Learning and memory

Question 1

What do we learn?:

Answer 1

• Remembering learning to ride a bike.
  
  • Remembering the dinner bell makes you hungry.
  • What are the molecular and cellular processes to account for learning and memory?

Question 2

Learning:

Answer 2

• Learning - the response of the brain to environmental events and involves adaptive changes in synaptic connectivity which will in turn alter behaviour.
  
  • Donald Hebb (1949) - suggested a hypothesis for how, through neuronal networks, the brain can process and store information:
  • “When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased”
    · “Cells that fire together wire together”
    · Strengthening and weakening synaptic connections in the brain provides a means by which learning occurs and memories can be formed.

Question 3

Sensory inputs from Grandma:

Answer 3

· Sensory inputs from Grandma processed and converge on a cell in the hippocampus - converge on the hippocampus
· Cell A - sensory input for sight of Grandma
· Cell B - sensory input for smell of perfume
· Initially an individual input might not be sufficient to stimulate the hippocampal neuron.
· The EPSP is not great enough to fire an action potential.
· If this association is made repeatedly, the synapses of A and B onto the hippocampal neuron will be strengthened, so that the individual inputs are sufficiently strong to fire the hippocampal neuron, and just the smell or a picture of Grandma is sufficient to recall a complete memory.

Question 4

Long term potentiation:

Answer 4

· Long term potentiation (LTP) - mechanism underlying synaptic strengthening
· Hippocampus - shape and anatomy means pathways can be easily distinguished and recorded from electrophysiologically.
· LTP has now been studied in most other brain areas too.
· Record from cells within the dentate gyrus - subsequent perforant pathway stimulation results in increase in EPSP amplitude (size).
· High frequency electrical stimulation (HFS) of the perforant pathway.
· One HFS - LTP lasts hours
Multiple HFS - LTP lasts days/months

Question 5

The hippocampus:

Answer 5

· Most talked about in learning and memory
· Where memory is easy to study, the hippocampus is seen to be involved
· Spatial memory is based on the hippocampus
· Memories that are used to study learning and memory are often based in hippocampus

Question 6

Long term potentiation (LTP) 2:

Answer 6

· Properties:
- Temporal - summation of inputs reaches a stimulus threshold that leads to the induction of LTP e.g., repetitive stimulation (HFS)
- Input specific - LTP at one synapse is not propagated to adjacent synapses (input specific).
- Associative - simultaneous stimulation of a strong and weak pathway will induce LTP at both pathways (Spatial summation)
- Coincidence detection

Question 7

LTP and learning:

Answer 7

· Is LTP is the mechanism underlying learning?
· Hippocampal involvement?

Question 8

Animal experiments - Morris water maze:

Answer 8

· Parameters:
- Escape latency (training)
- Time in quadrant (probe trial)
- Annulus crossings (probe trial)

Question 9

Lesion studies - hippocampus:

Answer 9

· The hippocampus is essential for spatial memory and learning
· The LTP experiments were in the right place

Question 10

Probe trials:

Answer 10

· Across trials it gets faster and faster until its plateaus swimming straight to the platform and a hippocampal lesion rat stays bobbing around in the water trying to find the platform for longer.
· Looking at acquisition across trials
· Control rat is spending significantly more time in the target quadrant than the other ones
· Whereas the hippocampal lesion track is spending an equal amount of time, not focusing on a specific quadrant

Question 11

Glutamate at its receptors - Neuronal transmission:

Answer 11

· Glutamate is released from a presynaptic terminal, lands on different types of glutamate receptor in the postsynaptic terminal.
· There’s AMPA and NMDA receptors
· AMPA channel open and sodium travels through
· NMDA has magnesium sitting inside the channel blocking movement of ions
· NMDA does not activate but AMPA does, so only EPSP is coming through AMPA

Question 12

Glutamate at its receptors - postsynaptic membrane in excited state:

Answer 12

· The resting membrane potential is going to shot up
· The membrane is going to be depolarised - so magnesium gets ejected out of NMDA receptor
· Channel is now open
· Much bigger EPSP when you have transmission through both receptors

Question 13

Role of NMDA in LTP and learning:

Answer 13

· Morris water maze task:
- NMDA antagonist (AP5) - no evidence of learning or LTP

Question 14

What’s happening at the synapse?:

Answer 14

· Glutamate release onto inactive cell (membrane at resting potential):
- AMPA receptor activated to create EPSP
- NMDA receptor blocked by Mg2+ ion
- depolarisation from AMPA activation not sufficient to expel Mg2+
· Glutamate release onto an active cell (membrane depolarised):
- AMPA receptor activated
- Mg2+ block on NMDA receptor relieved
- Na+ through AMPA and NMDA channels
- Ca2+ through NMDA channel

Question 15

What’s happening at the synapse? 2:

Answer 15

· Ca2+ entry through the NMDA receptor leads to activation of calcium calmodulin-dependent protein kinase 2 (CaMK2)
1. Phosphorylates existing AMPA receptors increasing their effectiveness
2. Stimulates the insertion of new AMPA receptors into the membrane
· Before - few AMPA receptors, small EPSPs
· After - more AMPA receptors working more effectively, larger EPSPs, LTP

Question 16

CaMK2 - molecular switch - sustained activity after repolarisation:

