Learning and memory

What is learning?

What is learning?

• the response of the brain to environmental events

• It involves adaptive changes in synaptic connectivity which alter behaviour

How does learning work in the brain?

• the excitatory post synaptic potential (EPSP) is not great enough to fire an action potential

• If an association is made repeatedly, the synapses of both neurons onto the hippocampal neuron will be strengthened and a “lighter stimuli” will be sufficient to recall a complete memory

• Titanic stimulation increases number of synapses

Long-term potentiation (LTP)

process involving persistent strengthening of synapses that leads to a long-lasting increase in signal transmission between neurons

Hippocampus and learning

shape and anatomy means pathways can be easily distinguished and recorded from electrophysiologically (Bliss & Lomo, 1973)

High-frequency electrical stimulation (HFS)

induces a long-lasting enhancement of event-related potentials but does not change the perception elicited by intra-epidermal electrical stimuli delivered to the area of increased mechanical pinprick sensitivity.

Temporal properties of LTP

• summation of inputs reaches a stimulus threshold that leads to the induction of LTP (for example, repetitive stimulation (HFS))

Input specific properties of LTP

LTP at one synapse is not propagated to adjacent synapses

Associative properties of LTP

• simultaneous stimulation of a strong and weak pathway will induce LTP at both pathways – spatial summation, coincidence detection

Morris water maze

• test of spatial learning for rodents

• relies on distal cues to navigate from start locations around the perimeter of an open swimming arena to locate a submerged escape platfrom

• One prevalent disadvantage is its undulating stress on animals due to the maze-aversive condition

– parameters:

• Escape latency (training)

• Time in quadrant (probe trial)

• Annulus crossings (probe trial)

Lesion studies - hippocampus

• directly relate brain dysfunction — in the form of a lesion — to behavioral deficits.

• Control rats acquired the learning patterns and their time in reching platform decreased, along with their time spent in non-target quadrants

Glutamate effect on LTP

• LTP induction and maintenance require optimal glutamate extracellular concentration

• Glutamate binds to several different sub-types of receptors on the post-synaptic neuron (AMPA, NMDA)

Glutamate release on inactive cell (membrane at resting potential)

• AMPA receptor activated to create EPSP

• NMDA receptor blocked by Mg2+ ion

• Depolarization from AMPA activation not sufficient to expel Mg2+

Glutamate release onto an active cell (membrane depolarized)

• AMPA receptor activated

• Mg2+ block on NMDA receptor relieved

• Na+ through AMPA and NMDA channels

• Ca2+ through NMDA channel

Role of NMDA in LTP and learning

• the predominant molecular device for controlling synaptic plasticity and memory function.

• the receptor is a synaptic coincidence detector that can provide graded control of memory formation.

CaMKII (molecular switch) sustained activity after depolarization

• Ca2+ entry through the NDMA receptor leads to activation of Calcium calmodulin-dependent protein kinase II

• CaMKII becomes phosphorylated, when this is constitutively active no longer requires Ca2+

• Maintains phosphorylation, insertion of AMPA receptors after the depolarizating stimulus has left

• Molecular switch maintains increased excitability of neuron for minutes to hours

Presynaptic events in LTP

long term potentiation can also involve presynaptic events

— postsynaptic neurons can feed back to presynaptic neuron by retrograde neurotransmitter

1. Ca2+ through the NMDA channel activates Nitric oxide synthase

2. Nitric oxide diffuses from site of production and activates guanylyl cyclase in the presynaptic terminal

3. Guanylyl cyclase produces the second messenger cGMP

4. Signal transduction cascade leads to increased glutamate release from the synaptic bouton

Late phase LTP

• lasts hours, days or months

• requires new protein synthesis

• can involve morphological changes and the establishment of new synapses

Early phase LTP

• lasts a minute to an hour

• explained by the actions of Ca2+ through the NMDA receptor and subsequent enhancement of AMPA receptor efficiency, presynaptic events…

Long-term depression (LTD)

• Low-frequency stimulations causes the opposite reaction to LTP , we get a decrease in EPSP amplitude on further stimulation

• NMDA dependent process

• AMPA receptors are de-phosphorylated and removed from the membrane

• Low level rises in Ca2+ activate phosphatase rather than kinase

Tetanic stimulation

• artificially high stimulation – is there a physiological equivalent?

Theta rhytms

• hippocampal theta activity accompanies behaviour such as running, swimming, head movements and spatially orientated responses in the rat

• role in synchronising activity in different brain regions

• Depolarizing stimulation coincident with peak of wave generates LTP and coincident with through generates LTD

• disruption in theta waves causes deficits in learning tasks that are similar to those caused by hippocampal lesions

Enhancing LTP

genetically – increased amounts of a type of NDMA receptor (NR2B receptor) leads to enhanced LTP → Tang et al 1999

– enrichment

a) Enhanced acquisition in the Morris and water maze

b) Potentiated LTP

Age (diminished memory and LTP)

• decreased acquisition in the Morris Water Maze

• decreased LTP

• decreased expression of the NMDA receptors

Neuronal circuitry of conditioned fear

• unconditioned stimulus paired with conditioned stimulus for cued or contextual fear conditioning → conditioned response

• strong input from the unconditioned stimulus leads to depolarisation of the postsynaptic cell

• weak input from the conditioned stimulus is strengthened by the postsynaptic depolarisation leading to activation of NMDA receptors leading to LTP of this synapse