NEUR533 - Molecular mechanisms of learning and memory Flashcards
MUST READ THIS
LEARNING OUTCOMES
LEARNING OUTCOMES
What does the acquisition of short-term memory essentially require?
- Physical brain modifications caused by incoming sensory information
- Modifying synaptic transmission between neurons
What does long-term memory consolidation require?
New gene expression and protein synthesis
Flow of sensory information into long term memory
what animal was a lot of learning and memory studies conducted on in the early days?
Aplysia
Californian sea slug
Studies done in the 70’s
Advantages
- large brain
- simple brain
- large abdominal ganglia
- Neurons can be easily identified
-
Repeated stimulation =
- no changes presynaptically
- BUT sees changes in excitatory post-synaptic potentiation
= HABITUATION
SENSITIZATION CELLULAR MECHANISM - KNOW
What is neuron L29?
- secondary motor neuron
- Interneuron
- Activated by stimulation (electrical) in the head ganglia
- Released 5-HT
- Binds to GPCR
- Closes K+ channels
- Delays K+ repolarization
What does an increase in closing K+ channels do for an action potential?
- Shift to the right
- Longer repolarisation
- Increased VG Ca2+ channels
= Increased Ca+ influx
= Increase NT
= Increased post-synaptic potential
= Sensitisation
youtube this
Cellular mechanism of classical conditioning of the gill withdrawal reflex.
- Opens presynaptic Ca++ channels
- Ca++ influx
- Ca+ activates AdCy
- Changing nature of presynatpic terminal
- Stimulates L7 neuron
(needs to be paired by cAMP)
Structure of the cerebellar cortex - always understand
What are the 4 layers of the cerebellar cortex?
Molecular layer
Purkinje cell layer
Granule cell layer
White Matter
What do climbing fibres do?
Innovate a single purkinje neuron
Long term depression of synaptic transmission in cerebella cortex
A mechanism of LTD induction in the cerebellum
What do climbing fibres do?
- Activate Na+ channels
- Releases glu
- Activates VG Ca++ channels on post synaptic membrane
- Increases intracellular Ca+
(must be paired) - Large stimulatory activation prior to PKC
= FEWER post synaptic AMPA receptors
What does a reduction in AMPA receptors do to PSM
- LTD
- Reduction in PS excitation
- Only when parallel fibres and climbing fibres come together
What does the internalisation of AMPA receptors and LTD do intracellularly?
Getting rid of movements that dotn need
fine tuning of motor system
- Reduces errors in movement
LTS in the cerebellum - LEARN AND DRAW THIS GRAPH
What does the increase of internal Ca++ concentration do?
Increase AdCy
What does the increase in AdCy do?
Increase cAMP
Increase PKA
Increase phosphorylation
Increase gene transcription
What does the increase internal Na+ concentration and activation of PKC do PLUS combine with internal Ca++ concentration?
Internalise AMPA receptors
= Decrease openings of AMPA receptor channels
= Reduce LTP
= Initiate LTD
What increases the internal Ca++ concentration?
Strong depolarization of Purkinje cell dendrites
What is the area IT associated with?
visual area
FACIAL RECOGNITION
Memory storage of objects
Can every neuron form a memory of recent patterns of activity?
Yes
Responses to faces in the inferotemporal cortex (IT area)
remember IT = facial recognition
= Visual association
Distributed memory storage
Model of distributed memory
REMEMBER AND DRAW OUT THIS PATHWAY
KNOW: what is the first path of the trisynaptic circuit of the hippocampus?
- Entorhinal cortex -> dentate gyrus (perforant path) synapses
KNOW: what is the 2nd path of the trisynaptic circuit of the hippocampus?
- Dentate gyrus > CA3 (Mossy fibre) synapses
KNOW: what is the 3rd path of the trisynaptic circuit of the hippocampus?
- CA3 > CA1 (Schaffer collateral) synapses
KNOW: what is the complete path of the trisynaptic circuit of the hippocampus?
- Entorhinal cortex -> dentate gyrus (perforant path) synapses
- Dentate gyrus > CA3 (Mossy fibre) synapses
- CA3 > CA1 (Schaffer collateral) synapses
Who studied that high-frequency electrical stimulation (tetanus) of excitatory pathway produces LTP?
