulus seems stronger, or conditioning, 
is another type of learning.

learning: the neural events underlying 
acquisition and storage of information obtained from experience which can 
then result in short or long term memory

recovery: events underlying 
restoration of function after specific PNS or CNS damage. 

in learning 
there are several major theories, most of which can be shot down. one is 
that there are learning or memory centers in the brain - that's pretty 
bogus. it has been shown that it's not true. hippocampus has a role in 
short term memory and temporal lobe has a role in long term memory, but 
they have other functions and are parts of longer pathways anyway. there 
is no such thing as learning center - learning and memory involve 
circuits that are already there and may be doing other things. 

short 
term memory used to be thought of as a system of reverberating neural 
circuits - little loops that self perpetuated - but this isn't true 
either based on Aplysia study which shows that memory and learning use 
existing nonreverberating circuits.

long term memory - weeks and longer 
- this isn't clear - there is some thinking that it isan extension of 
short term memory (true) but also involves synthesis of new proteins and 
growth of not new synaptic connections (well, sometimes it does that) but 
enhancement of the existing synaptic connections occurs. probably there 
is some truth in the synthesis of new proteins part.

moving on to actual 
mechanisms of learning based on Aplysia study:

basically you have a 
tail, a siphon, a respiratory gill, and some other parts of the animal 
(mantle). some of these parts of the marine snail when activated by 
touch, shock, nociceptive stimulus - will produce withdrawal of siphon 
and gill as part of a reflex arc involving sensory neurons. there are 24 
sensory neurons connecting through interneurons or directly to the six 
motor neurons which produce the gill withdrawal. if an animal is 
stimulated by touch on the siphon, it will cause through these 
connections a withdrawal of th egill. 
with repeated stimulation (light 
tactile stimulation) snail will get habituated to ignore the stimulus and 
no longer produce the withdrawal, b/c it learns it isn't a danger. what 
seems to be happening is that with repeated stimulus coming to 
presynaptic terminal, the Ca++ channels  become fatigued. they release 
all this Ca++ to allow NT release, but eventually they become exhausted, 
and the following impulses do not produce as much NT and finally the gill 
won't retract anymore. so habituation is a decrease in response strength 
when a stimulus is repeatedly applied, based on calcium channel fatigue


sensitization: this is where the marine snail gets a nociceptive shock on 
the tail, which causes a brisk gill withdrawal. it is through a 
facilitating interneuron which releases serotonin onto the presynaptic 
area of the neurons on the siphon skin - so serotonin causes presynaptic 
facilitation of input from the siphon skin. then, if you lightly touch 
the siphon skin, the animal will withdraw the gill defensively. even if 
you do it enough so that you should produce habituation, snail doesn't 
get habituated. so serotonin binds to serotonin receptor and via G 
protein produces cAMP which then links up with kinases which then go in 
and do several things - it will shut down K+ channel which tends to 
repolarize the ending which would make nerve ending not fire- so membrane 
stays depolarized longer- membrane has lower threshold - so now the Ca++ 
channel remains open to release more Ca++ which produces more NT release. 
the cAMP kinase really also through noncalcium mechanism will also 
encourage vesicles through an unknown mechanism to go to the active sites 
on presynaptic membranes and make themselves more available to release NT 
which they will. so this is sensitizing the presynaptic terminal, getting 
it totally ready to release NT - so now you need less of a stimulus to 
make it release NT. 

now, if these changes go on long enough, b/c this 
is kind of a short term memory thing, if it goes on longer, the longer 
you keep the shock to the tail going, the longer the sensitization - 
instead of minutes it may last days to weeks. say instead of one time you 
stimulate with noxious stimuli four times. then the sensitization may 
last not just hours but perhaps weeks. so in the short term, there is 
some longer lasting effect by increasing the sensitization stimulus

with 
habituation if you use the benign stimulus repeatedly and repeat over 
several sessions, this is also going to last for several weeks. if you 
only do it over one session, it doesn't last as long.

if this goes on 
long enough you get into a situation of chronic changes that may occur. 
so with a sensory neuron ending on the dendrite of a motor neuron - with 
long term habituation you may have a shrinkage of synaptic endings - 
fewer axonal connectinos to the dendrite. with sensitization long term 
you may get increased synaptic endings of the axon on the dendrite. also 
with habituation will have fewer vesicles/NT, and with sensitization more 
vesicles/NT. eventually these changes will impact the morphology, in 
other words. 

