Test 3 Flashcards
1
Q
What is Neural Plasticity? 2
But other types of plasticity are also necessary 3
A
Any change to the circuitry that leads to a change in neural processing
Storing information (i.e., a memory) requires a change (i.e., learning) within a neural circuit
Development
Adaptation
Compensation after damage
2
Q
Plasticity isn’t just synaptic… 3
A
1. Synaptic plasticity (electrophysiological response) 2. Intrinsic plasticity (ion channels, Rm) 3. Structural plasticity (synapse, spine, dendrite, axon morphology)
3
Q
Hebbian Plasticity
A
When an axon of cell A is near enough to excite cell B and repeatedly or persistently takes part in firing it, some growth process or
metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased
4
Q
Hebbian Plasticity Requires
that leads to
Predicted outcome:
A
presynaptic activity
postsynaptic activity
change in connection strength
5
Q
Long-term potentiation (LTP) was discovered using
showed a
A
hippocampal field potential recordings
long-lasting change in synaptic strength (Hebb: efficiency) after stimulation
6
Q
Field Potential Recordings 3
A
Field potential recording electrodes are placed within the circuit, recording the summed electrical activity of a population of cells
Different electrode placement gives
different information
Different filtering of signal gives different
information (population or single
cell activity)
7
Q
Field EPSPs
3 parts
A
Field potential electrodes can record evoked synaptic responses from a group of neurons
The Population Spike is the electrical signal of all the postsynaptic APs
The Fiber Volley is the electrical signal of the
presynaptic action potentials
The fEPSP is the electrical signal of all the postsynaptic dendritic EPSPs
8
Q
Field Potential Plasticity: Lømo recorded fEPSPs before and after bursts of high frequency stimuli 3
A
The fEPSP gets stronger
The Fiber Volley does not change! Indicating that the difference is not just
stimulation of more axons
The change is long-lasting, can last
as long as the recording can be made
9
Q
(Note: often fEPSP slope
A
is quantified rather than amplitude. Slope is a good indicator of increasing synaptic strength while amplitude can be confounded,
e.g., by population spikes)
10
Q
Induction: Stimulation/Pairing = Stimuli designed to ensure that postsynaptic cells were highly activated, fire lots of APs 2
A
- HFS - high frequency stimulation.
100 Hz for 1 second, repeated.
Very effective, not physiological. - Theta bursts - patterned input with timing based on on theta oscillations.
Bursts of 4 pulses @ 100 Hz, repeated at 200 ms inter-burst interval
More physiological, more efficient.
11
Q
To encode a specific input
sequence,
A
only the synapses
active should undergo plasticity
12
Q
Synapse Specificity 2
A
Synapses that are stimulated show LTP, other synapses don’t
This is key: (for this types of plasticity) only synapses given LTPinducing bursts show LTP
13
Q
What can change at the synapse to make the response bigger (or smaller)?
A
LTP and AMPAR trafficking
14
Q
What is the molecular mechanism of LTP?
