Final Flashcards
1
Q
Runaway LTP 4
A
Cell A fires, drives activity, synapse potentiates
Next time Cell A fires, the
probability of driving activity is increased; more likely to potentiate again
Potentiation driving potentiation: positive feedback loop?
Same for LTD: after depression, probability of synapses driving activity is decreased; synapse more likely to depress
2
Q
Compensating for LTP 4
A
There must be mechanisms to limit plasticity, in both directions
Otherwise, neurons will just narrow down their inputs to one set
of the strongest synapses
relative changes to synaptic strength induced by LTP/D should be maintained, or no memory will persist
Homeostatic Plasticity/
Synaptic Scaling
3
Q
Activity Homeostasis 2
A
Hypothesis: Neurons have an activity “set point”
When activity levels change, in either direction – Physiological properties re-tune to bring activity back to the set point
4
Q
Balanced Mechanisms
A
Multiple opposing but balanced mechanisms to keep a neuron’s
activity within a normal range
5
Q
balanced mechanisms draw
A
pp 36
6
Q
Synaptic Scaling 2
A
Amplitude: Size of EPSC (number of AMPARs) goes up or down
Frequency: Probability of
presynaptic release and number of synapses stays the same
7
Q
To add, or to multiply… 3
A
Low activity, synapses scale up
Previous plasticity has changed the relative
strength of synapses. To retain that information…
To retain information, synapses should scale up and down multiplicatively
8
Q
How do Synapses Scale? 3
A
Additive Scaling? Each synapse gets the same number of receptors added (or subtracted)
Multiplicative Scaling?
Each synapse gets an increase (or decrease) in receptors proportional to
synapse size
Multiplicative Scaling
maintains the ratio of synaptic strengths
9
Q
Probability Distributions 2
A
Probability Density Function - Very common generally Tells us how many (neurons, synapses, etc) have a given value
Cumulative Distribution Function (aka Cumulative Probability Curve); CDF is the integral of the PDF
10
Q
Probability distributions give more info than
just mean±SD draw (changes)
A
pp 36
11
Q
Cumulative distributions show
2 versions
A
multiplicative scaling
Additive Scaling - Midpoint
changes
Multiplicative Scaling - Midpoint changes & slope changes
12
Q
Data realignment 3
A
Isolate all your events
Sort by amplitude
Graph experimental
group as a function of
control group
13
Q
Data realignment draw changes
A
pp 36
14
Q
Multiplicative Scaling 2
A
Synapses scale such that the ratio of sizes is maintained
Maintains ratios made by
previous potentiation or
depression
15
Q
Mechanisms of homeostatic plasticity: Calcium as an indicator of activity
A
But, the point is neurons use general calcium levels to measure activity and activate mechanisms to scale up or down
16
Q
Why is homeostatic plasticity hard to study? 2
A
1) cultured cells/slices- Easier to manipulate molecularly
Don’t always behave in physiological ways
2) in vivo long term changes in activity - Harder to manipulate molecular pathways
Processes induced are more complicated,
impossible to completely control a neuron’s inputs and outputs
17
Q
Multiple Mechanisms of Scaling
We’ll focus on 2:
A
Many proteins are involved, pathways complex/hard to tease apart
Downscaling
Homer1a/mGluR
Upscaling
Retinoic Acid
18
Q
Homer/mGluR interactions Under normal conditions: 2
A
Homer1b links mGluRs with the PSD scaffold
Glutamate activation can
release mGluRs from Homer1b and activate signaling cascades
19
Q
Homer1a/mGluR Downscaling 5
A
Under high activity
conditions:
Homer swap!
