Learning And Ltd/ltp

Front 1

What is the evidence for the role of the hippocampus in declarative memory?

Back 1

Scoville and Milner 1957. Bilateral hippocampal removal as a treatment for epilepsy suffered by patient H.M., resulted in anterograde amnesia and explicitly identified the importance of the role of the hippocampus and temporal lobe structures in memory. HM lost approximately two-thirds of his hippocampal formation, parahippocampal gyrus (all his entorhinal cortex was destroyed), and amygdala. After the surgery, although H.M.’s short-term memory was intact, he could not commit new events to long-term memory. He suffered from severe anterograde amnesia, and therefore could not recall events which occurred only moments earlier once attention had shifted to something else. H.M. also suffered moderate retrograde amnesia, and could not remember most events in the 3-4 day period before surgery, and some events up to 11 years before, meaning that amnesia was temporally graded. However, his ability to form long-term procedural memories was still intact; he could still learn new motor skills.

Front 2

Describe the first study on LTP.

Back 2

Bliss and Lømo (1973). Repeated stimulation of the perforant pathway to the hippocampus produced a long-term potentiation of the size of the extracellular population response recorded in the molecular layer of the dentate gyrus of rabbits.

Increasing the rate of stimulus presentation from 0.5 per second to 15 per second for 15 seconds led to an initial strong facilitation of the epsp. This then declined rapidly at the end of the period of increased stimulation but then gradually increased to levels above baseline over a period of several minutes.

Front 3

Describe the neural connections in the hippocampus.

Back 3

The hippocampus has three main excitatory pathways from the subiculum to the CA1 region of the hippocampus. The perforant pathway runs from the subiculum to the to the granule cells in the hilus of the dentate gyrus. The axons of the granule cells form a bundle called the mossy fibre pathway that runs to the pyramidal cells in the CA3 region. The pyramidal cells of the CA3 region send excitatory collatorals (Schaeffer collatorals) to the pyramidal cells in the CA1 region.

Front 4

What happens short-term once calcium enters the cell?

Back 4

Once calcium has entered the cell, it binds to a protein called calmodulin to form a calcium/calmodulin complex (CaM) which can activate a number of protein kinases including calcium/calmodulin kinase II (CaMKII). CaMKII is implicitly required for LTP. Activation of NMDA receptors causes the translocation of CaMKII from actin filaments within the cytoplasm to activated synapses. CaMKII may then phosphorylate the AMPA receptors causing an increase in their conductance. i.e. the amount of positive current entering the cell for a given amount of transmitter. This effect occurs over a relatively short time period (seconds to minutes).

Front 5

What are the long-term actions of calcium entering the postsynaptic terminal?

Back 5

Calcium/calmodulin can activate adenlylate cyclase leading to the production of cAMP. cAMP binds to PKA which in turn activates MAPK. Both PKA and MAPK translocate to the nucleus and activate a transcriptional cascade beginning with CREB-1 which then activates CRE. This then can stimulate the production of a number of targets that lead to the growth of new synaptic connections.

Front 6

What is the importance of the hippocampus for spatial memory?

Back 6

Pyramidal cells in areas CA1 and CA3 of the hippocampus encode extra-personal space. In rats and mice, a given pyramidal cell will fire strongly whenever the animal is in a specific location in an environment. Because these cells respond only to specific spatial areas, they are called “place cells” (O'Keefe and Dostrovsky, 1971). This observation subsequently led to the hypothesis that the primary function of the rat hippocampus is to form a cognitive map of the rat's spatial environment. On exposure to a new environment, place fields become established within minutes. LTP is thought to provide a mechanism for the acquisition of new place fields, i.e. the acquisition of spatial memory.

Front 7

Describe some NMDAR subunits.

Back 7

NMDA receptors are encoded by 3 different subunits, NR1, NR2 and NR3. At least four isoforms of the NR2 subunit exist and these are called NR2A, NR2B, NR2C and NR2D. NMDA receptors are tetrameric and are composed of 2 NR1 subunits and 2 NR2 subunits. NR1 subunits bind the co-agonist glycine. NR2 subunits bind the neurotransmitter glutamate. The composition of the NR2 subunit depends upon the location within the CNS.

Front 8

Describe some experiments showing spine specificity of LTP, and action of calcium-sensitive molecules.

Back 8

Reviewed in Lisman 2012. Glutamate uncaging was used to stimulate single dendritic spines - spine specific potentiation was seen. CaMKII was transiently activated as a result. Over a prolonged period, there was an increase in spine volume and CaMKII translocation. These findings were taken from various papers.

Front 9

Describe a study on LTP and learning.

Back 9

Tsein 1996. Selective KO of NMDARs in the mouse hippocampus by specifically targeting expression of NR1 subunit. DG neurons were therefore normal.

LTP was unable to be induced in the KO mice in CA1. Shows NMDA dependance of LTP. KO mice were slower at learning the hidden platform task. However learning was normal in the landmark test.

