LEARNING + MEMORY

Question 1

What is learning?

Answer 1

Learning is the response of the brain to environmental events and involves adaptive changes in synaptic connectivity which will in turn alter behaviour -> Donald Hebb in 1949 suggested a hypothesis for how, through neuronal networks, the brain can process and store information -> ‘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 2

Lecture summary

Answer 2

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 -> sensory input for smell of perfume -> initially an individual input might not be sufficient to stimulate the hippocampal neuron -> the excitatory post-synaptic potential (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 3

What is long-term potentiation?

Answer 3

Mechanisms underlying synaptic strengthening -> hippocampus shape and anatomy means pathways can be easily distinguished and recorded from electro-physiologically – LTP has now been studied in most other brain areas too.

Question 4

What is electrophysiology?

Answer 4

Record + stimulating the 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

What is temporal summation?

Answer 5

stimulation, high-frequency stimulation, 100hz (100 stimulations in a second). multiple stimuli from single neurone.

Question 6

What is tetanic stimulation?

Answer 6

Increase in the size of EPSP -> collective charge of EPSP.

Question 7

What is asynchronous stimulation?

Answer 7

no stimulation in neuron groups during stimulation of another ESPS (to cancel it out)

Question 8

What does input specific mean?

Answer 8

LTP at one synapse is not propagated to adjacent synapses

Question 9

What is the spatial summation pathway?

Answer 9

simultaneous stimulation of a strong and weak pathway will induce LTP at both pathways

Question 10

What is coincidence detection?

Answer 10

cells that fire together wires together.

Question 11

LTP and Learning in animals

Answer 11

morris’ water maze -> big arena full of water, inside you have a platform underwater that cannot be seen and you put a rat in the environment where it investigates its surroundings -> learns where the spatial cues are -> where the platform is. After 10 trials, the rats swim straight to the platform. probe trial - arena is split in quadrants to measure how much the rat stays in on area of the arena. Lesions to the hippocampus - rats spend more time in non-target quadrant areas.

Question 12

What is glutamate in relation to LTP?

Answer 12

important neurotransmitter for LTP. Lands on different types of glutamate receptors (AMPA and NDMA receptors) -> AMPA receptors releases sodium once combined -> under normal conditions magnesium blocks any receptors being transmitted through the NDMA receptor -> however if the neuron is an excited state -> depolarisation -> magnesium is ejected -> ndma releases calcium influx and sodium in post synaptic neuron -> getting a larger EPSP (collective action of calcium and sodium).

Question 13

Role of NMDA in LTP and Learning:

Answer 13

Morris Water Maze task -> injected NMDA receptor antagonist in hippocampus -> hippocampus is faulty and learning and LTP

Question 14

Glutamate synapse role of LTP overview:

Answer 14

Glutamate release onto inactive cell (membrane at resting potential) -> AMPA receptor activated to create EPSP -> NMDA receptor blocked by Mg2+ ion -> Depolarization from AMPA activation -> not sufficient to expel Mg2+
Glutamate release onto an active cell (membrane depolarized) -> AMPA receptor activated -> Mg2+ block on NMDA receptor relieved -> Na+ through AMPA and NMDA channels -> Ca2+ through NMDA channel.
Ca2+ entry through the NMDA receptor leads to: Activation of Calcium calmodulin-dependent protein kinase II (CaMKII) -> phosphorylates existing AMPA receptors increasing their effectiveness -> stimulates the insertion of new AMPA receptors into the membrane. Before -> few AMPA receptors, fewer EPSP -> After: more AMPA receptors working more effectively -> larger EPSPs -> LTP.

Question 15

What is CaMK11?

