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sparse and non-variant
---
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## Short-term plasticity of the gill-withdrawal reflex in sea slugs
Facilitation in the marine mollusk *Aplysia californica*
<div><img src="figs/Neuroscience5e-Fig-08.03-1R_copy_3f9f1c7.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 8.3</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.03-2R_copy_2b59a30.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 8.3, Squire and Kandel 1999</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.03-3R_copy_0fbd016.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 8.3, Squire and Kandel 1999</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.03-4R_copy_784bb55.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 8.3, Squire and Kandel 1999</figcaption></div>
Note:
Squire and Kandel. *Memory: From Mind to Molecules* 1999
---
## Epilepsy
Disorder characterized by periodic seizures from synchronous firing of large groups of neurons in the nervous system. Kindling and synaptic plasticity plays a role.
<figure><img src="figs/Neuroscience5e-Box-08C-0_57467fe.jpg" height="100px"><figcaption>Neuroscience 5e Box 8C, Dyro 1989</figcaption></figure>
Reid et al., Prog Neurobiol 2009
Scheffer adn Berkovic Trends Pharm Sci 2003
McNamara et al., STKE 2006
Engel 2008, *Epilepsy: A Comprehensive Textbook*
---
## Synaptic mechanisms of short-term sensitization in sea slugs
<div><img src="figs/Neuroscience5e-Fig-08.04-1R_copy_840c43d.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 8.4</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.04-2R_copy_7c288a4.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 8.4, Squire and Kandel 1999</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.04-3R_copy_9e8b3eb.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 8.4, Squire and Kandel 1999</figcaption></div>
Note:
Squire and Kandel. *Memory: From Mind to Molecules* 1999
---
## Molecular signals underlying short- and long-term sensitization in *Aplysia*
<div><img src="figs/Neuroscience5e-Fig-08.05-1R_copy_1739967.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 8.5, Squire and Kandel 1999</figcaption></div>
<div><figcaption class="big">persistent PKA (green)
unindentified proteins responsible for synaptic growth (yellow)
</figcaption><img src="figs/Neuroscience5e-Fig-08.05-2R_copy_2b6b868.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 8.5, Squire and Kandel 1999</figcaption></div>
Note:
Squire and Kandel. *Memory: From Mind to Molecules* 1999
---
## CamKII signaling in a dendritic spine during LTP
<div><img src="figs/Neuroscience5e-Fig-08.11-1R_d67561b.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 8.11</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.11-2R_f40021e.jpg" height="100px"><figcaption>Neuroscience 5e Fig. 8.11, Lee et al., *Nature* 2009</figcaption></div>
---

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## Long term potentiation (LTP) in the amygdala
## Long term potentiation (LTP)
<figure><img src="figs/Neuroscience5e-Fig-08.09-0r_17f2f6b.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.9</figcaption></figure>
@@ -368,6 +368,8 @@ TODO: review this figure legend
NMDA receptor opening leads to strengthening of synapses
**LTP in the amygdala**
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## Insertion of more AMPA receptors in synapse

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## Synaptic plasticity
## Synaptic plasticity
* Synaptic connectivity between neurons is not static– it is dynamic
* The ability of a neuron to adjust its synaptic excitability in response to incoming neural signals (i.e. synaptic transmission) is called synaptic plasticity
**Plasticity**
: *the quality of being easily shaped or molded*
: *the adaptability of an organism to changes in its environment*
Note:
structural vs functional connectivity
* The influence one neuron has on another through a chemical synapse can be changed
Non-volatile memory digital storage: NAND flash memory (SSDs), hard disk drives, floppy disks, and magnetic tape), optical discs, punch cards
NAND logic gates is used to map data in SSDs
from [wikipedia flash memory page](https://en.wikipedia.org/wiki/Flash_memory):
>NAND flash also uses floating-gate transistors, but they are connected in a way that resembles a NAND gate: several transistors are connected in series, and the bit line is pulled low only if all the word lines are pulled high
floating-gate MOSFET (FGMOS)
: is a field-effect transistor
: gate of the FGMOS is electrically isolated
: results in a floating node in DC
: secondary gates or inputs are deposited above the floating gate (FG)
: the secondary gates are also electrically isolated from it and only only capacitively connected to the FG
: because the FG is surrounded by material of high resistance, the charge contained in it can remain unchanged for long periods of time
metal–oxide–semiconductor field-effect transistor (MOSFET)
: a transistor used for amplifying or switching electronic signals
: most common transistor in digital and analog circuits
field-effect transistor (FET)
: a transistor using an electric field to control electrical conductivity of a channel for charge carrying in a semiconductor material
: Julius Edgar Lilienfeld in 1925
--
## Synaptic connectivity
<div style="font-size:0.7em">
<div></div>
If connectivity is defined as an association or link between two nodes (e.g. two neurons, two brain areas, two people), how do we define *connectivity* in neuronal networks?