Bloss and Lomo
LTP in CA1 - know
LTP is only in association with input 1 - doesn;t change input 2
Mechanism of LTP at CA1
LTP in CA1 - KNOW AND LEARN
How long does it usually take for AMPA and NMDA receptors to activate kinases?
Minutes
how do kinases influence the AMPA receptor?
phosphorylates the AMPA receptor and keeps them open longer
or
Insertion of extra AMPA receptors
= LTP
e.g. from a significant event that needs to be remembered or learnt
CA++ imaging from single dendrite
Showing morphological change
Sprouting new dendritic spines
(induced LTP)
LTD - weakening of synapses
What is homosynaptic LTD?
- Synapses Weakened by weak depolarization
What i bidirectional plasticity governed by?
LTP
LTD
Spike timing-dependent plasticity
Mechanisms of LTD in CA1
What are the 2 receptors regulating homosynaptic LTD at Schaffer collateral-CA1 synapse?
- GPCR glu receptors (mGluRs)
- NMDA receptors
How do NMDA receptors increase LTD in CA1?
Rise in PS Ca++ to trigger LTD
Is LTP and LTD bidirectional regulation?
Yes
Is a rise in Ca++ needed for LTD and LTP?
Yes both need it
How Ca++ can trigger both LTP and LTD in hippocampus
HFS = high frequency stimulation
Egg carton model of AMPA R
Who did the first experiments with inhibitory avoidance and found NMDA -receptor processes in memory?
Morris
Who did genetic knockouts in mice deleting CaMK11 NMDA subunits and found hippocampal LTP and memory parallel deficits ?
TONEGAWA , Silva, and colleagues
Hippocampal __________ receptors play a key role in synaptic LTP and LTD and learning and memory
NMDA
Morris experiment
What does area IT abbreviate for?
Inferotemporal cortex
Synaptic homeostasis
Meta plasticity - know and remember
Youtube metaplasticitiy
Synaptic scaling
Youtube and know
How long does synaptic scaling take?
Occurs over hours to days
Memory consolidation
What 2 things regulate the molecular switch hypothesis?
CAMKII and LTP
Look this up and youtube
Protein synthesis and memory consolidation
Who did studies on weak stimulation endowing synapses with a tag?
Julietta Frey and Richard Morris
Synaptic tagging and capture experiment - youtube
What is CREB?
cAMP response element binding protein
- Regulate neighbouring gene expression
Who identified that CREB regulates gene expression for memory consolidation?
Tully and Yin
CREB gene expression regulation
Structural plasticity and memory
Summary
Invertebrate research has clearly shown that Hebb was right: Memories_____ reside in synaptic al- terations.
can
Are faces declarative memories?
Yes
Responses to faces in the inferotemporal cortex.
The IT is part of the _______ stream
ventral stream
__________ is a selective amnesia for familiar faces (including one’s own) that can result from damage to the _____________cortex in humans.
prospagnosia
inferotemporal
A model of a distributed memory.
A mechanism for sensitization of the gill-withdrawal reflex.
KNOW AND DRAW THIS
What doess the Ammons horn entail?
CA2 and CA1
(CA stands for cornu Ammonis, Latin for “Ammon’s horn”).
The entorhinal cortex sends information to the hippocampus by way of a bundle of axons called the ___________.
perforant path.
A major input to the hippocampus is the ___________ cortex.
entorhinal
Perforant path axons synapse on neurons of the _____________.
dentate gyrus
Dentate gyrus neurons give rise to axons (called ___________) that synapse on cells in CA3
mossy fibers
The CA3 cells give rise to axons that branch. One branch leaves the hippocampus via the _________. The other branch, called the ________________, forms synapses on the neurons of CA1
fornix
Schaffer collateral
Long-term potentiation in CA1.
In 1973, an important discovery was made in the hippocampus by Timothy Bliss and Terje Lømo, working together in Norway. They found that brief, high-frequency electrical stimulation of the _______________ synapses on the neurons of the dentate gyrus produced ________.
perforant path
LTP
LTP can last a long, long time
The synapse gets stronger when the glutamate released by the presynaptic terminal binds to postsynaptic NMDA recep- tors and the postsynaptic membrane is depolarized strongly enough to displace ______from the NMDA receptor channel.