Local translation of
Homer1a is increased
Homer1a replaces 1b
interacting with mGluR
With Homer1a: mGluR activates without glutamate, induces LTD
20
Q
Retinoic Acid (Vitamin A) Under normal conditions: 4
A
Calcium is always coming in due to ongoing activity
Calcineurin always a little bit active
Calcineurin suppresses
Retinoic acid formation
Local translation of AMPAR mRNA suppressed
21
Q
Retinoic Acid and Upscaling 6
A
Low activity conditions:
Calcium levels drop
Calcineurin activity ceases (stops suppressing)
Retinoic acid is formed and binds to RARα
Translation of AMPAR mRNA no longer suppressed
New AMPARs inserted
into synapses
22
Q
Balancing Plasticity 2
A
Non-Hebbian plasticity balances Hebbian, controls runaway LTP
Multiplicative scaling maintains ratios of synaptic strength
23
Q
What is plasticity? 4
A
So far: plasticity = change in synaptic strength
But: “…A’s efficiency, as one of the cells FIRING B, is increased…”
Our assumption is: the outcome of plasticity is a change in the probability of Cell B firing action
potentials
(if synapse strength changes, but it doesn’t change probability
of cell firing, has plasticity occurred?)
24
Q
Does plasticity have to be synapse-specific? 3
A
What if the efficiency of Cell A at driving
Cell B’s outputs changes, but so does
the efficiency of all of Cell B’s inputs?
What if the plasticity involves the entire neuron, or an entire
dendrite, or a dendritic branch?
Heterosynaptic plasticity
25
Steps for synaptic transmission/inducing plasticity 6
1. Receptors open, EPSP
2. EPSPs propagate to soma
3. AP induced
4a. AP backpropagates to dendrites
4b. Dendritic plateau potential
5. AMPARs trafficked into (or out of)
synaptic density
26
VGCs shape
the neuron’s response to synaptic input
27
VGCs shape the neuron’s response to synaptic input draw
pp 37 slide 27
28
Intrinsic Plasticity Channel types: 4
Changes: 4
Alter: 3
VGKCs
VGCCs
HCN channels
VGSCs
Location
Trafficking
Gating
Translation
EPSPs/summation
Plateau potentials/complex spikes
Action potential initiation/timing/number/bursts/
backpropagation
29
K+ channel plasticity
Multiple types of K channels are altered…
…via multiple signaling pathways…
…with different outcomes
30
Kv4.2 channels:
What does this suggest about what the neuron thinks is important
about this channel? 2
high dendrite expression
Location of channel
Level of expression
31
K+ channel internalization 3
Live imaging of Kv4.2 in
spines
Ion channels in membrane decrease with high
Blocking NMDARs
blocks Kv4.2
internalization
stimulation
32
K+ channel internalization end point
Increasing neural activity reduces Kv4.2
| channels in the membrane
33
Kv4.2 channels control 5
dendrite responses
Blocking Kv4.2 channels (with 4AP) allows dendrites to have large, elongated plateau potentials
Kv4.2 suppress subthreshold EPSPs; even small EPSPs get
bigger when Kv4.2 blocked
(note channel interaction:
blocking Kv4.2 leads to more VGSC amplification, which is then blocked with TTX)
So… changes to Kv4.2 could change a lot about neuron responses
34
_____after K channel internalization
After Kv4.2 internalization,
Enhanced signaling
subthreshold
EPSPs propagate farther, activate other VGCs
35
Effects of K channel internalization What will happen to:
EPSPs?
Dendritic spikes/plateau potentials?
bAPs?
This change could be
larger, longer lasting (increased temporal
summation), propagate farther
will trigger more easily, longer duration
propagate farther into dendritic arbor
local to a dendritic
branch, or global to all dendrites
36
Effects of K channel internalization 5
Stimulus that induces synaptic LTP
Internalizes VGKCs
Increases dendritic excitability
EPSPs into plateau
potentials
Increased spike probability
37
Plastic VGKCs 3
Change to trafficking
Number of channels matters
Enhances dendrite/neuron
excitability on top of synaptic LTP
38
The AIS 3
Region of highly
concentrated VGSCs
Na spikes initiated in AIS
Size and location varies across cell types
39
Extended period of
change in activity: AIS
can
2 versions
change location
and size
Making AIS bigger or
closer to soma increases excitability
Making AIS smaller or
farther away decreases excitability
40
Staining for AIS 3
structural protein
shows that extended
activation moves it
away from the cell body
This increases AP
threshold (and makes
APs recorded at the
soma smaller)
AIS moving away from
cell body decreases
excitability
41
Is this structural plasticity,
| or physiological plasticity 2
Is the AIS the ion channels, or the structure holding them in place?