* Structural connectivity– the physical wiring diagram of the nervous system (i.e. the spatial location of the nodes and their wires in the circuit. The location/juxtaposition of synapses between pairs of neurons)
* Functional connectivity– the presence of a functional association/link in the neural activity between two nodes in the nervous system
* Maybe a direct connection (A --> B) or indirect (A --> C --> B)
* The strength of synaptic coupling or 'weight' for the structural connection between node A and B. (e.g. node A has a positive effect on node B's probability action potential generation)
</div>
Note:
* c. elegans is the only complete physical wiring diagram we have for an organism
* but we don't have a functional wiring diagram for even c. elegans
* direct vs indirect connections-- monosynaptic vs di– tri– synaptic circuits
* DTI vs fMRI
* antero- retrograde tracing (muscle fibers to alpha motor neuron pools) vs patch clamp recordings
*water pipe resistance example for strength weight of inlfluence to work/effort. Amount of effort need*. I=V/R. I=gV. need sufficient EPSC and associated EPSP to depolarize neuron enough to generate a spike.
---
## Short-term synaptic plasticity
facilitation:
<div><img src="figs/Neuroscience5e-Fig-08.01-1R_copy_c4e008f.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 8.1, Charlton and Bittner *J Gen Physiol* 1978</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.01-2R_copy_7efffef.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 8.1, Charlton and Bittner *J Gen Physiol* 1978</figcaption></div>
Note:
squid gian synapse. pair of presynaptic APs elictit two epsps that show facilitation. IF two more APs within msecs of ea other. 10s of msec plasticity.
Likly due to prolonged elecvation of pre-synaptic clacium levels after synaptic activity (Ca2+ buffering/extrusion to resting levels is slow)
--
## Short-term synaptic plasticity
synaptic depression and augmentation:
<div><figcaption class="big">squid giant synapse</figcaption><img src="figs/Neuroscience5e-Fig-08.01-3R_copy_a81a0df.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 8.1, Swandulla 1991</figcaption></div>
<div><figcaption class="big">frog neuromuscular synapse</figcaption><img src="figs/Neuroscience5e-Fig-08.01-4R_copy_f5730b9.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 8.1, Betz *J. Physiol* 1970</figcaption></div>
Note:
1. strong and fast depression from high frequency stimulus and depression of epsps at squid giant synapse
2. slower depression mixed with augmentation seenn when lowering external Ca2+ concentration
3. augmentation alone after further reducing Ca2+ levels
* synaptic depression causes NT release to decline during sustained synaptic activity
* depression caused by progressive deplection of synaptic vesicle pool that is available (vesicle depletion under high freq stimulation)
* augmentation incr amount of transmitetr released from presnypatic termainals (over a few seconds)
* potentiation same but over tens of secs to minutes
* thought to arise from prolonged elevation of presynaptic calcium levels durin synaptic plasticity
--
## Short-term synaptic plasticity
post-tetanic potentiation (at spinal motor neuron synapse):
<div><img src="figs/Neuroscience5e-Fig-08.01-5R_copy_aac2681.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.1, Lev-Tov *J. Neurophysiol* 1983</figcaption></div>
Note:
---
## Short-term plasticity at the neuromuscular synapse
<div><img src="figs/Neuroscience5e-Fig-08.02-1R_copy_399cdb3.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.2, Katz and Miledi *J. Physiol* 1966</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.02-2R_copy_e167ce2.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.2, Malenka and Siegelbaum *Synapes* 2001</figcaption></div>
Note:
* train of stimulait appoled to presynaptic motor nerve prod changes in EPP amplitude
* dynamic changes in transmitter release caused by severl forms of short term plasticity
* facilitation and augmenation first, followed by pronounced synaptic depression. Potentation begins late in stimulat train and persitst form many secs after end of stimulus-- leading to post-tetanic potentiation
---
## Hippocampus anatomy
Hippocampal circuits are used for studying the physiological basis of synaptic plasticity and memory.
<figure><img src="figs/Neuroscience5e-Fig-08.06_63eafc7.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.6</figcaption></figure>
Note:
---
## Potentiation of synaptic responses in hippocampal pyramidal neurons
<div><img src="figs/Neuroscience5e-Fig-08.07-1R_copy_500c602.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.7, Malinow *Science* 1989</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.07-2R_copy_178b51a.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.7, Malinow *Science* 1989</figcaption></div>
Note:
---
## Potentiation of synaptic responses in hippocampal pyramidal neurons
<div><figcaption class="big">Long term potentiation</figcaption><img src="figs/Neuroscience5e-Fig-08.07-3R_copy_847eedc.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.7, Malinow *Science* 1989</figcaption></div>
<div><figcaption class="big">Long term potentiation in vivo</figcaption><img src="figs/Neuroscience5e-Fig-08.07-4R_copy_c736775.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.7, Abraham *J. Neurosci* 2002</figcaption></div>
Note:
* called long term potentiation
* 3R LTP of tetanized pathway
---
## Long term potentiation (LTP)
* Paired pre- and post-synaptic activity causes LTP
* NMDA receptor antagonists block LTP
<figure><img src="figs/Neuroscience5e-Fig-08.08-0_642969e.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.8, Gustafsson *J. Neurosci* 1987</figcaption></figure>
Note:
Lomo and Bliss 1960s in Per Andersen's lab at Oslo.
