Learning and Memory

Question 1

Give the definition of learning

Answer 1

An adaptive change in behaviour from experience

Question 2

Define memory

Answer 2

The retention of learning

Question 3

Describe the mechanism of learning

Answer 3

Fill in later

Question 4

Name the two types of memory and their availability, formation, short term storage, and long term storage attributes

Answer 4

Fill in later

Question 5

Disorders of declarative memory stem from…….

Give a case study which supports this

Answer 5

…. damage to the medial temporal lobe

Case Study: HM - had epilepsy from 10 y/o. Had a bilateral resection of MTL which controlled epilepsy. HM could recall early memories and IQ of 112 was unchanged but he had severe anterograde amnesia

Question 6

Give three features of declarative memory and evidence for each

Answer 6

1: DM is distributed in various cortical sites

Evidence: Karl Lashley (1920’s) - Rats with brain lesions given maze tasks. Showed location of lesion wasn’t significant, only extent of lesion and task difficulty - ‘MASS ACTION PRINCIPLE’

2: Hippocampus is the organisational centre for DM

Evidence: Hippocampal inputs (afferents) match outputs (efferents) - place where recall happens as well as learning

3: Different regions of MTL are responsible for different aspects of DM

Evidence: Daselaar et al (2006) - subjects given 120 english and 80 non-words (2 s/item), after 30 mins they were tested on recall and familiarity and brain activity measured. Recollection - Highest activity in posterior hippocampus; Familiarity - Highest activity in posterior parahippocampal cortex; Novelty - Highest activity in anterior hippocampus and rhinal cortex

Epstein and Kanwisher (1998) - Post Para Hippocampal place (PPA). Subjects were shown pictures and their brain activity measured. PPA is strongly activated by spatial information, but not objects or faces. People with damaged PPA have trouble navigating novel environments

Question 7

Describe the basic mechanism of non-declarative memory

Answer 7

Input enters cerebellum - striatum (doing part of brain) - motor cortex - action

When two signals reach the cerebellum at the same time, the become associated
e.g. Tone + Airpuff = Eye blink -> Tone = Eye blink

Question 8

Describe how MRI and fMRI works

Answer 8

MRI - Uses strong magnetic field to align protons. Burst of radio waves flip protons out of alignment. When protons flip back, the energy change is recorded

fMRI - measures areas with higher levels of oxygenated blood (activity) - Not infallible: people have taken readings from dead salmon

Question 9

Give a brief summary of declarative memory encoding

Answer 9

• Object information is represented by the perirhinal cortex (relational information comes from neo cortex)
• Contextual information processed by the para hippocampal cortex
• The two types of info are integrated by the hippocampus

Question 10

Describe Hebb’s postulate and Hebb’s learning rules

Answer 10

The synaptic connection between cells A and B is affected (strengthened) because A keeps firing B

Learning Rules:
Correlated pre- and post-synaptic activity causes synaptic strengthening/stabilisation (A + B firing)
Uncorrelated pre- and post- synaptic activity causes synapse weakening/elimination (A firing, B not)

“CELLS THAT FIRE TOGETHER, WIRE TOGETHER”

Question 11

Define Synaptic Potential

Answer 11

Depolarising/hyper-polarising potential die to activation of neurotransmitter receptors

Question 12

Define EPSP

Answer 12

Excitatory post synaptic potential - measure of synaptic strength at excitatory synapse

Question 13

Describe a study which shows the associativity of LTP

Answer 13

Nicoll et al (1998)

Tetanic stimulation of a weak input does not produce a high enough EPSP to fire the post-synaptic cell (No LTP occurs)

Tetanic stimulation of a strong input causes the post-synaptic cell to fire (resulting in LTP)

Tetanic stimulation of strong and weak inputs at the same time causes firing of the post synaptic cells and causes LTP in both strong and weak pathways

Example: Pavlovs dogs -
Strong signal = Food
Weak signal = Bell

Question 14

State how LTD occurs

Answer 14

Generated by repetitive low frequency stimulation of input - results in persistently reduced synapse strength

Question 15

Describe Bliss and Lomo’s 1973 study and it’s findings

Answer 15

To do later

Question 16

Give the mechanisms of pre-synaptic plasticity

Answer 16

Probability of release
Filling of vesicle
Transmitter concentration in synaptic cleft

Question 17

Describe the mechanism of retrograde messages in terms of synaptic plasticity

Answer 17

Signals that can diffuse out of the post synaptic terminal and influence activity of the pre-synaptic terminal
e.g. NO, CO, neutrophins