(analogous: is a synapse
the PSD or the receptors?)
```
Is it both? mechanisms is
rearrangement of
intracellular scaffold, but
physiological change
caused by movement of ion channels
```
42
Effects of Na channel movement 3
Activity that induces synaptic scaling
Moves AIS/ VGSCs
Changes spike threshold/probability
43
Plastic VGSCs
Change to distribution/location
Where channels are
matters
Enhances neuron
excitability after activity reduction
44
HCN channels and plasticity 3
HCN plasticity during both LTP and LTD
LTP induction linked to a change in Rinput
NMDAR-dependent LTP
stimulus also induces
NMDAR-dependent decrease in Rinput
45
(HCN) LTP induction linked to changes in 4
spiking
After LTP: spontaneous APs
decrease
probability of spikes from potentiated synapses increase
Spike threshold hyperpolarizes to potentiated synapses, stays the same for non-potentiated synapses
46
HCN channels and LTP After potentiation 4
EPSPs are bigger, but also
faster
Temporal summation
decreases after
potentiation
ZD7288 blocks HCN channels, potentiation still happens, but change in kinetics doesn’t
HCN block shows
potentiation & increased
temporal summation
47
HCN plasticity requires 5
CaMKII, protein synthesis
Change to Rinput depends on CaMKII
Change to Rinput depends protein translation
LTP doesn’t depend on protein translation over this timeframe
Continued maintenance of LTP does depend on protein translation
48
LTP-inducing stimulus also induces HCN trafficking
4
2
3
NMDAR activation
Ca2+
Calmodulin
CaMKII
p-AMPARs, p-TARPs
LTP
Translation
HCN insertion
Excitability decrease
49
HCN channels and LTD 4 (start)
NMDAR-dependent LTD
stimulus also induces
NMDAR-dependent increase in Rinput
NMDAR-dependent increase in Rinput reduces threshold,
increases number of spikes
Depressed synapses are
smaller, and also slower
Effect occluded by
blocking HCN channels
50
Blocking HCN makes
LTD _____by blocking HCN channels
all synapses slow
not blocked
51
HCN channels and LTD (last) 4
LTD requires EPSPs AND bAPs
HCN plasticity requires only
EPSPs
LTD requires NMDARs AND
mGluRs
HCN plasticity requires only
mGluRs
52
HCN channels and LTD 2 path (3 and 4)
- NMDAR and mGluR activation
- AMPAR endocytosis
- LTD
- mGluR activation
- PKC
- HCN removal
- Excitability increase
53
What about VGKC plasticity? 5
Stimulus that induces synaptic LTP
Internalizes VGKCs
Increases dendritic excitability
EPSPs into plateau potentials
Increased spike probability
54
Local vs. global intrinsic plasticity 4
Locally internalized
VGKCs
Increased local
dendritic excitability
Global increase in
HCN channels
Global decrease in
excitability
55
Plastic HCN channels 4
Changes to trafficking
Number and distribution/
location matter
Enhances excitability after LTD,
decreases excitability after LTP
56
Deleterious intrinsic plasticity: status epilepticus 4
SE is an extended seizure, sometimes the first sign of epilepsy
This long lasting burst of hyperactivity can induce intrinsic plasticity
Fires rapid bursts to
long stimulation
Fires complex spikes to
simple stimulation
57
Deleterious intrinsic plasticity
Depends on Ca channels
specifically in dendrites
Bigger Cav3.2 currents in
dendrites after SE
Higher levels of Cav3.2
expression in dendrites after SE
58
Plastic VGCCs 2
Changes to expression
Increases excitability by
promoting complex and
bursting APs
59
Inhibitory Plasticity We must be careful of our descriptions, this can mean
two very different things:
1. Plasticity of inhibitory synapses
2. Plasticity of excitatory synapses onto inhibitory neurons
Both of these types of plasticity happen, both will alter
circuit function
60
Excitatory circuits are complex
Different types of
excitatory neurons
