Biological 2: Spatial learning and LTP 1

Question 1

What is learning?

Answer 1

Change in behaviour that results from experience i.e., acquiring knowledge & skills through experience.

Corresponding physical change in the brain.
Criteria for learning to occur, should be the same as the neural mechanisms

Question 2

How does Pavlovian conditioning propose that learning occurs?

Answer 2

Behaviour is a learned process, occurs through association.
2 stimuli become linked, generate a new behavioural response to a previously neutral stimulus.
NS paired with an US, triggers an UR.
NS becomes a CS, trigger a now CR.

Question 3

What is the neural basis of learning?

Answer 3

Looking for a neural mechanism that would allow associations to be formed - how events can be biologically linked in the brain

Question 4

Where in the brain is the hippocampus located?

Answer 4

It is a folded bit of cortex in the temporal lobe

Question 5

What comprises the hippocampus?

Answer 5

It is a loop of synaptic connections

Question 6

What are the main input and output of the hippocampus?

Answer 6

Entorhinal cortex = main input
CA1 = main output

Question 7

What is Kindling’s model of epilepsy? (pre LTP)

Answer 7

Prior stimulation increases the likelihood of neurons firing (preceding a seizure)
This logic applies whether you stimulate and measure single neurons or thousands of neurons
- Like kindling starting a fire
- Electrical stimulation of neurons - makes them more reactive in future - chain of neuronal activity spreading

Question 8

What kind of information does the hippocampus process?

Answer 8

Multimodal sensory and spatial information

Question 9

What do you have to seperate to understand how neurons fire together?

Answer 9

Pre-synaptic and post-synaptic neurons

Need to be able to stimulate one neuron and see what happens in following neuron
Need seperate populations of neurons

Question 10

Why is LTP commonly studied in the hippocampus?

Answer 10

Anatomy of hippocampus makes it easy to study - pre and post synaptic neurons are segregated and readily identifiable

Can stimulate cell bodies in one area, measure effect of this in another area
Can stimulate axons in one area and measure effect of this in another area
(pre and post synapse)

e.g. cell bodies in EC - axons in perforant path - dendrites in dentate gyrus
Can stimulate axons in perforant path and record post-synaptic activity in the dentate gyrus

Question 11

Who was Bliss and Lomo’s early work on LTP conducted on?

Answer 11

Anaesthetised rabbits
Later work in isolated slides

Question 12

What did Bliss and Lomo find from their initial LTP experiments? (stimulating pre-synaptic neurons and measuring effects on post-synaptic neurons)

Answer 12

EPSP = excitatory post synaptic potential (excitatory charge after action potential)

Before repeated (tetanic) stimulation - some EPSP
Tetanic stimulation - over time EPSP increases

Over time - one week or one month later - EPSP of post synaptic neuron for which the pre-synaptic neuron received tetanic stimulation - still has elevated EPSP compared to neuron that has not received tetanic stimulation

Maps onto learning - change based on experience
Repeatedly stimulating a neuron - the neurons that it is connected to then become more responsive to that neuron

Question 13

What are the three phases of stimulation and response that happen to elicit a change from LTP?

Answer 13

Phase 1 - weak stimulation and weak response
Phase 2 - strong stimulation and strong response
Phase 3 - weak stimulation and strong response

Question 14

What is a strong post-synaptic response a result of?

Answer 14

Neurons repeatedly firing together at the same time

Question 15

What is the critical factor in LTP?

Answer 15

LTP only occurs when firing of presynaptic neuron is followed by firing of postsynaptic neuron
- This co-occurrence (close together in time) is now seen as the critical factor in LTP - crucial for learning to happen

Question 16

What is Hebb’s postulate for learning?

Answer 16

Assumption that co-occurrence is a physiological necessity for learning and memory is often named

Question 17

What is the Hebbian basis of memory?

Answer 17

Neurons that fire together wire together - neuronal activity that co-occurs in time, they will become stronger and more likely to fire

If the synapse is active at same time as the post-synaptic neuron fires, physical changes to the synapse will take place that strengthen it

Question 18

What is the rabbit eye blink conditioning paradigm?

