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Integrative Neuroscience > Molecular Mechanisms of Learning > Flashcards

Molecular Mechanisms of Learning Flashcards

1
Q

What are the two steps of learning and memory?

A
  1. Acquisition of STM
    - Physical modification in the brain caused by incoming sensory information
    - STM persists without conscious effort (unlike WM, which involves repeating something over and over)
  2. Consolidation of LTM
    - Some experiences are selected for permanent storage
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2
Q

How do area IT neurons show stimulus selectivity?

A
  • They respond to some stimuli but not all
  • Response of area IT neurons change after repeated presentation of the same stimuli
  • Response of neuron to face becomes more stable and more selective after repeated stimulations
  • Nearby area IT neurons show similar changes but their response grows and diminishes to different faces
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3
Q

What is distributed memory?

A
  • Upon first encounter with a stimulus, cortical neurons have no selectivity (no neuronal signature to distinguish one face from another)
  • After repeated exposure, the neurons of the network acquire selectivity although all neurons respond to all faces
  • Transformation of responses occurred by changing the strength of the synaptic inputs that converge onto one cortical neuron
  • After learning, there is a unique ratio activity in the cortical neurons for each face
  • The more neurons that are available in a cortical circuit, the more unique memories can be stored and the less memories are disturbed following damage to a given neuron
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4
Q

What is graceful degradation?

A
  • when neurons are gradually pulled from the network over time, memories also degrade gracefully (rather than abruptly)
  • Representations tend to blend together as neurons are lost
  • Less neurons are available to hold onto unique memories
  • Model of memory loss seen n old age
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5
Q

What are the two sheets of neurons in the hippocampus?

A
  • Two thin sheets of neurons folded onto each other:
    1. Dentate gyrus
    2. Ammon’s Horn (CA1-CA4)
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6
Q

Explain the trisynaptic circuit of the hippocampus

A
  1. Entorhinal cortex inputs to the hippocampus by synapsing with the dentate gyrus via the perforant path
  2. Dentate gyrus cells have mossy fibres that synapse with pyramidal CA3 neurons
  3. CA3 neurons have two branches
    - One branch leaves hippocampus via the fornix and synapses with the thalamus, then hypothalamus
    - Other branch consists of Schaffer collaterals that synapse with neurons in CA1
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7
Q

What region is LTP most understood?

A

CA1 region

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8
Q

Explain how LTP is measured.

A
  • Before LTP, EPSP is measured by giving a mild input. The same stimulus will produce the same EPSP over time / over multiple occasions.
  • Use tetanus at input and record EPSP in PSP cell. Can be induced by stimulations less than 1 second in duration. EPSP will be massively increased over time
  • Input-specific: If input 2 is stimulated, EPSP will not change. Demonstrates that one synapse got strengthened while another did not.
  • When EPSP is measured over 360 days, shows that it remains high over time.
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9
Q

What is the minimum requirement for LTP to occur?

A
  • Strong tetanus not necessary

- A particular synapse must be active at the same time that the postsynaptic CA1 neuron is strongly depolarized

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10
Q

What are the 2 requirements for achieving LTP?

A
  1. Synapses must be stimulated at frequencies high enough to cause temporal summation of EPSPs
  2. Enough synapses must be active simultaneously to cause significant spatial summation of EPSPs.
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11
Q

What is cooperativity? How does it provide a mechanism for associations within the hippocampus?

A
  • Synapses must cooperate to produce enough depolarization to cause LTP
  • Hippocampal neuron with 3 inputs
  • If 1 and 2 fire repeatedly and simultaneously, spatial and temporal summation will cause firing in the postsynaptic cell and result in LTP only in active synapses
  • Because of LTP, inputs 1 and 2 alone can depolarize the postsynaptic neuron, but input 3 cannot
  • LTP has caused an association of inputs 1 and 2
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12
Q

Explain the molecular mechanisms of LTP.

A
  1. CA1 pyramidal cells have AMPA and NMDA receptors. Sodium influx through AMPA receptors causes EPSP at Schaffer collateral synapse
  2. Once there is enough depolarization, magnesium block is displaced. Calcium influx through NMDA receptor signifies simultaneous activity of pre-synaptic and post-synaptic cells. NMDA receptors are permeable to calcium only when glutamate binds and the postsynaptic membrane is depolarized.