another type of learning , more complex, kinda like 
sensitization but it's important that there is an association b/w the 
benign stimulus and other stimulus - so if you were shocking the tail of 
the snail you'd have to pair that with a benign stimulus in a certain 
narrow range to get conditioning - which is more robust in sensitizing 
interneurons and motor neurons of gill reflex than is sensitization. what 
occurs is you must pair the light tactile stimulus with the nociceptive 
stimulus. the light tactile stimulus of the mantle is applied about 1/2 
second before applying nociceptive stimulus to the tail. the light 
stimulus is the conditioned stimulus and it doesn't cause reflex activity 
on its own. nociceptive stimulus is the unconditioned stimulus, is very 
strong, works through facilitating interneurons/serotonin to produce 
sensitization of conditioned stimulus.
the mechanism for this is 
important for learning, training, etc. first, the conditioned stimulus 
permits an influx of calcium. Ca++ channels are open and Ca++ enhances 
calcium dependent adenyl cyclase, which binds to calmodulin, prior to 
unconditioned nociceptive stimulation. then unconditioned stimulus comes 
along, serotonin release, binds receptor, binds adenyl cyclase which is 
bound with calmodulin, and you change the conformation of adenyl cyclase 
so you increase conversion of AMP to cAMP. with that extra cAMP you 
activate the protein kinases that are cAMP dependent, you increase NT 
release, you mobilize NT vesicles, etc. this is a more complex form of 
sensitization b/c it requires a weak conditioning stimulus which is weak 
and normally doesn't do much AND a more robust, closely associated 
stimulus applied shortly after conditioning stimulus. eventually the 
conditioning stimulus itself will produce the reflex.

this drives home 
the important role of transduction mechanisms in phenomena of learning, 
which exists in pathways, not in circuits or particular areas, and which 
uses the same pathways that exist for other purposes. again, it dosen't 
involve independent processes - changes existing connectivity.

keep that 
stuff in mind. 
now, other stuff.

we're shifting away from the 
anatomical changes here b/c of time constraints. under mammalian 
plasticity - we're not talking about sprouting - we'll talk about 
functional changes b/c this is what translates into behavioral changes. 
the rat has these 35 long whiskers or vibrissae. these vibrissae on the 
face are in 5 rows of 7 and eventually they connect with some neurons in 
layer 4 of somatosensory cortex. not only that, the pattern of the 
whiskers is mirrored in the pattern of the neurons in the CNS. so by 
changing activity of whiskers you can look at plasticity in NS> 

since 
there is such discrete connectivity in cortex, you know the relationships 
are maintained on the way up. central process comes with trigeminal nerve 
to brainstem trigeminal complex and each whisker goes into its own area, 
and then the trigeminal complex through thalamic tract goes to VPM, and 
there are cell aggregates there in the same pattern, and then from here 
it goes to somatosensory cortex. 

if you activate one whisker for 45 min 
following injection of radioactive metabolism marker (like glucose), you 
follow into the brain, which uses glucose for metabolism, the stuff 
accumulates in areas of activity - so you can trace it through pathways 
and infer function through this since amount of tracer will correlate to 
amount of activity. you will see a single column through the cortex - one 
spot will light up for a single whisker. there is functional and 
anatomical localization. if you denervate the whiskers all except one on 
one side, and then leave the other side ok, and allow animal to exist for 
45 or so days, and then clip the good whisker, and see what happens in 
the brain - the whisker which had working whiskers around it has smaller 
representation than the whisker which was alone on the side of the face 
which takes up more of the cortex.

in an older animal, if you do this, 
there is still some effect, but less so.

more remarkably - if all 
follicles were removed from one side of a young animal, and the forepaw 
is activated, you don't see any activity in the face area on the normal 
side. but on the side where follicles were removed, forepaw activity will 
show up in the face area as well as in the forepaw area - the forepaw 
took over that area which was deprived of input. 

what we did in another 
animal is that they clipped the whiskers but didn't really do 
deafferentation - not making any true injury. just clipped whiskers so 
they don't get bumped. still - the whisker which had normal length 
neighbors has normal cortical representation. the whisker which has 
shortened neighbors has increased cortical representation. same thing in 
adult, but less so. 

if you stimulate one whisker for 5 minutes a day, 
representation of that whisker shrinks. this is habituation. but if you 
feed the animal glucose water (unconditioned) and stimulate whisker 
simultaneously (conditioned stimulus) there is an increase in 
representation of the whisker - so size is affected by context of 
stimulus. this is important - if patients in rehab are exercising out of 
context, they get habituated, but if you use conditioning stimulus they 
may do better. 

also - if median nerve is damaged, ulnar nerve can 
occupy some of that area in the cortex of the monkey. so if one 
peripheral nerve is damaged, another one may capture that cortical 
territory.

also if a monkey is asked to put a finger onto a rotating 
wheel in response for a food reward, the areas of the representation of 
the fingertip got increases in cortical representation.

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