Answer 16

· Ca2+ entry through the NMDA receptor leads to activation of
· Calcium calmodulin-dependent protein kinase II (CaMKII)
· CaMKII has autocatalytic activity - becomes phosphorylated
· When phosphorylated is constitutively active - no longer requires Ca2+
· Maintains phosphorylation, insertion of AMPA receptors etc. after the depolarizing stimulus has receded
· Molecular switch which maintains increased excitability of neuron for minutes to hours

Question 17

Presynaptic events in LTP:

Answer 17

· Long term potentiation can also involve presynaptic events.
· Postsynaptic neuron can feed back to presynaptic neuron by retrograde neurotransmitter - Nitric Oxide (NO)
1. Ca2+ through the NMDA channel activates Nitric oxide synthase
2. NO 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

Question 18

Late phase LTP:

Answer 18

• Protein synthesis required for long-lasting LTP (days, months)
  
  • Protein synthesis inhibitors prevent the consolidation of longterm memories and LTP
  • Stages of memory formation
  • Acquisition (training)
  • Consolidation
  • Recall (testing)
  • Protein synthesis inhibitor injected just post-acquisition (training) inhibits recall
  • necessary for consolidation
    · CREB - a transcription factor
  • activated by phosphorylation
  • phosphorylated by kinases (e.g. PKA, CaMKII etc.)

Question 19

Early vs late phase LTP:

Answer 19

· 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 etc.
· Late phase LTP - lasts hours, days or months… requires new protein synthesis and can involve morphological changes and the establishment of new synapses
· Ca2+ activated signal transduction cascades:
- activate new protein synthesis (dendritically localized mRNAs)
- signal to cell body… new gene transcription CREB –mediated).. protein synthesis and recruitment of new proteins to the synapse

Question 20

LTP - increase in number of synapses:

Answer 20

· Development of new synaptic connections following tetanic stimulation

Question 21

Always an opposite - long term depression:

Answer 21

· Long Term Potentiation is created in slice preparations by High frequency stimulation (HFS: 1 sec of 100Hz (Hz = stimulations per second))
· Low frequency stimulation (LFS: 100 x 1 Hz) actually causes the opposite and rather than getting an increase in EPSP amplitude on further stimulation you get a decrease

Question 22

Long term depression (LTD):

Answer 22

· Same players involved:
- NMDA dependent process
- AMPA receptors are dephosphorylated and removed from the membrane
· (low level rises in Ca2+ activate phosphatase rather than kinase)

Question 23

Is LTP a real of physiological phenomena?:

Answer 23

· Tetanic stimulation in rat hippocampus…
· Is LTP a quirk of rat hippocampi?
· Or
· Does tetanic stimulation do the same in the human brain?

Question 24

Studies on animals - relevance to humans?:

Answer 24

· Human inferotemporal cortex removed during course of surgery - maintained in vitro
· Chen 1996 - from Bear

Question 25

Mechanism?:

Answer 25

· Tetanic stimulation is artificially high stimulation
· Is there a physiological equivalent?

Question 26

Theta rhythms:

Answer 26

· Hippocampal theta activity accompanies behaviours such as running, swimming, head movements and spatially orientated responses in the rat.
- Seems to play a role in synchronising activity in different brain regions.

Question 27

Is LTP physiological?:

Answer 27

· Waves of neuronal activity - hippocampal theta rhythms
- involved in arousal, alertness, fire during exploration etc.
· Depolarizing stimulation coincident with peak of wave generates LTP
· Depolarizing stimulation coincident with trough generates LTD
· (disruption in theta waves causes deficits in learning tasks that are similar to those caused by hippocampal lesions)

Question 28

Manipulating LTP:

Answer 28

· If LTP underlies learning and memory…
- are there ways of boosting it and do they increase memory?
- are there ways of reducing it and do they decrease memory?

Question 29

Enhancing LTP:

Answer 29

· Genetically:
- Increased amounts of a particular type of the NMDA receptor (NR2B receptor) leads to enhanced LTP

Question 30

Diminished memory and LTP:

Answer 30

· Age:
a. Decreased acquisition in the Morris water maze
b. Decreased LTP
c. Decreased expression of the NMDA receptors (NR1 and NR2B)

Question 31

Enhanced memory and LTP:

Answer 31

• Enrichment:
  a. Enhanced acquisition in the Morris water maze
  b. Potentiated LTP

Question 32

Reversal of aging effects by enrichment?:

Answer 32

• Spatial maze task:
  
  • Aged mice in improverished environment (IE) show greater deficits than those in normal (SE) or enriched environment (EE)

Question 33

Cells that fire together wire together:

Answer 33

· Most LTP experiments
· Temporal LTP
- Tetanic stimulation
· Input specific
· Associative learning requires
· Associative LTP
- Spatial summation

Question 34

Neuronal mechanisms underlying conditioned fear:

Answer 34

· Synaptic connections in the amygdala
· Ideal connectivity for long-term potentiation to occur
· Strong input from the US (shock) leads to depolarisation of the postsynaptic cell.
· Weak input from the CS (tone) is ‘strengthened’ by the postsynaptic depolarisation leading to activation of NMDA receptors leading to long-term potentiation of this synapse