have different jobs
in neural circuitry
61
Inhibition in Neural Circuits 2
Many sources of inhibition, which play different roles in controlling circuit activity
Each source of inhibition may itself be activated in different ways
62
Inhibitory Plasticity Within Neural Circuits
If each one of these pathways is plastic, this makes the circuit much more flexible (and much more complicated)
63
Inhibition onto different excitatory neurons
```
Different types of
pyramidal neurons
get different input
from inhibitory
interneurons
```
64
Interneurons express
different types of plasticity
65
2 example mechanisms of GABAergic plasticity:
Activated by 2
LTP: Nitric oxide (NO)
LTD: Endocannabinoids (eCB)
the same thing: bursts of action potentials
(no activation of AMPARs or NMDARs or mGluRs or
GABARs necessary at all)
66
LTD of Inhibition (iLTD): eCBs 3
First discovery: long lasting depolarization (>1 sec) of pyramidal neuron depresses some inhibitory synapses
Long enough depolarization (>5 sec) causes iLTD
iLTD blocked with antagonist (AM251) for cannabinoid receptors
67
Endocannabinoid Production 3
eCBs and precursors are already present in dendrites/spines
```
Calcium influx (via wherever: NMDARs, VGCCs, or metabotropic
pathways) activates production/release
```
The activator(s) not entirely clear, PLCβ and PLD are both candidates
68
Cannabinoid receptors are 3
GPCRs
CB1 (neural) and CB2 (non-neural) are G-protein coupled receptors
Typically interact with Gαi/o (inhibits adenylyl cyclase),
can inhibit VGCCs, enhance VGKCs
69
Endocannabinoid signaling 4
Retrograde signal: eCB from postsynaptic neuron acts on presynaptic receptor
Initial, short-term depression is linked to Gβɣ signaling
Directly interacts and suppresses presynaptic VGCCs
Reduces calcium influx into presynaptic terminal; reduces vesicle fusion and NT release
70
Endocannabinoid signaling Not as common?
Very common?
Some mechanisms
Homosynaptic Excitatory LTD
Heterosynaptic Inhibitory LTD
```
Some mechanisms
are considered to be
more common/robust ( might be
because we
understand one more
than another)
```
71
Transitioning short to
long term depression
requires
Increases
Gαi/o suppression of AC
PKA activity, pathway unclear, suppresses presynaptic release
72
endocannabinoid mediated disinhibtion phasic 3
tonic 1
hypothetical transformations performed on excitation 3
dendritic
somatic
somatodendritic
global
reduced threshold
enhanced sensitivity (gain)
threshold and gain shifts
73
NO-dependent LTPi 2
```
Other inhibitory synapses
show the opposite of
eCB-iLTD: long
depolarization causes
iLTP (or LTPi, same thing)
```
As with eCB-iLTD, clearly
a presynaptic change
74
Pathway for NO plasticity 5
Blocked by BAPTA
(requires calcium entry)
Blocked by Nifedipine
(requires VGCCs)
Blocked by L-NAME (requires nitric oxide synthase)
Blocked by ODQ (requires guanylyl cyclase)
Blocked by KT5823 (requires PKG)
75
Circuit effects of LTPi 3
Less temporal summation
Lower spike probability
Increased temporal precision
76
Chloride Transporters Early Development 4
Mature Neurons 4
NKCC1:
Na+, K+, Cl- Cotransporter 1
depolarizes
in current
KCC2:
K+, Cl- Cotransporter 2
hyperpolarizes
out current
77
Plasticity and ECl iSTDP
Asynchronous inhibition/AP = iLTD
Synchronous inhibition/AP = iLTP
78
iSTDP and ECl
+ 3 path
+ 1 change
iLTP -> EGABA changes
Reversal potential change
Driving force change
Equal conductance now leads
to different amplitude current
Caused by change in activity
of chloride transporters
79
But which direction is this plasticity? (GABA) 3
Gsynapse hasn’t changed
Current amplitude is bigger
because shift in reversal
potential means that driving
force gets bigger
Reversal potential change
IPSP gets…
smaller?