A
Starts with NMDARs
15
Q
The LTP pathway 6
A
NMDARs ->
Calcium entry ->
Calmodulin (CaM) ->
CaMKII ->
AMPAR / AMPAR auxiliary subunit phosphorylation ->
AMPARs: greater conductance, more to synapses, LTP
16
Q
NMDAR Dependence
A
Blocking NMDARs blocks LTP, removing antagonist rescues LTP
17
Q
LTP increases 2
A
AMPA currents
LTP increases AMPA currents, not as much
change in NMDA currents
18
Q
Calcium Dependence 2
A
LTP depends on calcium entry through NMDARs
Calcium chelators block LTP
19
Q
Calcium/calmodulin 2
A
Calmodulin associated with Neurogranin when no calcium present
After binding, Ca/CaM disconnects and
diffuses, acts on substrates
20
Q
CaMKII 4 basics
A
Ca/calmodulin-dependent protein kinase II
Mostly α and β, but also γ and δ
12 subunits in a heteromer
CaMKII heteromers open up after binding
Calmodulin, expose catalytic sites
21
Q
CaMKII 3 major domains
A
Association: heteromer formation
Regulatory: activation
Catalytic: acting on substrates
22
Q
CaMKII: Calmodulin binding opens
Phosphorylation
and ________ persistent
A
catalytic domain
keeps catalytic domain open
Autophosphorylation or oxidation
can make activity persistent
23
Q
CaMKII has multiple actions in LTP 2
A
- Direct phosphorylation of AMPA receptors
2. Phosphorylation of AMPA receptor auxiliary subunits (TARPs; transmembrane AMPAR regulatory proteins)
24
Q
AMPAR Phosphorylation 4
A
CaMKII phosphorylates AMPAR
intracellular C-terminal domain directly
AMPAR phosphorylation increases single channel conductance
This means: bigger synaptic response
Does increase synaptic strength, but not fully sufficient to be LTP
25
TARP Phosphorylation 2
Non-phosphorylated TARP diffuses around in membrane
Phosphorylated TARP binds to PSD-95 more readily, gets trapped by PSD-95 in synapse
26
AMPAR Trafficking/Trapping
More AMPARs at the synapse means more
| conductance, bigger EPSC/P, bigger synaptic response
27
Synaptic Plasticity is Bidirectional 3
If all synapses can only get stronger, eventually all the synapses will become as strong as they can be
The neuron will be overwhelmed by its inputs
Thus, if synapses can get stronger (potentiate), there must also be
mechanisms for synapses to get weaker (depress)
28
Synaptic Strength is on a Spectrum
The amount of plasticity you can induce in either direction depends on your starting point on the spectrum
29
Synaptic Strength Diminishes 2
As opposed to the HFS that induces LTP, early experiments showed that low frequency stimulation could decrease synaptic strength
LFS: 1 Hz for 15 minutes = 900 stimuli
30
LTD doesn’t occur when
the synapse isn’t active, it occurs specifically during low levels of activity
31
Is LTD Hebbian? 2
Hebb doesn’t actually mention weakening of connections
But, LTD works within this framework, high activity strengthens, low activity weakens, so we generally call this Hebbian
32
How does NMDAR-dependent LTD
| work? pathway 6
NMDARs ->
Calcium entry ->
Calmodulin ->
Calcineurin (PP2B) to PP1 -> Dephosphorylation of targets ->
AMPAR removal from synapse by endocytosis
33
Calcium/Calmodulin (LTD)
Calmodulin binds calcium,
changes conformation, and is
able to bind substrates
34
Ca/Calmodulin has
2 opposing substrates (PP2B (Calcineurin) and CaMKII)
35
Ca/CaM can bind both Calcineurin 3
and CaMKII 3
Phosphatase: phosphate remover
Inhibitor
LTD
Kinase: phosphate adder
Activator
LTP
36
Calcineurin LTD mechanism 1 + 3
Inhibits Inhibitor-1, which activates PP1
3. I-1 Inactivation increases amount of
active PP1
2. PP2B inactivates I-1
1. Ca/CaM activates PP2B
37
Phosphotases can
2 examples
undo LTP changes to AMPARs