Answer 18

Can be done with light or tone

Bit of air blow in eyes = blink
Put light on at same time as air puff
Eventually, light causes rabbit to blink alone

Question 19

What happens to neurons during the rabbit eye blink paradigm? (simplistic breakdown)

Answer 19

Puff of air to the eye - stimulates pre-synaptic neuron in somatosensory system, which stimulates post-synaptic neuron in motor system to cause a blink
1000 HZ tone paired
Initially, stimulating auditory neuron with the tone causes a weak response in the post-synaptic motor neuron
However, over time with more firing together, stimulation of the auditory neuron causes a strong response in the motor neuron (synapse strengthened), even when the auditory neuron is stimulated weakly and without the original somatosensory neuron (puff of air)

Tone alone becomes sufficient to generate a postsynaptic response

Question 20

What is an action potential?

Answer 20

Change of electrical activity in cell

Stimulus threshold met
Depolarisation - Na+ ions in
Repolarisation - K+ ions out
Hyperpolarisation
Back to resting state

Question 21

What is the primary excitatory neurotransmitter?

Answer 21

Glutamate

Question 22

What happens when action potential reaches a synapse?

Answer 22

Neurotransmitter is released

Question 23

What is the ‘normal/ non-fussy’ glutamate receptor?

Answer 23

AMPA receptor

Question 24

What happens when glutamate binds to the AMPA receptor?

Answer 24

AMPA receptor opens membrane channels leading to depolarisation (allowing positively charged ions into the cell)

Question 25

LTP is widely studied at synapses with lots of what type of receptor?

Answer 25

NMDA receptors (Often seen in same synapses that have AMPA receptors)

Question 26

When does an NMDA receptor work maximally?

Answer 26

When the post-synaptic neuron is partially depolarised This is why NMDA receptors are called fussy receptors

Question 27

What are NMDA receptors' roles in allowing co-occurence to happen?

Answer 27

They work the best when the post-synaptic neuron is already partially depolarised, allowing the pre and post synaptic neuron to fire at the same time

Question 28

When do NMDA receptor-linked channels open? (Channels associated with the binding of glutamate to NMDA receptors on post synapse)

Answer 28

Only open in the presence of neurotransmitter AND when post-synaptic membrane (cell) is depolarised

Question 29

Why are NMDA receptor-linked channels also called coincidence detectors?

Answer 29

There are biological in-built mechanism that detects when certain things are happening at the same time - detect the conditions required to glutamate to bind to NMDA

Question 30

What is the ion channel associated with the NMDA receptor normally blocked by? When does it unblock?

Answer 30

A positively charged magnesium ion This ion is no longer attracted to the cell once the membrane is sufficiently depolarised (on the post-synapse) Detaches due to increase in voltage

Question 31

What happens when magnesium ion detaches from the NMDA receptor?

Answer 31

Glutamate is able to bind to receptor Ion channel is now open - calcium enters the post-synaptic cell - influx of calcium ions

Question 32

What happens to AMPA receptors after calcium enters a cell through an NMDA receptor ion channel? What effect does this have on the cell?

Answer 32

They increase in number This makes the cell more responsive to glutamate - this happens quite rapidly

Question 33

Does LTP change NMDA receptor numbers?

Answer 33

No - only AMPA receptors

Question 34

What happens to LTP when AMPA receptors are blocked?

Answer 34

LTP does not happen - mechanism is blocked because LTP depends on increase of number of AMPA receptors

Question 35

What is the main effect of early phase LTP?

Answer 35

AMPA receptor trafficking - increase in number

Question 36

What happens when you block protein synthesis during LTP?

Answer 36

Blocking protein synthesis, through inhibiting transcription after stimulation, prevents LTP (especially longer term) This shows that protein synthesis is part of LTP/ LTP affects protein synthesis

Question 37

Calcium cascades influence what process?