depolarizing?
80
But which direction is this plasticity? (GABA) draw
pp 40 slide 10
81
Pathological ECl plasticity 3
Hyperpolarizing IPSPs
are inhibitory
Hyperexcitable bursts
induce weeks-long
changes in ECl
Depolarizing IPSPs are
mixed inhibitory/excitatory
82
Plastic ECl 2
Recently, other systems show plasticity/neuromodulation/
hormonal/circadian changes in ECl
Drugs targeting transporters controlling ECl are being tested for treating epilepsy, autism, PTSD, chronic stress, etc.
83
Plasticity of Excitatory Synapses onto
| Inhibitory Neurons difference? 2
Inhibitory neurons
don’t express CaMKII
No CaMKII = no NMDAR LTP/D
84
Different Signals Spread Differently 4
Spine volume, neck width and length restrict diffusion
Biochemical compartmentalization by
spines allows for synapse specific plasticity
Inhibitory neurons don’t have spines
No spines = reduced synapse specificity
85
How does synaptic plasticity of excitatory
| synapses onto interneurons work? Two major mechanisms
mGluR-mediated
plasticity
Calcium-permeable
AMPAR plasticity
86
different plastcity types draw
pp 40 slide 19
87
Activity dependent structural changes 2
path 5
Linear relationships allow imaging measurements to relate to physiology
Thus, you can infer synaptic physiology from imaging
```
Image brightness
Spine volume
PSD size
# vesicles
Strength of synapse
```
88
Axons/presynaptic terminals are 4
dynamic over time
Some axons are highly stable (thalamocortical)
Some axons show more
change (intracortical)
Presynaptic terminals can
come and go
89
Axon stabilization during 3
learning
MOST presynaptic structures are stable over time
During learning, existing presynaptic structures become more stable
90
How dynamic are dendrites? 3
Many dendritic spines are stable, but new are formed, others disappear
Shape of spines is also dynamic
PSD proteins are turned over in spines
91
New structures can
form and be quantified
92
Stages of spine formation 3
New spines start as narrow filopodia, make contact and form a synapse, thicken and mature
Mature dendrites have spines of each type, but ratios change over development
Stability increases with each step along this spectrum
93
Spines change at both
short and long time scales
94
Why spines dynamics
| are hard to study
Timing and frequency of
measurement dictates what
types of changes you’ll see
95
Who reaches out first, axons or dendrites? 2
We have more evidence of de novo spines reaching out to axons
Most of what we know of axon plasticity is post-injury sprouting, which is harder to study with these methods
96
LTP and spine size In mature neurons: 2
LTP causes spines to
get bigger
Number of small
spines decreases
after LTP
97
Balanced dendritic changes during LTP 3
Early development:
LTP causes addition of new spines, but
synapse areas is smaller
Late development:
LTP causes reduction in spine number,
but synapse areas is bigger
Change in synapse number and size are balanced
so overall synapse area remains the same after LTP
98
Ongoing activity drives
structural changes
Activity changes increase stabilization of newly formed spines
99
Molecular mechanisms of Structural Plasticity 2
CaMKII activates Rho GTPases
Ephrin/Eph Receptors
100
CaMKII activates Rho GTPases path 5
NMDAR activation
Calcium influx
CaMKII
Rho
Rho activates lots of things
101
Rho activates 3
capping proteins - actin filament extension
cofilin - actin depolymerization
ARP2/3 complex - actin nucleation/polymerization
102
Homosynaptic Changes 4
Ephrin/Eph receptor activation can cause structural plasticity
Spine enlargement
Spine shrinkage
Ephrin/Eph receptor combination and cell contact partner dictate
direction of response
103
Ephrin/Eph Receptors: Bidirectional Signaling 5
Ephrins are membrane bound proteins
Eph receptors are receptor
tyrosine kinases
Both ephrins and Eph receptors send signals
intracellularly
Bidirectional signaling allows
both cells to interact and
respond to contact
Vital for developmental
patterning and other
functions
104
Eph receptors activate many different
cascades, including Rho GTPases
105
Actin pools/zones 3
Actin mostly stable
Actin highly dynamic
Actin controlling spine
size, interacting with PSD
106
Actin dynamics path/circle 4
Arp2/3 promotes actin polymerization to generate
branched actin, formins drive linear actin polymerization,
and coflin and ADF mediated severing creates uncapped
barbed (+) ends for polymerization.