1. Dephosphorylate AMPARs
2. Dephosphorylate TARPs
38
LTD Requires 3
Endocytosis
LTD stimuli lead to AMPAR endocytosis via multiple mechanisms
e.g., Calcineurin interacts with dynamin in clathrin process
39
Dephosphorylation Activates
GSK3
40
Activated (dephosphorylated) GSK3
helps endocytose AMPARs
41
Mechanisms of LTP Postsynaptic mechanisms 4
* AMPAR insertion/migration into synapse
* Increased AMPAR stabilization
* Increased channel conductance
* Unsilencing of silent synapses
42
Mechanisms of LTP Presynaptic mechanisms 2
• Increase in probability of release (Pr)
• Increase in quantal content (amount of
neurotransmitter/vesicle)
43
LTP Postsynaptic mechanisms =
LTP Presynaptic mechanisms =
Increased AMPAR-mediated currents
Increase in neurotransmitter release
44
Mechanisms of LTD Postsynaptic 2
* Internalization of AMPARs
| * Decreased channel conductance
45
Mechanisms of LTD Presynaptic 2
* Decreased Pr
| * Decreased quantal content
46
LTD Postsynaptic mechanisms =
LTD Presynaptic mechanisms =
Decreased AMPAR-mediated current
Decreased neurotransmitter
47
What signals activate presynaptic plasticity? 2
Direct activation via increased Ca2+
through voltage-gated calcium
channels
Retrograde messengers send
signals from postsynaptic side
48
Examples of presynaptic plasticty Autoregulation
Glutamate acts on presynaptic mGluRs,
| changing glutamate release
49
Examples of presynaptic plasticty Direct activation
| VGCCs
High frequency stimulation causes increased Ca2+ concentrations, increasing
glutamate release
50
Examples of presynaptic plasticty Retrograde signaling
Endocannabinoids released from postsynaptic neuron binds receptors on presynaptic terminal, decreasing release
51
How to differentiate pre vs. post? • What is the experimenter measuring? 1 + 3
Post-synaptic responses (PSPs, PSCs) = Field potential
Current clamp
Voltage clamp
52
How to examine presynaptic changes while
| measuring postsynaptic responses? 4
* Paired-pulse ratio (Pr)
* Failure rate
* Variation in postsynaptic responses
* Miniature spontaneous activity
53
Paired-pulse ratio 2
* PPR = amplitude of the second response/ amplitude of first response
* PPR is inversely correlated with release probability
54
PPR and LTP
PPR and LTD
Decrease in PPR (increased Pr)
Increased PPR suggests a decrease in Pr
55
So, what does PPR tell us? 2
Problems with PPR as a meaure of Pr 2
=
* Increased PPR = possible decreased Pr
* Decreased PPR = possible increased Pr
* Postsynaptic receptor desensitization
* Diffusion/uptake of neurotransmitter
• PPR is a good but not perfect measure of Pr
56
Minimal stimulation failure rates 3
* Assuming a constant # of synapses, Pr is inversely correlated with failure rate
* In minimal stimulation experiments, stimulation intensity is adjusted so that one or only a few axons are activated
* Decreased failures = increased Pr and vice versa
57
Minimal stimulation failure rates equation
Rfail = (1 - Pr)^n
58
Example of LTP with no change in Rfailure
Example with decreased Rfailure
Postsynaptic changes
Suggests increased Pr
59
Evidence of decreased
failures/increased Pr at a
| single synapse without postsynaptic changes
60
What does a change in failure rate suggest? 2
* Decreased Rfailure = Increased Pr
| * Increased Rfailure = Decreased Pr
61
What’s the problem with failure rates? 2
Remember that your are assuming that you are measuring a constant number of synapses
Silent synapses
62
Silent synapses 2
have NMDA but no AMPA
need depolarization for AMPA to enter
63
What provides the depolarization for synapse
| unsilencing?