** rises in intracellular calcium = induction of LTP

  1. Calcium activates two protein kinases: protein kinase C and calcium calmodulin-dependent protein kinase II
  2. Protein kinases begin phosphorylation which increases the effectiveness of post-synaptic AMPA receptors by increasing conductance of AMPA’s ion channels.
  3. CaMKII triggers vesicular organelles studded with AMPA receptors to fuse to the membrane and create new AMPA receptors.
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13
Q

What is the BCM theory of learning and memory?

A
  • Bidirectional regulation of synaptic strength
  • Synapses will undergo synaptic weakening when they are active at the same time that the postsynaptic cell is only weakly depolarized by other inputs
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14
Q

Compare and contrast LTP and LTD

A

LTP
- Synaptic transmission occurring at the same time as strong depolarization of post-synaptic neuron

LTD

  • Synaptic transmission occurring at the same time as weak or model depolarization of post-synaptic neuron
  • Shown to occur in hippocampus following low frequency stimulation of Schaffer collaterals
  • When time difference between pre and post-synaptic cells are small, LTD and LTP responses are large
  • When time difference is large, LTD and LTP are small
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15
Q

Explain how calcium can also signal LTD.

A
  • Difference is level of NMDA receptor activation
  • Weak depolarization (less than threshold) of post-synaptic neuron produces a partially displaced magnesium block, resulting is low calcium influx
  • Concentration of intracellular calcium has huge implications on its effects
  • Low levels activates protein phosphatases that dephosphprylate proteins (i.e., AMPA receptors)
  • In response to low frequency stimulation, AMPA becomes dephosphorylated at CA1 synapses
  • Associated with internalization of AMPA receptors – glutamate still binds, but AMPA less able to let sodium into the cell
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16
Q

What is glutamate receptor trafficking?

A
  • AMPA receptors are constantly being replaced in the post-synaptic membrane in the absence of any stimulation
  • Synaptic transmission remains stable throughout constant flux
  • LTP and LTD disrupt this equilibrium by increasing / decreasing the net change of synaptic AMPA receptor expression
17
Q

What are scaffolds and slot proteins?

A
  • Synaptic capacity (how much sodium the postsynaptic cell can take in) is determined by the size of the scaffold (placeholder) for slot proteins (AMPA receptors)
  • As long as scaffolding remains constant, slot proteins will be plugged in at a consistent rate
  • If size of scaffolding changes, then the number of slot proteins plugged into the post-synaptic membrane will change accordingly
18
Q

How does LTP and LTD influence scaffolding?

A
  • LTP: Increases size of scaffold, creating new slots for AMPA receptors and increases in PSD-95
  • LTD: Decreases size of scaffold, removing AMPA receptors and decreasing PSD-95
19
Q

What is PSD-95?

A
  • Postsynaptic density protein 95
  • Molecular basis of scaffold
  • Increasing PSD-95 expression in neurons increases synaptic capacity of AMPA receptors
  • AMPA receptors plugged into PSD-95 contain GluR1 subunit that contains AMPA receptors
  • LTP selectively increases GluR1 containing AMPA receptors (increases PSD-95 transcription)
  • As AMPA receptors are turned over, GluR1 containing AMPA receptors are replaced by those that lack GluR1
20
Q

What evidence do we have that links LTP/LTD to learning and memory?

A
  • Box with light and dark side – dark side delivers shock every time rat enters
  • Record from CA1 – EPSP will increase over time as rat learns
  • If rates given NMDA receptor antagonist, it will never learn to avoid the dark side
21
Q

What is the synaptic modification threshold / synaptic homeostasis?

A
  • At some level of NMDA receptor activation, there is no change to synaptic strength
  • Threshold shifts according to history of integrated postsynaptic activity
  • As LTP occurs, modification threshold is adjusted and LTP is more difficult to achieve. As LTD occurs, modification threshold is adjusted to that LTD is less likely and LTP is more likely
22
Q

What is metaplasticity?