Therefore: KO mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning.

However, learning was still present in absence of CA1 LTP, suggesting although it plays a part it is not crucial for spatial memory acquisition. Theses results have been debated.

Front 10

Describe a study showing action of CaMKII.

Back 10

Jourdain 2003. Intracellular application of autophosphorylated CaMKII to hippocampal neuron cultures triggered enhancement of synaptic response, filopodia growth, and spine formation. CaMKII blockade prevented synaptic enhancement and spine formation triggered by LTP induction. This provided evidence that CaMKII contributes to the control of activity-dependant plasticity.

Front 11

Describe the basic afferent inputs to the cerebellar cortex.

Back 11

Mossy Fibres:
Supply cerebellar cortex with information from motor cortex (via pontine nuclei) and sensory afferents (via spinocerebellar pathways).
Provide contextual information about movements.
Innervate granule cells (intrinsic to the cerebellum), whose axons bifurcate in the molecular layer to form

parallel fibres (PFs):
PFs supply Purkinje cells with excitatory, glutamatergic (AMPA and mGluR) input. Sufficient input causes simple spikes.

Climbing Fibres.
Originate from the inferior olive.
Have a one to one relationship with adult Purkinje cells
Signal errors in actual performance (external errors) or intrinsic internal errors. Cellular signal is a complex spike associated with a global calcium transient

Front 12

Describe the output of the cerebellar cortex.

Back 12

Purkinje cells provide the sole output from the cerebellar cortex. Contact 3 deep cerebellar nuclei.

1. fastigial nucleus. Involved in balance - sends information mainly to vestibular and reticular nuclei.
2. interposed nuclei
3. dentate nuclei
2 and 3 are involved in voluntary movement - send axons mainly to the thalamus and the red nucleus.

Front 13

What sort of plasticity occurs in the cerebellum?

Back 13

LTD.

Front 14

What was Marr's theory?

Back 14

1969. Input patterns in cerebellum caused a particular pattern of output. He thought the purkinje cell could learn to recognise a particular set of firing patterns, and fire as a result.

He thought the neural representation of movement could be provided via the inferior olive (CFs), with PFs providing "context" of movement.

Synapses from parallel fibres PFs-PCs are facilitated by PF and CF activity.

Therefore the role of the climbing fibre is to "teach" the cell. It senses when there has been a mistake, and teaches the PC to associate this with contextual PF input. He was wrong though - LTD not LTP.

Front 15

Describe experiment on cerebellar LTD.

Back 15

Ito 1982. Experiment on decerebrate rabbits. Conjunctive stimulation of a vestibular nerve (PF) at 20/sec and the inferior olive (CF) at 4/sec, for 25 sec per trial, effectively depressed parallel fiber to Purkinje cell synapses. The depression recovered in about ten minutes. This recovery was followed by the onset of a slow depression lasting for an hour. The depression was absent when the two inputs were stimulated alone. Further experimentation showed that it was mGluR-dependent.

Limitation: this could have been due to cell death. However CF responses remained constant. Only PF response was reduced.

Front 16

what is the physiology of cerebellar input?

Back 16

Voltage clamp recordings of PF stimulation show inward current is stopped by CNQX - therefore AMPAR-dependant.

Current clamp recording with tetanic stimulation of PFs show slow component of depolarisation which is mGluR-dependant.

There is a localised increase in Ca2+ as a result of stimulation of PFs. The increase at point of stimulation is quite long lasting.

In contrast, stimulation of CF produces cell-wide Ca2+ increase, therefore distributing the error message along the whole PC.

If PF stimulation precedes CF, you get summation of Ca2+ signal. Obviously, the best way to learn association is when priming occurs before stimulus. PF=priming, CF=stimulus. Therefore, the climbing fibre is the "teacher", PF is the associated factor, and the CF teaches the PF to elicit a response on its own.

Front 17

What are the molecular mechanisms behind cerebellar LTD?

Back 17

PF output is glutamate. Glu activates AMPARs on PC. With intense PF stimulation and subsequent glu release, glu can "spill over" the edge of the synapse, where mGluRs are found. Leads to activation of PLC, production of pip2, activation of tyrosine kinase, production of DAG etc etc. Elsewhere, CF input causes whole cell depolarisation and opening of VGCC, leading to global Ca2+ influx. Ca2+ combines with inositol phosphate (created as a result of concomitant mGluR activity) to mobilise internal Ca2+ stores. Therefore you have more calcium when PF/CF activity is coincident.

More calcium is though to activate PKC, leading to AMPAR phosphylation which for some reason in this context down regulates ion conductance, leading to LTD...

Also, PFs release NO, a highly diffusable neurotransmitter, which is thought to reinforce the above process through activation of cGMP, PKG, causing disinhibition of AMPAR phosphorylation through other pathway. This (NO) can spread - not hebbian.