• AMPA receptors in neighboring synapses
• Extrasynaptic AMPARs
•Depolarizing GABAergic responses (as in my graduate
work)
64
Coefficient of variation of postsynaptic response formula 3
CV^2 = (1-Pr)/nPr
Cv = Standard Deviation / Mean
Measure the variation of the amplitude of the postsynaptic
response before and plasticity induction
65
Coefficient of variation of postsynaptic response: Assuming a
• CV2 is 3
Again, if
constant number of synapses (n doesn’t change),
negatively correlated with Pr
• When Pr increases, CV2 decreases
• When Pr decreases, CV2 increases
n changes (like postsynaptic synapse unsilencing or
formation of new synapses), CV is not a reliable
measurement of Pr
66
Quantal experiment: Miniature PSCs (minis) 3
• Minis are a measure of spontaneous vesicle release
• Recorded in presence of sodium channel antagonist (TTX) to
block action potential mediated release
• Each event is thought to be the release of a single vesicle
67
minis equation 1 + 3
Reponse = NPrQ
```
n= num vesicles/synapses
Pr= prob of release
q = quantal size
```
68
change in mini frequency 2
amplitude
changes in N or Pr
Q
69
Mini frequency is correlated with Pr 2
Reduced Ca2+ = Lower Pr – Lower mini freq
Increased Ca2+ = higher Pr – higher mini freq
70
Mini amplitude is correlated with Q 2
* Could be presynaptic - change in quantal content (amount of neurotransmitter release per vesicle)
* Could be postsynaptic –change in number or conductance of receptors
71
What about postsynaptic changes? 3
•Insertion or diffusion of AMPARs into synapse
•Increased stabilization/reduced internalization of
AMPARs
•Increased conductance of AMPARs
72
How to measure postsynaptic changes? 2
these measurements tell us
* Mini amplitude
* AMPA/NMDA ratio
• These measurements just tell us if there are postsynaptic changes, not which type of change occurs
73
AMPA/NMDA ratio 2 general
• In general, plasticity involves changes in AMPARs, not
NMDARs
• Measured using voltage-clamp
74
AMPA/NMDA ratio 3 specific interpretations of results
• Increased AMPA/NMDA suggest increased AMPAR conductance
• Decreased AMPA/NMDAR suggest decreased AMPAR conductance
• No change in AMPA/NMDAR with plasticity is used as an argument for
presynaptic changes
75
So, is plasticity mostly presynaptic or postsynaptic??? 2
Depends on the synapse and induction protocol
Some synapses have strictly presynaptic mechanisms,
other strictly post, and some have both
76
Induction vs. Expression 2
Induction phase
Occurs during or shortly after the stimulation used to initiate LTP. Consists of all the steps and mechanisms that lead to long lasting changes in
associated with LTP
Expression or maintenance phase
Persistent changes in synaptic strength mediated by long-lasting alterations in synaptic function
77
Expression: Protein kinases & Phosphorylation 3
Protein kinases
Enzymes that phosphorylate specific amino acids in a protein that change the function of that protein
Protein kinases implicated in LTP (Calcium-calmodulin dependent kinase II (CAMKII))
Protein kinases have been implicated in induction, expression, and both.
78
Maintenance:
Transcription and translation in LTP
79
Bidirectional changes in long-term plasticity 2. Branch point =
calmodulin
80
_______ determines plasticity
Intracellular calcium
81
Calmodulin 2
An enzyme shared by LTP and
LTD pathways
How does it know to activate LTP vs LTD pathways?
82
Calcineurin 3
Activated at low calcium concentrations by Calmodulin
Very sensitive to small, transient calcium signals
Sets off signaling cascade to dephosphorylate AMAP receptors
83
CaMKII 3
CaMKII is activated by phosphorylation
CaMKII can activate itself via autophosphorylation
Deactivating CaMKII requires dephosphorylation
84
there is a _____ for long-term plasticity
Sliding Threshold
85
Synaptic Tag Hypothesis
Proposed properties of synaptic tags 5
Synaptic tags identify synapses where activity promotes local changes in
synaptic strength
1. Generated in an activity-dependent manner
2. Have a lifetime of 1-2 hours
3. Two types: LTD and LTP
4. Tags are input specific
5. Tags can interact with newly
transcribed mRNA
86
A brief history: Otto Leowi’s frog hearts
message is a chemical released by the nerve
87
Sutherland and Rall discover cAMP
stimulation of cells from organs throughout the body resulted in
increased levels of cyclic adenosine monophosphate
(cAMP).
discovery was made by stimulating various organs and measuring levels of cAMP in those organs.