A
  • Synaptic plasticity depends on the history of synaptic activity
  • Ensures synaptic modifications are constrained to maintain neuronal stimulus sensitivity and memory
  • Prevents grand-mal seizures
23
Q

What are the molecular mechanisms behind shifting synaptic modification threshold?

A
  • Involves adjusting the molecular composition of the NMDA receptors
  • NMDA receptors have 4 subunits: two NR1 and two NR2 subunits
  • Ratio of subunit subtypes dictates properties of receptor such as calcium conductance, influence of intracellular processes, etc.
  • LTP is favoured when more NR2B containing receptors are expressed while LTD is favoured when more NR2A containing receptors are expressed
  • Ratio of subtypes depends on which proteins are available in the neuron
  • High cortical activity is associated with increases in NR2A production and decreases in NR2B production
  • Low cortical activity is associated with increases in NR2B and decreases in NR2A, promoting LTP over LTD
24
Q

If there is a constant flux of synaptic strengths, how do carefully tuned patterns of synaptic weights keep stored memories?

A
  • Synaptic scaling
  • Relative differences in strengths on a neuron remain unchanged, even as absolute effectiveness goes up or down
  • Neurons adjust by multiplying or dividing the values of all synaptic weights by the same number
  • Thought to be a consequence of CaMKIV: Elevated activity increases its transcription and periods of inactivity decrease its transcription
  • Increases or decreases AMPA and NMDA receptor insertion cell wide
25
Q

Why is phosphorylation by protein kinases problematic for memory consolidation? What is a proposed mechanism of how this is able to work?

A
  1. Phosphorylation is not permanent – Phosphate groups are removed in the absence of activated protein kinases
  2. Protein molecules themselves are not permanent. Proteins are replaced every 2 weeks. Proteins are normally turned on in the presence of 2nd messengers but are otherwise turned off.
  • Some protein kinases can become independent of their 2nd messengers
  • They remain turned on and capable of phosphorylating synaptic proteins at all times
  • Thus CAMKII maintains synaptic strength even in absence of calcium
26
Q

Explain the molecular switch hypothesis.

A
  • CAMKII has 10 subunits that are each responsible for phosphorylating a substrate in the presence of calcium calmodulin
  • Each subunit has a catalytic region and a regulatory region: catalytic phosphorylates while regulatory turns off phosphorylation
  • In the absence of a 2nd messenger, catalytic region is inhibited by the regulatory region
  • When calcium calmodulin is present, the regulatory region is lifted and exposes the catalytic region
  • Each subunit is capable of autophosphorylating adjacent subunits
  • If the initial activation of CamKII by calcium calmodulin is sufficiently strong, autophosphorylation occurs at a rate faster than dephosphorylation and the molecule is permanently switched on
27
Q

What happens when you prevent protein synthesis following a strong titanic stimulation? Just before a learned task?

A
  1. Does not prevent induction of LTP, but the increase in synaptic strength fades within a few hours
  2. An animal will not remember the next day
28
Q

How do newly synthesized proteins know where to go?

A
  • Wave of new proteins are not only limited to synapses that received strong excitatory input: Also consolidate synapses that received only weak stimulation
  • Weak stimulation tags a synapse and allows it to capture the newly synthesized proteins that consolidate LTP
  • Any synapse that receives weak stimulation is tagged for about 2 hours and will be able to capture newly synthesized proteins during that window
  • Strong stimulation will depolarize the neuron which leads to protein synthesis and bringing proteins to the synapse that was weakly depolarized before
29
Q

What factors regulate protein synthesis in response to excitatory input?

A
  • Cyclic AMP response element binding protein (CREB)
  • Transcription factor that is involved in regulating protein synthesis required for induction of LTP
  • CREB-2 binds to CREs and represses gene expression
  • CREB-1 activates gene expression when bound to CREs, but only when phosphorylated by PKA
  • Mutations that cause over expression of CREB-2 prevent any gene expression of CRE and block memory consolidation
  • CREB-1 over expression results in massive increases in learning efficiency of behavioural tasks

Integrative Neuroscience (9 decks)

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