Neurobiological MechanismsI. A slice of the nervous system (LTP and LTD)A. Long-term potentiation (LTP)1. First discovered in the hippocampus2. Researchers knew that they hippocampus is evolved through learning and when it is damaged (through things like Alzheimer’s) there is a lack of learning and memory3. If we want to study how neurons work, we need to put it in something that will keep them alive, as well as their architecture preserved to study their propertiesa. When you section the hippocampus, it stays together – makes it very simple to study4. Demonstration of LTP hippocampal neurona. Neurons project in on a perforant path and contact the cell bodies of the mossy fibersb. To study: stimulate pertinent path and recordc. Low intensity input  low intensity outputd. Strong intensity input  strong intensity outpute. Mild intensity input  stronger outputi. This is the phenomenon of long term potentiation5. Properties of LTPa. Induced by brief stimulationi. Can encode brief stimulationsb. Input specificityi. The only input that is strengthened is the one that is active (releases glutamate)ii. Only inputs that are active are strengthenedb. Cooperativityi. Suppose you have two medium inputs; each alone will produce a medium response (not enough to produce LTP though)What is nice is that the two can work together to produce the required depolarizationii. Multiple inputs can work together to induce the depolarization to produce LTPb. Associabilityi. Now we have two inputs: one weak (alone could never produce LTP), one strong (alone, it will produce LTP)ii. If inputs are implemented at the same time, the weak input gains from the strong input to produce the required depolarization for LTPiii. Think of it as Pavlovian conditioning: Weak = CS; Strong = USWeak gains from the strongiv. Associability readily produces an example of Pavlovian conditioning2. Neurochemical mechanisms (review)a. NMDA receptor is a gated channel that is blocked by magnesiumi. For the channel to work, you need magnesium to be dislodged, as well as glutamate released from the pre-synaptic cellii. Two events:Pre-synaptic – glutamate releasePost-synaptic – strong depolarization (dislodging of magnesium will induce this)b. If these two things occur, a change will be seen in the channeli. Change is produced by the AMPA receptorc. NMDA then allows calcium into the celld. AMPA receptor is modified and supercharges, which allows sodium into the celle. Also moves more AMPA receptors to the active zonef. Donald Hebb:i. Said that “neurons that fire together wire together”  that is what is happening hereg. These properties then yield the features of the synapse that researchers have found the NMDA receptors to be so interestingB. Long term depression (LTD)1. Cells are stimulated at 100 Hz; if you stimulate the cell at a lower frequency (1 Hz) you will see a depression2. Also relies on NMDA receptors3. Could be due to amount of calcium in the cell:a. Low frequency = low calciumb. High frequency = high calcium4. Low frequency stimulation = LTD5. High frequency stimulation = LTP6. Stress and other negative factors can cause LTD and prevent LTP – reasons for this are unknown7. May prevent saturationa. Suppose in a system we only have LTP – every connection will be strengthened and each input will produce each outputi. Network is now saturated and cannot represent distinct patterns of outputb. LTD acts to weaken connections in these situations to keep the system in an operational range and allow the different inputs to result in different outputsC. Long term mechanisms yield structural modifications1. If we repeatedly induce LTP in the same place, we will induce protein synthesis which will ultimately result in structural modificationLinking LTP/LTD to BehaviorA. Pharmacological studies1. Antagonists: APV (AP5) and MK-801  unsure what is being blocked here, LTP or LTD (Robitussin is a similar drug)a. Affect induction, not expressionb. Block NMDA receptorsc. If the antagonist is given before the LTP is induced, the induction of LTP would be blocked because you have to NMDA receptors to get processes going to modify the synapsed. Once LTP is induced, and then put the antagonist into the system, nothing will occur because you do not need the NMDA receptorse. Blocks the induction of LTP, not the expressioni. Depends on the AMPA receptorii. Blocks “new learning” but not “retention retrieval”2. Impact on spatial learninga. Platform in a water trough maze: if you take away the platform, the rat will go into the maze looking for the platform in the general area it was located previously– this shows that they have spatial learningi. Requires the hippocampusii. If a cue is involved, no hippocampus is requiredb. Give the rat MK-801 prior to training and bring them back the next day, they have no idea where the platform was – drug went everywherec. If the MK-801 is directed to go only to the hippocampus, learning is again disruptedd. MK-801 blocks learning, but does not block retention retrieval when the rat is tested later3. Impact on fear conditioning (Fanselow)a. Context  Shock (day 1, day 2 situation)b. Hippocampus is needed to encode a configuration of cuesc. If you microinject AP5 into the hippocampus before context conditioning, the rats do not freeze the next day – blocks learning about the configuration of cuesd. If you wait to give AP5 to rat on day 2, learning is not effected  they will freezeGenetic ManipulationsA. Gene targeting: knockout and transgenic1. Need other tools to get to intracellular cascades2. Genotype – the genes you are born with (get from mom and dad); identical twins’ genes are not the same3. Phenotype – how the genes are expressed4. Many people studied fruit fliesa. Would radiate them and then put them through various learning testsb. If they had dumb fruit flies, they would work backwards to figure out what the cause wasc. Result: these mutations were caused by faulty/negatively mutated genes present in the genome5. Two basic procedures used here:a. Knockout – do a genetic manipulation that takes out the particular gene (neurobox – chapter 11)i. The mouse can no longer make said geneii. Have to ensure to target a gene that plays an important role, but is not vital to lifeb. Transgenic – insert a new gene that the mouse may never have hadB. Evidence1. Impact of knocking out CaMKII (alpha subunit) (Silva)a. Disrupts hippocampal LTP and spatial