hypothesized that cAMP acts as a second messenger molecule
88
Basic g-protein functions 3
Gs stimulate adenlyl cyclase = increase cAMP
Gi/o inhibit adenlyl cyclase = decrease cAMP
Gq: activates Phospholipase C
89
G-proteins activate many pathways
GPCRs do a bunch of stuff, response depends on which receptors a cell expresses, which G-proteins they bind, which pathways are present to be activated
90
fragile x mutation
form of protein synthesis-dependent synaptic plasticity, long-term depression triggered by activation of metabotropic
glutamate receptors, is selectively enhanced in the hippocampus of
mutant mice lacking FMRP
91
Gq protein signaling pathway 6
result
```
mGlu5 ->
gq activation ->
PLC, DAG ->
PKC ->
AMPAR phosphorylation, release from GRIP and PICK1 ->
AMPARs leave synapse, endocytosis
```
Fewer AMPARs means fewer ion channels, smaller EPSC, smaller EPSP
92
metabotropic glutamate receptors induce
a form of LTP controlled by translation and arc signaling in the hippocampus
93
Gq protein signaling
| pathway 2
Similar signaling pathways are involved in mGluR mediated LTP and LTD. The largest difference has to do with the
stimulation frequency associated with each process.
The molecular signaling differences associated with LTP vs LTD are not well
understood.
94
Gs protein signaling pathway 6
Gs-protein coupled receptor activation ->
Adenylyl cyclase (AC) activation ->
Increased cAMP production ->
Release of catalytic (C) subunit of PKA by cAMP binding to regulatory (R) subunit ->
Activation of cAMP response element binding protein (CREB) ->
Protein translation: Including structural and synaptic proteins supporting LTP
95
local potentiation of synapses
and is altered in
by serotonin
rodent models of depression
96
Gi/o receptor activation – 5HT-1B 2 paths (2, 3)
```
Adenylyl cyclase (AC) inhibition -> decreased cAMP
production
```
PLC activation -> CamKII activation -> AMPA phosphorylation
97
TA Synapses in stressed rats
The underlying reason for this difference is
Behavioral data show that the
do not respond to 5HT1B
receptor activation the same
as control rats.
not understood, however, authors hypothesize
that it has to do with the
therapeutic effects of antidepressant medication.
SSRI fluoxetine restores
sucrose preference in rats that
have undergone social defeat
stress.
98
Multi-modality sensory modulation:
| neuromodulators, HCN channels, dendritic spikes
Inputs in different layers come from different sources
99
draw Multi-modality sensory modulation:
look at thing
100
Multi-modal cortico-cortical problem
Synapses are too distal, EPSPs
don’t propagate all the way to
the soma
Input is weak
101
add Neuromodulatory synapses path 9
```
Norepinephrine ->
binds alpha-2A receptor ->
activates gi ->
inhibits adenylyl cyclase ->
decreases cAMP ->
less activation of HCN channels ->
higher Rinput ->
EPSPs become dendritic spikes ->
Propagate farther, enhance
synchronous modal input
```
102
result of Multi-modality sensory modulation
Hearing a scary sound
makes your brain pay more
attention to other sensory
inputs
103
AMPAR subunits 2
AMPA receptors can form homoor hetero-oligomers (heterooligomers more common in vivo)
Subunit composition depends on: development, cell type, brain area and activity
104
What do subunits matter? 3
Kinetics: sets the duration of gsynapse
Permeability: Which ions will flow through the channel (Na+, K+, Ca2+)
Single channel conductance:
influences the amplitude of
the EPSP
105
AMPAR permeability
BUT
“Most” AMPAR subunit combinations (any made up of
GluA1, 3, and/or 4) form receptors that are permeable to calcium
“Most” AMPARs in the brain contain a GluA2 subunit,
which makes that receptor impermeable to calcium
106
GluA2 R/Q 3
GluA2 has a positively charged R within the pore where other
subunits have a neutral Q
This is enough to stop divalent cations from passing through
But that R isn’t encoded in the GRIA2 gene…
107
GluA2 R/Q editing 4
GluA2 mRNA is edited by ADAR2
very specific to GluA2; very efficient
Virtually all GluA2 in the brain has the R (except in certain
pathological states)
Post-transcriptional editing plays a vital role in normal synaptic physiology
108
Nonlinear AMPAR I/V curves (rectifying I/V curve) 4
As Vm depolarizes toward
0mV, non-GluA2 AMPARs
are blocked by intracellular
polyamines
Analogous to NMDAR block
by Mg, but in reverse
GluA2-containing AMPARs
aren’t blocked
Physiological marker of
subunits composition
109
AMPAR single channel conductance
GluA2-containing AMPARs have lower single channel conductance
110
So is there plasticity of AMPAR subunits? 4
Yes!