Capping proteins CapZ and Eps8
stabilize actin flaments
and restrict their elongation.
Coflin and ADF promote actin severing
that can enhance actin disassembly.
Proflin binds G-actin to promote
ATP loading, allowing it to be
polymerized more readily.
107
Heterosynaptic Changes 3
RhoA and Rac1
can exit the
spine, alter other
local spines
```
BDNF is an
autocrine signal,
released and
then acts on the
same cell
```
(BDNF also acts
on presynaptic
cell)
108
BDNF 3
BDNF has multiple active forms
mature-BDNF binds/activates the TrkB receptor
BDNF/TrkB signaling is important
for many cell functions in the
developing and mature brain
109
Plasticity and memory
What is an engram?
Synaptic plasticity is necessary for memory
Memory requires communication across brain regions
110
What is an engram? 2
LTP induction; memory evoked by CS only
But not all cells in each region are involved in
encoding a memory
111
How do we study engrams? 4
Activity induces expression of
gene such as c-fos
```
Activity dependent labeling:
inducible construct uses c-fos
promoter to activate
expression of a fluorescent
label and channelrhodopsin
```
After fear conditioning,
engram cells are fluorescent
and activity can be
manipulated
Engram cells can be activated via channelrhodopsin
112
Blocking synaptic plasticity 2
result 4
Fear conditioning changes AMPA/NMDA in engram cells
Blocking protein synthesis stops this LTP
Fear conditioning increases spine number in engram cells
Blocking protein synthesis stops spine addition
More than synaptic plasticity is required
Blocking LTP blocks memory
(amnesia)
Stimulating the engram evokes behavior
The memory is in there despite no LTP, just not accessed
113
More than synaptic plasticity is required
The LTP and the behavior may come and go, but the memory is still there
114
LTP: pros and cons What is great about LTP? 5
What isn’t great about LTP? 3
- Increases synaptic weight
- Long lasting
- Input specific
- Reversible/Bidirectional
- Increases spike probability
- Single trial learning happens, but is there single trial LTP? (actually, yes)
- Runaway LTP: won’t LTP just induce more LTP? (controlled by other mechanisms)
- Synaptic penetrance
115
Synaptic penetrance 2
spikes are hard to evoke
Single EPSPs are very small -- Even with LTP of multiple, perfectly synchronous inputs,
threshold hard to reach
116
What other types of plasticity are there? 2
intrinsic plasticity
LTP + intrinsic plasticity + synchronous inputs =
suprathreshold
117
What can intrinsic plasticity really do?
Increase EPSP amplitude
change threshold (alter spike probability)
118
What does intrinsic plasticity do? HCN plasticity
VGSC plasticity
increased excitability
reduced excitability
119
Intrinsic plasticity: pros and cons What is great about intrinsic plasticity?
What isn’t great about intrinsic plasticity?