Mg2
Henry Markram, Bert Sakmann, and their colleagues at the Max Planck Institute investigated what hap- pens when a postsynaptic spike is generated (via a micro- electrode) at various time intervals before or after an EPSP. Remarkably, they found that if a postsynaptic action potential follows the EPSP within about_____ msec, the synapse po- tentiates.
50
Nothing happens in response to the spike or the EPSP alone; LTP results specifically from the precise tim- ing of EPSP and spike, just as Hebb suggested! In addition, the timing requirements for LTP in these studies agreed very well with those originally reported by Levy and Steward. This is an example of what is now referred to as spike timing– dependent plasticity.
Review
The rise in [Ca2] activates two protein kinases: _________ and calcium-calmodulin-dependent protein kinase II, also known as ________
protein kinase C (PKC)
CaMKII (pronounced “cam-K-two”)
What does PKC and CaMKII do?
protein kinases regulate other proteins by phosphorylating (attaching phosphate groups to) them
Routes for the expression of LTP in CA1. REMEMBER AND KNOW
DRAW OUT PROCESS
The growth of spines following LTP.
An ex- tension of Hebb’s theory, designed to account for bidirectional (up and down) regulation of synaptic strength, is called the______ theory, named for its authors, Elie Bienenstock, Leon Cooper, and Paul Munro, working at Brown University.
BCM
(brain cognitive map)
The human inferotemporal cortex, is a region believed to be a repository of _______memories.
visual
Homosynaptic LTD in the hippocampus.
review and know
LTD is input-specific, so there is no change in the response to input 2 after a tetanus to input 1.
LTP can result when the EPSP caused by synaptic glutamate release _________ an action potential in the postsynaptic neuron; this is an example of ______________ plasticity
precedes
spike timing–dependent
MAYBE YOUTUBE THIS?
if LTP is putting phosphate groups on, LTD apparently is taking them _____
off
biochemical evidence now indicates that _______ receptors are ___________ in response to stimulation that induces LTD
AMPA
dephosphorylated
A model for how Ca2 can trigger both LTP and LTD in the hippocam-
pus
there is evidence that a protein called PSD-95 (a postsynaptic density protein with a molecular weight of______ kilodaltons)
95
Increasing the expression of _______ in neurons increases the synaptic capacity for AMPA receptors.
PSD-95
Bidirectional synaptic modifications in human area IT.
Slices of human temporal cortex, removed during the course of surgery to gain access to deeper structures, were maintained in vitro. Synaptic responses were monitored following various types of tetanic stimulation. In rat CA1, stimulation of _______ Hz produced LTD, while ______ Hz stimulation produced LTP.
1 Hz
100 Hz
LTP in CA1 induced by learning
Tonegawa, Alcino Silva, and their colleagues “knocked out” (deleted) the gene for one subunit () of CaMKII, and found parallel deficits in hippocampal LTP and memory. Since then, many genes have been manipulated in mice, with the aim of assessing the role of LTP and LTD mechanisms in learning.
If too little hippocampal NMDA receptor activation is bad for learning and memory, what would happen if we boosted the number of NMDA receptors? Amazingly, animals engineered to produce more than the nor- mal number of NMDA receptors show enhanced learning ability in some tasks. Taken together, the pharmacological and genetic studies show that hippocampal NMDA receptors play a key role not only in synaptic modifi- cation, such as LTP and LTD, but also in learning and memory.
At some level of moderate NMDA receptor activation, between that required for LTD and for LTP, there is no net change. This value is called the ________________ threshold.
synaptic modification
When activity rises, due perhaps to too much LTP, the modification threshold slides _____, making LTP more difficult to produce. Conversely, if activity levels fall, due perhaps to too much LTD, the modification threshold slides ______, making LTD less likely and LTP easier to produce.
up
down
This general concept, that the rules of synaptic plasticity change depending on the history of synaptic or cellular activity, is called ____________.
metaplasticity
NMDA receptors are composed of how many subunits?
4
two NR1 subunits and two NR2 subunits.
What are the 2 subunit names for the NMDA receptors?
NR1 andNR2
At many synapses in the cerebral cortex, two types of NR2 subunits are used to construct the receptor: ______ and ______
NR2A
NR2B
The ratio of NR2A to NR2B subunits determines the properties of the receptor, including how much Ca2 can pass and what intracellular enzymes are activated.