Cells that express Ca-permeable AMPARs also express Caimpermeable AMPARs
What matters is: what receptors are at the synapses
During plasticity receptors at active synapses are swapped out (note: whole receptors are traded, not individual subunits within a receptor)
111
What neurons is plasticity of AMPAR subunits relevant for? 2
Many cells expressing Capermeable AMPARs are
aspiny, many are GABAergic
Consider implications for
circuit activity: this is plasticity of excitatory synapses made onto nonexcitatory cells
112
High activity causes
a subunit switch
113
Mechanism of Ca-permeable AMPAR plasticity 4
1. High synaptic activity leads to calcium buildup, activates PKC
2. PKC activates PICK to bring GluA2 AMPARs into synapse; phosphorylates GluA3 dissociating it from GRIP
3. NSF replaces PICK
4. GRIP replaces NSF, stabilizing new AMPAR at synapse
114
Ca-permeable AMPAR swapping plasticity
Same number of receptors, decreased response (lower single channel conductance)
Self-limiting: next train of inputs won’t induce calcium buildup
Anti-Hebbian: high activity leads to synaptic weakening
115
Pathological Ca-permeable AMPARs 3
After ischemia, GluA2 expression drops
More synapses have Ca-permeable AMPARs (even in pyramidal neurons that don’t
usually have them)
Ischemia induces chromatic remodeling via REST, silences GRIA2
116
GRIP, PICK, PKC with Ischemia 4
Ischemia also activates PKC
at synapses
Instead of removing Ca-permeable AMPARs, this time it removes GluA2
With GRIA2 expression
limited, removed GluA2 is
replaced by Ca-permeable
AMPARs
Added calcium load leads to cell death
117
Inducing Plasticity 3 methods
HFS - High Frequency Stimulation (aka Tetanus)
LFS - Low Frequency Stimulation
TBS - Theta Burst Stimulation
118
Is there a physiological
basis for
“takes part in firing”?
EPSP: “takes part”?
119
Input timing
The timing between input (EPSP) and output (AP) makes all the difference for plasticity
EPSP takes part in firing AP
(“Positive Pairing”)
EPSP not part of firing AP
(“Negative Pairing”)
120
Spike timing dependent LTP protocol 2 postive
Positive Pairing LTP
induction protocol - Stimulate presynaptic axons and Current clamp
postsynaptic neuron
(force an AP)
Paired EPSP/AP, 60 times @ 1Hz
121
LTP induction protocols Pairing 60 times @ 1 Hz = 2
frequency and timing don’t
necessarily define plasticity
Pairing protocol forces a consistent,
definitive output
122
Spike timing dependent LTD protocol 2 negative
Negative Pairing - STD LTD - Un-Paired EPSP/AP,
60 times @ 1Hz
Requires NMDARs
123
Plasticity determined by
relative timing between input and output
124
So… is postsynaptic activity necessary? 5 possible reasons why
• HFS and TBS protocols do evoke activity
• NMDAR-dependent plasticity is dependent on… NMDARs
• NMDARs require depolarization to activate
• APs backpropagate from soma into dendrites
• This is a great way to provide the depolarizing boost to
activate NMDARs
125
possible postsynaptic mechanism for NMDAR activation
Backpropagating APs
126
So… blocking bAPs will block LTP?
because
Not necessarily.