- Modulates activity level and output efficiency
- Long lasting
- Reversible/Bidirectional
- Single trial plasticity
-Not input specific
120
Intrinsic plasticity: enough? necessary? 2
Hard to say… Blocking channels is easy, antagonists are great for that
Blocking a change in intrinsic properties is much harder
121
Does an engram cell need both? LTP & Intrinsic 3
Hypothesis: yes.
LTP - labels specific connections
Intrinsic - sliding threshold/changing gain
122
Theoretical models of learning
How is learning modeled computationally? 2
The goal of a neuron is to learn which patterns of
inputs to respond to
Unsupervised learning Supervised learning
123
Unsupervised learning 2
Connections are strengthened when presynaptic cell activity causes postsynaptic cell activity
Hebbian
124
Unsupervised learning: synaptic plasticity explanation 5
Maximize information by weighting inputs
When one input becomes
more active than another:
Synaptic strength will shift
to favor more active inputs
Functionally, this allows the
cell’s activity to best represent how its inputs are weighted
Can be accomplished with synaptic changes alone
125
Unsupervised: Synaptic/intrinsic
| coordination 3
Maximize information by shifting dynamic range
Initial output curve too low:
low synaptic penetrance
Intrinsic plasticity shifts threshold, neuron more active across a range of inputs
126
Intrinsic vs. homeostatic 3
Synaptic plasticity + Homeostatic scaling could do the same thing
homeostatic Scale all synapses multiplicatively
Intrinsic plasticity more economical: less energy demand, less potential loss of synaptic weight information
127
Supervised learning 2
Neuron needs to learn to classify inputs into two
categories:
1. those it should respond to
2. those it shouldn’t respond to
Receives an error signal to help learn this task
128
Theoretical models of learning supervised 3
Neural error signals
In Purkinje cells: climbing fiber inputs evoke a spike burst, which then causes a pause in ongoing activity
Synaptic learning rule tuned to that pause, depresses synapses, guided by error signal
129
Supervised: error signals
Neuron with two inputs: Respond to these
| combinations; Don’t respond to these other combinations
130
Supervised: classification 3
By giving inputs relative
weights, synaptic plasticity
adjusts the angle of the learning rule line
By setting overall excitability, intrinsic plasticity adjusts the distance from origin
Thus, the two together can set the dividing line between respond and don’t respond
131
Supervised: sequence learning 5
Neuron has to learn to be active at specific points in time during a sequence of changing input rates
Sequence of inputs should evoke a patterned output
Active zone input combos
will always cause response
Not active zone gets no response
Neuron has a bistable zone:
active in this region if it enters from above, inactive if it enters from below
132
Supervised: sequence learning results 5
Activity evoked by Start inputs induces intrinsic plasticity
Neuron is switched to “Active in the bistable zone”
Passing into Inactive zone reverses intrinsic plasticity
Neuron switched to “Inactive in the bistable zone”
Neuron is able to learn a sequence via adjusting
threshold so as to be bistable
133
The mesolimbic pathway 3
VTA - Ventral Tegmental Area: midbrain; where (some) dopamine
comes from
NAc - Nucleus Accumbens
ventral striatum; basal ganglia
mPFC - Medial Prefrontal Cortex
134
The Reward pathway 4
incentive salience (motivation, desire)
pleasure fear
executive function, cognitive processing
addiction, schizophrenia, depression
135
VTA - Ventral Tegmental Area Inputs: 4
Output:
Glutamatergic, GABAergic,
Cholinergic, Orexinergic
Dopaminergic projection neurons
136
VTA Plasticity 2
