Memory and Learning 2

Question 1

What is LTP, where is it seen and what causes it?

Answer 1

Long-term Potentiation: Long-lasting improvement in communication between two neurons following simultaneous stimulation.
Seen at glutamatergic synapses, decays over hours.
Caused by a high frequency train of stimuli to presynaptic fibres which elicits strong EPSPs at the postsynaptic cell

Question 2

How are LTP and memory related?

Answer 2

Memory is stored in networks of neurons through changes in synaptic function (proposed by Hebb, 1949)
LTP provides a mechanism for altering the connectivity of networks of neurons meaning you can store memory similar to Hebb’s postulate
LTP lasts weeks-months, longest recorded = 2 years

Question 3

What are the phases of LTP?

Answer 3

Early, intermediate and late phases

Question 4

What are the features of the early phase of LTP?

Answer 4

Duration: ~2hrs
Molecular mechanisms: protein modification e.g. phosphorylation
Cellular requirements: translation independent

Question 5

What are the features of the intermediate phase of LTP?

Answer 5

Duration: ~6hrs
Molecular mechanisms: mRNA editing, stability, translation and splicing
Cellular requirements: translation dependent/transcription independent

Question 6

What are the features of the late phase of LTP?

Answer 6

Duration: ~10hrs+
Molecular mechanisms: transcriptional regulation and epigenetic modification
Cellular requirements: transcription dependent

Question 7

What phase(s) of LTP are involved in short term memory?

Answer 7

Early and intermediate phases

Question 8

What steps occur to create short term memories?

Answer 8

NMDAR activation (postsynaptic) –> increased Ca2+ –> CaMKII activation –> AMPAR phosphorylation AND AMPAR insertion into membrane —-> increased AMPA current

Question 9

What phase(s) of LTP are involved in long term memory?

Answer 9

Late phase

Question 10

What steps occur to create long term memories?

Answer 10

NMDAR + AMPAR + mGluR ——> molecular messengers (PI-3K, PKA, PKC, CaMKII) —-> ERK —-> Signalling + cytoskeletal + nuclear proteins —–> gene transcription + protein synthesis + morphological changes —> LTP expression

Question 11

What is BDNF?

Answer 11

Brain-derived neurotrophic factor

Question 12

What are the functions of BDNF?

Answer 12

1. Regulates neuron survival and differentiation in the CNS + PNS
2. Regulates structure and function of neural circuits
   - Release activity dependent
   - Receptors often co-expressed with glutamatergic neurons
   - Synthesised, stored and released from glutamatergic neurons
   - Highest levels of expression in hippocampus

Question 13

How has the relationship between BDNF and LTP been shown in mice?

Answer 13

Knock-in Huntington’s disease mice with impaired LTP mechanisms

EPSPs recorded at CA1 region after Schaeffer collateral stimulation (theta burst stimulation -TBS)

Only mice supplemented with BDNF maintain LTP

Question 14

How does BDNF help maintain LTP?

Answer 14

Activates CaMKII and other molecular messengers
Reduces specific miRNA levels (miRNA binding to mRNA inhibits translation) and increases production of specific (<4%)cellular proteins

OVERALL: increased expression of proteins involved in learning and memory

Question 15

How are BDNF and exercise related?

Answer 15

Exercise+environmental enrichment –> increased BDNF —-> increased neurogenesis and LTP —-> improved learning and memory

Question 16

What happens to memory with age?

Answer 16

Weight of normal human brain decreases with age

Synapse counts in cortex decrease with age –> decreased connectivity between neurons and engrams of memories deteriorate

Cognitive decline can be made better (ameliorated) by continuing to use the full range of memory abilities

Question 17

What is the range of the spectrum of cognitive decline?

Answer 17

Normal memory loss —> dementia and Alzheimer’s disease

Question 18

What is dementia?

Answer 18

Failure of recent memory and intellectual abilities

Question 19

What is Alzheimer’s disease?

Answer 19

The most common form of dementia (60-80% in elderly)

Affects as many as 45% of US population over 85

Question 20

What are the clinical features of dementia?

Answer 20

1.Memory impairment and failure of language skills, visual-spatial orientation, abstract thinking and judgement and alterations in personality.

Question 21

How is diagnosis of dementia made?

Answer 21

Diagnosis based on clinical features but can only be confirmed by post-mortem

Question 22

What are the features of Alzheimer’s disease?

Answer 22

1. Neurofibrillary tangles - collections of intraneuronal cytoskeletal filaments
2. Senile plaques - Extracellular deposits of an abnormal protein called amyloid
3. Diffuse loss of neurons particularly in limbic structures (hippocampus, amygdala and associated cortices and some brain stem nuclei particularly basal forebrain)

Question 23

What effect does BDNF have on Alzheimer’s disease?

Answer 23

Transgenic mice (TG GFP) express amyloid protein –> senile plaques, progressive cell lose and cognitive decline 6-7 months —> Alzheimer’s

BDNF expression in amyloid expressing mice (TG BDNF) improved performance of TG GFP mice in water maze towards wildtype and increases synaptophysin (a synaptic vesicle glycoprotein) expression in hippocampus

Question 24

What are the steps to finding an engram?

Answer 24

1. Create a memory - fear conditioning
2. Label cells that make the engram of the memory
   - -> c-fos expressed in active cells during memory formation- use promoter to drive expression of a reporter gene (enhanced yellow fluorescence protein, EYFP)
3. Reactivate/recall memory without stimulus
   - —> channelrhodopsin (ChR2) also expressed under c-fos promoter- found in algae, opens when stimulated by blue light and allows Na+ entry thereby stimulating an AP
4. Viral transfection of neurons in hippocampus with ChR2- EYFP, fused to channelrhodopsin
5. Optical fibre implanted to provide light for ChR2 activation

Cells in the hippocampus were stimulated with blue light and a freezing response was observed without any foot shocks

Question 25

False memory

Answer 25

E.g. Given a list of words to remember - recall a word that wasn’t there due to association with words that were present.
E.g. Eyewitness misidentification

Question 26

How can a false memory be implanted?

Answer 26

Viral transfection with ChR2 and optical fibre implantation to hippocampus

Question 27

What is an example of a false memory created in mice

Answer 27

1. Mouse placed in one environment, memory formation and ChR2 expression in neurons forming memory
2. Mouse placed in another environment, gets foot shock and blue light to activate ChR2 and memory from environment 1
3. When mouse placed in environment 1’ it freezes even though it has never received a foot shock here because a false memory has been generated

c-fos expression shows cells in amygdala recruited for fear conditioned memory