Question 18

Give the mechanisms of post-synaptic plasticity

Answer 18

Insertion of new receptors

Gating of existing receptors

Question 19

Describe how Ca2+ is involved in short term plasticity

Answer 19

Paired paired pulse facilitation

Seen when two pulses are delivered in very quick succession (less than half a second apart). Pulse B results in higher excitation

Caused by residual Ca2+ in cell from pulse A. excitation is Ca2+ dependant

Question 20

Briefly describe the synaptic vesicle cycle

Answer 20

Filling, Docking -ATP-> Priming -Ca2+-> Exocytosis and fusion -Ca2+-> Endocytosis

Question 21

Describe and give examples of four types of protein required for the synaptic vesicle cycle

Answer 21

Glutamate Transporters - required for vesicle content (KO = decrease in neurotransmission)

Synapsins - mobilisation of synaptic vesicles

Rab3/RIM1 alpha - Docking and priming of vesicles

SNAREs, munc18 - Synaptic vesicle fusion

Question 22

Name the protein required for synaptic vesicle mobilisation and state how they are required.

Answer 22

Synapsins

Vesicles mobilised by synapsins which bind them to the actin cytoskeleton

Question 23

Describe the process of vesicle docking and name the proteins involved

Answer 23

Rab3 (“Passport of vesicle trafficking”) which is a GTPase

GDP bound form is inactive. GTP bound form binds to vesicle and binds an effector (RIM1) on the membrane. This allows docking.

Once exocytosis occurs, Rab3 is hydrolysed and released from the vesicle

Question 24

Explain the process of synaptic vesicle fusion

Answer 24

Uses SNARE proteins (Synaptobrevin - vesicle associated, Syntaxin - embedded in membrane, SNAP-25 - present on membrane, Synaptotagmin - vesicle associated)

Synaptobrevin, Syntaxin and SNAP-25 form coiled coil and energy from ‘zippering’ brings membranes together

Synaptotagmin mediated Ca2+ dependant process

Vesicle tethered by Rab3 which brings the vesicle into membrance, munc18 is removed from membrane SNARE complex (priming). Full SNARE complex forms on membrane - zippering allowed once Ca2+ has bound to synaptotagmin. Fusion occurs, NT released, NSF and SNAP disassemble (ATP dependant)

Question 25

Describe studies to show the critical nature of synaptotagmin

Answer 25

Critical for Ca2+ dependence of vesicle fusion.

Difficult to prove. KO mouse dies before birth (mutants in Ca2+ chelating Amino acids are lethal)

Mutant in R233 amino acid in Ca2+ binding site (R233Q) reduces affinity of Ca2+ to synaptotagmin and also Ca2+ affinity of NT release

Question 26

Describe the two types of neurotransmitter receptor

Answer 26

Ionotropic (Ligand gated ion channels) - NT binds, conformational change in channel helices, ions flow in. ‘Fast’ receptor

Metabotropic (G-protein coupled) - NT binds, G protein a subunit binds to effector protein which send intracellular messages to ion channel. ‘Slow’ but potentially longer lasting

Question 27

Give properties of NMDA and AMPA receptors

Answer 27

NMDA and AMPA: Tetrameric, homodimers, glutamate binds in M3, M4 loop, NMDA/AMPA looks similar glutamate (only binds its respective receptor)

NMDA: Gates Ca2+ and Na+, D-AP5 is a blocker, in the absence of glycine the receptor does not function, Mg2+ block in the ion pore (voltage dependant, depolarisation removes Mg2+)

AMPA: Gates primarily Na+ and sometimes Ca2+, NBQX is a blocker

Question 28

Describe the Yeast 2 Hybrid Assay

Answer 28

Used to study protein-protein interactions

Bait is protein of choice, go ‘fishing’ in solution of protein (i.e. mushed up brain) and pull out what binds to bait

In post-synaptic setting - Get a transcription factor, split it in half, attach bait to one half and express the other half at the end of genes expressed in yeast, If they come together, transcription of the gene will occur

Question 29

Give an advantage and disadvantage of using aplysia as a model organism

Answer 29

Adv: Neurons arranged in ganglia, cell bodies are large

Dis: Relies on v. simple learning paradigms (i.e. tail shock, touching siphon)

Question 30

Give the definition of habituation

Answer 30

Reduction of psychological or behavioural response occuring when a specific stimulus occurs repeatedly

Question 31

Give the definition of sensitisation

Answer 31

The process of becoming susceptible to a given stimulus that previously had no effect or significance