Answer 15

Known as Molecular switch -> sustained activity after repolarization -> has two parts one that is regulatory and one that is catalytical.
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 16

Presynaptic events in LTP

Answer 16

Long term potentiation can also involve presynaptic events -> Postsynaptic neuron can feed back to presynaptic neuron by retrograde neurotransmitter - Nitric Oxide (NO) -> Ca2+ through the NMDA channel -> activates Nitric oxide synthase -> NO diffuses from site of production and activates guanylyl cyclase in the presynaptic terminal -> Guanylyl cyclase produces the second messenger cGMP -> Signal transduction cascade leads to increased glutamate release from the synaptic bouton. More glutamate released for AMPA receptors -> increased EPSP and strength.

Question 17

Late phase LTP

Answer 17

Protein synthesis required for long-lasting LTP (days, months) -> Protein synthesis inhibitors prevent the consolidation of long-term 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 18

Early vs Late phase LTP

Answer 18

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 19

What is Long-term Depression?

Answer 19

opposite of long-term potentiation. 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 Long Term Depression (LTD). 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 20

Human studies on LTP

Answer 20

Human inferotemporal cortex removed during course of surgery – stimulating LTP in the slices of layers of tissue -> recording of electrophysiology maintained in vitro. -> looking if there are the same processes in different layers of brain tissue -> using HFS = produced LTP, LFS = produced LTD (long-term depression). Tetanic stimulation is artificially high stimulation -> we don’t have these conditions in normal settings (in vitro).

Question 21

What are theta rhythms?

Answer 21

Waves of neuronal activity - hippocampal theta rhythm -> involved in arousal, alertness, fire during exploration etc. stimulating the theta rhythm at different amplitudes (frequency). When neurons are most inhibited/depolarized, and neuron stimulated their forms LTD. 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 22

Manipulating LTP animal experiment 1

Answer 22

Animal experiments -> Morris’ water maze -> can we get an enhancement of LTP with boost of a particular type of NDMA receptor (NR2B receptor) leads to enhanced LTP. Slices of brain tissue in transgenic and normal mice -> Higher EPSP and increase in LTP in transgenic mice by changing the NDMA properties. Rate of rating (acquisition) is greater in transgenic mice -> boosting memory and learning. Probe trial quadrant -> transgenic mice spend more time in target quadrant areas than wild mice.

Question 23

Manipulating LTP experiment 2

Answer 23

In age -> 4 months – 24 months -> Decreased acquisition in the Morris Water Maze -> Decreased LTP -> Decreased expression of the NMDA receptors (NR1 and NR2B). dissecting young and old mice brain tissue -> seen a decline in NDMA receptors. age is a factor

Question 24

Enhancement of LTP experiment

Answer 24

Enrichment -> enhanced acquisition in the morris water maze, potentiated LTP. Enriched mice find the platform much quickly, better memory, brain slices show enhanced LTP when stimulated.

Question 25

Reversal of aging effects by enrichment

Answer 25

Spatial maze task -> aged mice in impoverished environments (IE) show greater deficits than those in normal (SE) or enriched environment (EE). Number of errors -> show weaker cognitive functioning (less LTP, NDMA receptors). Impoverished rats show a higher number of errors -> memory and learning are also weakened. If you improve the lifestyle of these rats and enrich them -> we can reverse their performance in the task even at older rats -> improvements in cognitive -> plasticity of NDMA receptors.

Question 26

Associative learning - classic

Answer 26

Pavlov’s dogs -> associating objects with stimuli -> conditioned response = conditioned stimulus. (e.g., little albert – fear of rats). Unconditioned stimulus is paired with a conditioned stimulus for cued or contextual fear conditioning.

Question 27

what is the Auditory thalamus

Answer 27

sound stimulus imputed to the lateral amygdala. Lateral amygdala activates neurons in the central nucleus activating different motor outputs (hormones, blood pressure, freezing). Long-term potentiation of the associated pathways

Question 28

what is the somatosensory thalamus?

Answer 28

sensory input stimulus. imputed to the lateral amygdala. Converging sensory input from different environmental factors.
Lateral amygdala activates neurons in the central nucleus activating different motor outputs (hormones, blood pressure, freezing). Long-term potentiation of the associated pathways in stimulation A and B.

Question 29

Neuronal mechanisms underlying conditioned fear

Answer 29

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.