Dopaminergic (DA) neurons show
glutamatergic LTP
(of which inputs is hard to distinguish)
GABAergic neurons *don’t* show LTP
137
Cocaine-Induced VTA Plasticity 4
A single dose of cocaine (dopamine transporter blocker) causes LTP
specifically in VTA DA neurons
Lasts for several days, but
then fades away
Cocaine doesn’t induce
this plasticity in other cell
types or structures
NMDAR dependent
138
VTA Plasticity after Cocaine 3
LTP is occluded after
cocaine
LTD is enhanced after
cocaine
Indicates that LTP is maxed out by the cocaine-induced LTP
139
Other Drugs Induce VTA LTP 4
Drugs across
classes have similar
effects
```
Class 1: G-proteinmediated
Class 2: Ionotropic
mediated
Class 3: Transporter
interactions
```
140
VTA plasticity likely consequence
Likely consequences of VTA Glutamatergic LTP:
| increased dopamine release in target regions
141
VTA Orexin Plasticity 5
Orexin (Hypocretin) is made
exclusively in the hypothalamus
(Orexin regulates arousal,
appetite, narcolepsy, mood)
2 types of Orexin Receptor,
both GPCRs
Via PKC activation, causes
insertion of NMDARs at
glutamatergic synapses
More NMDARs ➜ Orexin receptors and LTP in the VTA -> cells more sensitive to inducing LTP,
potentiate more
142
Blocking Orexin 1 Receptor
blocks cocaine LTP
143
NO-LTP 4
Nitric Oxide Synthase activated by calcium influx through NMDARs
NO diffuses through membranes, activates Guanylate Cyclase
cGMP increases presynaptic release
LTP of synapses without those synapses needing to be active
144
VTA and iLTP 3
iLTP onto VTA DA neurons
(similar results in whole cell and perforated patch experiments suggest this is NOT a change in EGABA)
Presynaptic probability of release is changed
145
Activity in the reward
pathway is
VTA to NAc
The same LTP
mechanism
But happens in
enhanced by LTP, and by cocaine exposure
connection is strengthened
is used for aversive stimuli!
a different subset of VTA
neurons: subset that
project to mPFC
146
VTA plasticity -- Dopaminergic neurons in VTA show plasticity: 3
Drugs
NMDAR-LTP,
NO-iLTP,
Orexin heterosynaptic LTP of glutamatergic inputs
Drugs activate (hijack?) these plasticity processes
147
The Reward pathway
Inputs: 3
Within 2
Output 1
NAc - Nucleus Accumbens
ventral striatum; basal ganglia
Glutamatergic
GABAergic
Dopaminergic
GABAergic interneurons
Cholinergic interneurons
Medium Spiny Neurons (MSNs) are GABAergic projection neurons
148
NAc Connectivity 2
Core: motor functions associated with reward
Shell: cognitive, pleasure aspects of reward
149
NAc LTP, Modulated by Dopamine 2
NAc LTD 2
LTP disrupted by
dopamine depletion
LTP not maintained when
D2 receptors blocked
Single exposure to cocaine:
LTD of glutamatergic
synapses in NAc shell
but not in NAc core
150
NAc LTD (drugs) 3
eCB-LTD provides normal balance
Cocaine induces LTD, eCB-LTD stops
Withdrawal: homeostatic synaptic upscaling?
151
Dopamine-mediated NAc Intrinsic Plasticity 3
Dopamine modulates intrinsic properties (Na, Ca, and K VGCs)
Cocaine also modulates these properties
Decreases excitability
152
NAc plasticities balanced? 3
Shell
homeostatic hypothesis - balance excitability
signal-to-noise ratio hypothesis - change how signals are filtered
153
NAc plasticities unbalanced
Core
Permissive function hypothesis
154
NAc - Nucleus Accumbens final result
Dopamine/Cocaine modulate glutamatergic LTP/LTD and
| intrinsic plasticity in NAc
155
PFC Connectivity
PFC Plasticity
Different populations of PFC pyramidal neurons express
different dopamine receptors
DA receptors activate complicated
sets of intracellular signaling
pathways
156
PFC Dopamine Plasticity
from high -> low tonic dopamine 4
Dopamine modulates PFC synaptic plasticity
no plasticity (or LTD)
LTP
No plasticity
LTD
157
PFC Plasticity Learning Rule draw
pp 44 slide 20