Question 32

Describe habituation in Aplysia

Answer 32

Touch siphon -> Gill withdrawal

Gill withdrawal weaker after repeated stimulation of siphon

Question 33

Describe sensitisation in Aplysia and give methods for long and short term sensistisation

Answer 33

Pairs electrical stimulation of tail with light touch of siphon
Light touch of siphon -> Strong gill withdrawal

Short term: Single tail shock and siphon touch lasts a few hours (post translational modification)

Long term: Multiple trains of shocks ( 4 trains of 10 for four days) cause sensitisation to last days (requires structural changes at synapse - protein synthesis)

Question 34

Describe how Habituation and sensitisation affects the neural circuitry of Aplysia

Answer 34

Habituation: Glutamate release by sensory neuron decreases - responsible for decrease in behavioural response

Sensitisation: Serotonin is released from inter-neuron on to sensory neuron (skin) and enhances the action of glutamate (via PKA) (and skin sensory neuron)

Question 35

Describe structural changes seen at Aplysia synapses after sensitisation

Answer 35

Synaptic bouton number increases/decreases during sensitisation/habituation (Long term only)

Habituation decreases
Sensitisation increases

This requires gene expression and protein synthesis

Question 36

Describe the effect of PKA on sensitisation

Answer 36

When serotonin is released from inter-neurons to to sensory neurons, PKA is activated. PKA activity increases NT release in sensory neuron

PKA is required for short and long term sensitisation

Question 37

Describe fear conditioning in rodents

Answer 37

Classical: Sound paired with aversive foot shock. Association of sound with shock - fear of sound.

Extinction of fear requires exposure to sound with no shock

Operant: Skinner box - reinforcement positive (food) /negative (electric shock). Rewarded behaviour is repeated

Question 38

Describe spatial learning in rodents

Answer 38

Morris Water Maze - Hidden platform under water, rat must find platform

• After 10 trials, rat goes straight to platform (WT)
  
  • Rats with hippocampal lesions do not improve (PPA damage)

Latency, platform crossings and time spent in quadrants is measured

Rodents use surrounding areas to orientate themselves (i.e. chairs, clocks). Move objects and they struggle to find platform

Mutants in CREB struggle at improving with one trial per day, 4 trials per day see improvement similar to wild type

Question 39

Briefly summarise short term plasticity

Answer 39

Dependant on Post-synaptic activation of AMPA receptors and NMDA receptors

Ca2+ influs through AMPAR starts depolarisation. This removes the Mg2+ block in NMDAR. Ca2+ modulated signalling pathways (Calmodulin Kinase II and Proetin Kinase C) are initiated and substrate phosphorylation occurs, leading to the insertion of additional AMPA receptors

Question 40

For long term plasticity to persist beyond 2 hrs…

Answer 40

…synaptic signalling pathways initiated at the synapse (kinases) are required effect changes in the nucleus

Question 41

Give evidence that long term LTP requires gene transcription

Answer 41

in CA3:CA1 pathway, give multiple trains of 100Hz. Control shows normal long term LTP, Add actinomycin D (transcription inhibitor) or anisomycin (protein synthesis inhibitor) before tetanic stimulus and early LTP is demonstrated but late LTP is blocked

Apply inhibitors after stimulus and it has no effect suggesting that gene expression changes are induced early

Question 42

Give evidence that long term facilitation requires gene transcription

Answer 42

Simulation of pairing tail shock with gill withdrawal in Aplysia.

Apply serotonin to cell (in bath) for 5 mins. Look at EPSP immediately after and 24 hrs later (response similar each time) . 5 doses of 5 mins spaced 15 mins apart of serotonin shows long term faciliation of the neuron. 24hrs later, there is a huge enhancement of the response

(Application of actinomysin D or anisomycin at time of serotonin application blocks LTF)

Question 43

Name some Immediate early genes (IEGs) and give the role

Answer 43

Regulatory genes (encode for TFs): c-fos, zif268, c-jun

Effector IEGs:

• Arc - protein involved in exocytosis of AMPA receptor
• BDNF - Growth factor that alows synapse growth and can potentiate NT release
• Homer1a - Scaffolding protein that links proteins in post synaptic density

ALL ARE TARGETS OF CREB

Question 44

Describe the action or Arc as an effector IEG

Answer 44

Associate with Endophilin and Dynemin - mediates AMPA receptor endocytosis

Interacts with Wave3 (involved in actin remodelling) - possibly involved in structural plasticity of LTP