Answer 37

Protein synthesis

Question 38

What does protein synthesis alter in LTP?

Answer 38

The structure of the cell - post synaptic structural changes: Long-term increase in AMPAR's​ Growth of new spines​ - new synapses Enlargement of spines/synapses ​ Splitting of spines ​ All of this means - enlarged postsynaptic area, so area that glutamate can bind to on a cell is larger as a result of LTP

Question 39

Are there changes in the pre-synaptic cell as a result of LTP?

Answer 39

Yes Increased glutamate in the presynaptic cell

Question 40

How are LTP-dependent changes in the presynaptic cell measured?

Answer 40

Radioactively label glutamate Researchers have found increased radioactivity in synapse following LTP - increased glutamate

Question 41

What causes the presynaptic cell to release more glutamate following LTP?

Answer 41

When calcium enters the post-synaptic cell it activates second messengers within the cell (kinase enzymes) One consequence is that the post-synaptic cell releases nitrous oxide (NO) NO acts as a retrograde transmitter being detected by, and inducing changes in, the presynaptic cell - It does this through action on pre-synaptic cyclic GMP (guanosine monophosphate), which increases glutamate production

Question 42

What are retrograde transmitters and what might be the retrograde transmitter acting during LTP?

Answer 42

Retrograde transmitters - neurotransmitters/chemicals released from post-synaptic cell and go back to pre-synaptic cell Nitrous oxide

Question 43

What type of receptor is a coincidence detector?

Answer 43

NMDA

Question 44

What is the initial role of AMPA receptors in LTP?

Answer 44

Glutamate binds to them, allowing depolarisation of the post-synaptic cell

Question 45

How does LTP help associative learning?

Answer 45

- Associative learning requires the formation of links between the memories of different stimuli (e.g. bell and food, Pavlov’s dogs) - Long-term potentiation is a mechanism for the formation of links between neurons Maybe LTP is the neural basis of learning and memory

Question 46

How have researchers experimentally tested whether LTP is necessary for learning?

Answer 46

Impair LTP (using NMDA receptor antagonist AP5) during a learning task e.g. spatial navigation - Locate hidden platform - measure whether they swim in correct quadrant If LTP is necessary, LTP impaired animals should not be able to learn the task This tests necessity of LTP in hippocampus for learning

Question 47

How do rats with impaired LTP (AP5 NMDA receptor antagonist) perform on a Morris water maze task? What does this suggest?

Answer 47

Much more poorly than controls Failed to show a preference for a quadrant Only impacted new learning If previous training done before AP5, spatial navigation abilities were not impaired AP5 also did not impair visual discrimination Suggests LTP is necessary for spatial learning

Question 48

What is an issue with experiments using AP5 to impair LTP?

Answer 48

AP5 makes rats wobbly - Fall off platform - makes platform less rewarding - not learning in the same way Confounding variable of sensorimotor impairments - cannot assume that lack of learning is purely down to LTP impairment

Question 49

How can performance deficit and learning deficit from AP5 be dissociated to see if LTP actually is responsible for learning? (Bannerman et al., 1995 - upstairs downstairs)

Answer 49

2 water mazes, one upstairs, one downstairs Unique extra maze cues, learning in one would not help navigate in the other Just improve general not specific ability Rats pretrained to be really proficient swimmers before AP5 - should reduce sensorimotor impairments - recover deficit This happened in the downstairs maze Other group of rats not pretrained Some rats given AP5, others not Completed upstairs maze task

Question 50

What were results of Bannerman's upstairs downstairs experiment to see if impaired LTP or impaired sensorimotor abilities caused impaired spatial learning?

Answer 50

AP5 impaired performance when there was no pretraining BUT AP5 did not impair performance when rats had pretraining Hippocampal lesions impaired performance even when rats had pretraining Conclusion: When rats had pretraining on the water maze, AP5 failed to impair hippocampus-dependent spatial learning. This suggests that LTP in the hippocampus may not be necessary for spatial learning