Dendritic amplification activates NMDARs
127
Postsynaptic activity necessary: yes or no? 3
…it depends
Single paired stimuli don’t
evoke dendritic spikes
TBS does
128
What does a neuron pay attention to?
we should ask:
| what physiological stimuli cause calcium influx?
129
What IS physiological? 3
HFS Definitely no
TBS Pretty good, actually
Pairing No
130
What is a theta? 3
Local field potential (LFP) contains information at several different frequencies
(oscillations)
LFP filtered around theta
frequencies
spiking at downpart
131
What is a theta burst?
Theta burst protocols are designed to replicate the
| realistic inputs neurons receive during cognitive tasks
132
Theta bursts drive
and cause
calcium spikes
TBS causes supralinear summation and calcium spikes in dendrites
133
Synaptic Learning Rules
A synaptic learning rule tells us how the spatiotemporal
| pattern of activity will change synaptic strength
134
Hebbian rule
The BCM rule
(with asymptotic limits)
predicted a threshold at which plasticity would switch from one direction to another
135
Using Synaptic Learning Rules 2
Defining learning rules for different synapses allows us to
model cell and circuit behavior
Thus, we can make testable hypotheses about cell/circuit interactions (and in turn, improve our learning rules)
136
STDP - a learning rule about 2
I/O relative timing
STDP Learning Rule tells us about the relationship between inputs/outputs timing and plasticity
137
Plasticity rule changes 5
along dendrites
EPSP kinetics change with synapse location
```
Dendrite filtering (capacitance) makes distal inputs slower to
rise and decay
```
Kinetics (thus dendrite location) change how events temporally sum
Thus, dendrite location alters synaptic learning rules
138
TBS learning rules 3
TBS protocols have multiple variables that influence LTP
burst frequency
intra-burst frequency
etc.
139
______ drive plasticity
Plasticity is 2
Complex spikes
burst-dependent, and NMDAR/calcium dependent
140
Dendritic spike LTP doesn’t
Bursts of inputs are
even require APs
highly effective at inducing LTP
141
TBS ______ alters calcium spikes
TBS causes
intra-burst frequency
supralinear summation and calcium spikes in dendrites
142
Theta burst/pairing protocols
Pairing of synaptic stimuli with
drive calcium spikes
backpropagating action
potentials causes bursts of
complex spikes (sodium and calcium spikes combined)
143
Complex spike induction is
sensitive to timing, low threshold is in theta burst frequency
144
______ for theta bursts 3
STDP-like stimuli
Location/kinetics can shift plasticity (Notice: this is a
“POTENTIATING” positive-pairing paradigm, but some
synapses DEPRESS)
(Notice: this is a “DEPRESSING”
STDP paradigm, but some synapses potentiate)
145
_____ show “normal” STDP
_____ show “reversed” STDP
Basal synapses ______
Proximal synapses
Distal synapses
just show STDP potentiation
146
Distal synapses show “reversed” STDP 2
Complex spikes are induced well by negative pairing
Thus, negative pairing induces potentiation in distal dendrites
147
Dendrite Learning Rules draw
look at graph lecture 32
148
Dendrite Learning Rules: distal
proximal
Calcium spikes necessary,
best evoked by EPSPs
coming after AP (negative pairing), reverse of STDP
bAPs sufficient, best evoked by EPSPs coming before AP
(positive pairing), STDP
149
Dendrite learning rules and circuit organization 2
Different dendrite regions receive different types of input
Different learning rules, different neural processing
strategies for different types of information
150
Far distal dendrites receive
information from
L2/3 pyramidals transmit 2
L5 to L5 pyramidals 2
L5 pyramidals are the
higher cortical areas “top down pathway”
- thalamic information “bottom up pathway”
- Project to proximal and distal dendrites
- “interconnection pathway”
- Project to basal dendrites
output cells of the cortical circuit
151
The problem with STDP
Realistic inputs driving plasticity are much slower
152
The ITDP (input-timing) rule 3
Synched inputs from multiple
sources evoke dendritic spikes