LTP is favoured when more ________-containing receptors are expressed at the synapse
NR2B
LTD is favored when more _________-containing receptors are expressed.
NR2A
Research has shown that after a period of high cortical activity, NR2A levels increase and NR2B levels decrease, promoting LTD over LTP
(doesn’t need to expend so much energy creating new NR2Bs)
On the other hand, NR2B levels increase and NR2A levels decrease after a period of low cortical activity, promoting LTP over LTD
The sliding modification threshold.
As with metaplasticity, multiple mechanisms contribute to synaptic scaling. One appears to use Ca2 entering the soma through voltage-gated Ca2 channels and activating calcium-calmodulin-dependent kinase IV (CaMKIV, a close relative of CaMKII) to regulate gene expression.
A pe- riod of elevated activity increases CaMKIV-dependent gene expression, whereas a period of inactivity decreases it. The ultimate consequence of these changes in gene expression is the cellwide removal or insertion of glutamate receptors at synapses (both NMDA receptors and AMPA receptors)
How long is the induction of LTP and LTD?
seconds to miutes
Like metaplasticity, scaling occurs over a longer time period ____________
(hours to days)
In the case of LTD and LTP, this occurs at the ____________ ________ receptor and at proteins regulating AMPA receptor number at the synapse.
postsynaptic AMPA
The regulation of CaMKII.
How is the hinge of the protein kinase molecule kept open? The answer lies in the fact that CaMKII is an autophosphorylating protein kinase; each subunit within the CaMKII molecule can be phosphorylated by a neigh- boring subunit. The consequence of subunit phosphorylation is that the hinge stays open.
Recall that the entry of Ca2 into the postsynaptic cell and the activation of ______ are required for the induction of LTP in CA1.
CaMKII
CaMKII consists of ____ subunits
Each subunit catalyzes the phosphorylation of substrate proteins in response to a rise in Ca2-calmodulin.
10
If the initial activation of CaMKII by Ca2-calmodulin is sufficiently strong, autophosphorylation will occur at a faster rate than dephosphorylation, and the molecule will be switched on. Persistent ac- tivity of CaMKII could contribute to the maintenance of synaptic poten- tiation, for example, by keeping the postsynaptic AMPA receptors phos- phorylated
The general idea that an autophosphorylating kinase could store information at the synapse, initially proposed by John Lisman at Brandeis University, is called the molecular switch hypothesis.
Frey and Morris asked if the newly synthesized proteins acted only on the synapses whose activity triggered their synthesis. They found that the wave of protein synthesis triggered by _______________ of one synaptic input to a hippocampal neuron would also consolidate the LTP caused by the ___________________- of a second input
strong stimulation
weak stimulation
It appeared that the weak stimulation endows synapses with a_____ that enables them to cap- ture the newly synthesized proteins that consolidate LTP.
tag
By varying the interval between the weak and strong stimulation of the two inputs, Frey and Morris were able to determine that the tag lasts about ____ hours.
2
In this way, a trivial event that would otherwise be forgotten, like last Tuesday’s dinner, might be seared into long-term memory if it occurs ____________ of a momentous event that triggers a wave of new protein synthesis, like the first kiss of the love of your life.
within 2 hours
One transcription factor essential to memory is called the _______________________________ protein
cyclic AMP response element binding protein (CREB)
What does CREB do?
binds to specific segments of DNA,
called cyclic AMP response elements (CREs), and
regulate the expression of neighboring genes
There are two forms of CREB: CREB-2 represses gene expression when it binds to the CRE; CREB-1 activates transcription, but only when it is phosphorylated by ________________.
protein kinase A (PKA)
Tim Tully and Jerry Yin at Cold Spring Harbor Laboratory showed that CREB regulates the gene expression required for memory consolidation in the _______________ Drosophila melanogaster
fruit fly
Synaptic tagging and capture. KNOW AND LEARN THIS ?
The regulation of gene expression by CREB.
CREB-2 functions as a ___________ of gene expression.
repressor
CREB-1, an activator of gene expression, can displace _________.
CREB-2
When ___________ is phosphorylated by protein kinase A (and other kinases), transcription can ensue.
CREB-1
The modulation of gene expression by ______ provides a molecular mechanism that can control the strength of a memory.
CREB
Synaptic remodelling in the cerebral cortex during learning and memory.A