Synapses potentiate when inputs sum best
Timing mimics synchrony of gamma oscillations driving each input
153
The BTDP (behavioral timescale) rule
Plateau potentials induce LTP,
form new place fields
Learning rule covers
seconds, the realistic time it
takes animal to traverse area
Long-lasting depolarizations and plateau potentials
allow the learning rule to stretch over time
154
Cerebellar error signals and plasticity
Error signal takes a specific amount of time to get
coded back into the circuitry
Learning rule is specifically tuned to be sensitive to
error signal delay, strongly depresses when it receives signals with that delay
155
Synaptic learning rules depend on
and Synaptic learning rules depend on
The purpose of synaptic learning rules is to
stimulus parameters,
because different stimuli evoke different responses
synapse dendritic
location, because different dendritic locations evoke
different responses
understand
how neurons will behave as circuit activity changes
156
Synaptic plasticity in vivo
We hypothesize that
synaptic plasticity is
associative learning at
the cellular level
157
Amygdala is a
Integrates
Fear conditioning: 2
control center for emotion and behavior
sensory inputs and controls
systemic responses
- fast learning, strong memory
- Simultaneous auditory stimulus and foot shock
158
Optogenetic fear conditioning vs old school
Old-school fear conditioning:
CS is a sound stimulus, paired
with a foot shock
Optogenetic fear conditioning:
CS is direct optogenetic activation of auditory cortex axons in amygdala
159
When CS and US aren’t paired, mice
When CS and US are paired,
Behavioral change is
don’t care about CS
mice are scared of CS, stop pressing lever for reward
strong after CS/US pairing is learned
160
AMPA/NMDA as substitute for LTP 3
LTP is recorded by measuring baseline, inducing plasticity, and recording change
In vivo there is no baseline, the brain is removed AFTER the plasticity has already happened
AMPAR/NMDA of auditory
inputs is increased after
learning
161
Plasticity during fear conditioning 2
Synapses from auditory inputs onto amygdala neurons exhibit LTP following fear conditioning
Sound stimulus and optogenetically driven input (ODI) equally effective at inducing LTP
162
Synaptic plasticity turns 4
the memory on and of
Pairing CS and US causes
rat to be fearful of CS
Depressing those synapses
inactivates the fearful
behavior to CS
Re-potentiating those synapses reactivates the
fearful memory
163
Association has to 2
Note: before a memory is formed,
be formed first, otherwise plasticity doesn’t do anything
Inducing LTP or LTD in auditory inputs alone doesn’t change behavior, only after CS/US pairing does subsequent plasticity matter
changing the strength of then
activating these synapses alone isn’t sufficient to change behavior; after memory is formed, changing/activating these synapses IS sufficient to change behavior
164
Plasticity (and a learning rule) in vivo
These protocols effectively strengthen and weaken synapses in intact circuitry
165
Optical LTD
Memory then
undoes tone-associated memory
reactivated with
another CS/US pairing
166
Memory extinction: 4
not the same as LTD
```
Extinction: after associative
memory formation (CS/US pairing), rats repeatedly exposed to CS alone
```
Behavioral expression of the
memory is extinguished
(note: extinction isn’t forgetting)
Potentiating those synapses
doesn’t reinstate fear behavior
167
Memory extinction ≠
Extinction is
Extinction isn’t
forgetting ≠ LTD
the formation of a new memory,
involving different synapses/neurons, not reversal of an existing memory
LTD of the original potentiated
synapses, they’re likely still potentiated, so LTP after extinction doesn’t do anything
168
Associations cause
LTP
169
LTP is an integral part of
memory formation
170
When LTP isn’t enough… 2
LTP of a
but
circuits matter
Other changes must be happening in the neurons/circuitry
single set of synapses can be a
necessary component of memory formation
Even for simple memories, LTP of a single set of synapses may not be sufficient for memory
formation