---
## NMDA receptors open only during depolarization
<figure><img src="figs/Neuroscience5e-Fig-08.10-0_59fb457.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.10, Nicoll 1988</figcaption></figure>
Note:
Nicoll Philos Trans Roy Soc Lond B 2003
---
## Important properties of LTP
* Spatial localization (synaptic input specificity)
* Associativity (between synapses within the post-synaptic neuron)
<figure><img src="figs/Neuroscience5e-Fig-08.09-0r_17f2f6b.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.9</figcaption></figure>
Note:
* Properties consistent with role as specific coincidence detector
* Not generalized across whole neuronal ensembles, but localized
* Associativity utilized for associative learning or classical/Pavlovian conditioning (great early 20c russian physiologist, Pavlov's dogs (dinner bell association with food presentation and salivation))
at Schaffer collateral axon synapse betwen CA3 and CA1
* NMDA receptor opening leads to strengthening of synapses
* weak stimulation at pathway 2 can lead to synapse strengthening/potentiation through associative mechanisms-- EPSP summation
---
## Increased amplitude of AMPA mediated EPSCs after LTP
<div><img src="figs/Neuroscience5e-Fig-08.12-1R_5f07fe5.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.12, Matsuzaki *Nature* 2004</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.12-2R_88aaff5.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.12, Matsuzaki *Nature* 2004</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.12-3R_6993118.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.12, Liao 1995</figcaption></div>
Note:
* spatial maps of gluatamate mediated EPSC amplitudes before and after LTP induction
* timecourse of changes in glutamate sensitivity. Lasts >60min
* LTP induces AMPA receptors responses at silent synapses. Before, no EPScs elicited at -65mV. After LTP induction, same stimulus produces EPSCs mediated by AMPA-R
It is more than just presence or absence of NMDA receptors. Cnidarians (jellyfish, anemones), drosophilia express NMDA receptors (Ryan and Grant Nat Rev Neurosci 2009).
--
## Silent synapses
<div><img src="figs/Neuroscience5e-Box-08B-1R_copy_556c434.jpg" height="300px"><figcaption>Neuroscience 5e Box 8B, Liao *Nature* 1995</figcaption></div>
<!--
<div><img src="figs/Neuroscience5e-Box-08B-2R_copy_c8c8a41.jpg" height="200px"><figcaption>Neuroscience 5e Box 8B, M. Ehlers</figcaption></div>
<div><img src="figs/Neuroscience5e-Box-08B-3R_copy_230f3bf.jpg" height="200px"><figcaption>Neuroscience 5e Box 8B, Petralia *Nat Neurosci* 1999</figcaption></div>
-->
<div><img src="figs/Neuroscience5e-Box-08B-4R_copy_6149610.jpg" height="300px"><figcaption>Neuroscience 5e Box 8B</figcaption></div>
Note:
---
## Molecular signaling mechanisms underlying LTP
<div style="font-size:0.8em">
<div></div>
* Ca<sup>2+</sup> influx
* Ca<sup>2+</sup>/Calmodulin kinase II (CaMKII) and protein kinase C (PKC)
* Protein substrate phosphorylation
* Insertion of more AMPA receptors in synapse
</div>
<figure><img src="figs/Neuroscience5e-Fig-08.13-0_b08c55e.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 8.13</figcaption></figure>
Note:
---
## LTP dependends on post-synaptic protein synthesis
<div><img src="figs/Neuroscience5e-Fig-08.14-0_copy_854f793.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.14, Frey and Moriss Nature 1997</figcaption></div>
Note:
* treatment with anisomycin, inhibitor of protein synthesis causes LTP to decay instead of being persistent over long periods
---
## Long-lasting synaptic plasticity after LTP
Long-lasting LTP is result of PKA activation of the transcriptional regulator CREB, leading to transcriptional regulation and changes in synapse structure.
<div><figcaption class="big">Molecular signaling during early and late phases of LTP induced synapse plasticity</figcaption><img src="figs/Neuroscience5e-Fig-08.15-1R_c375165.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.15, Squire and Kandel 1999</figcaption></div>
Note:
---
## Long-lasting synaptic plasticity after LTP
Spine growth and creation– LTP can induce formation of new synapses between neurons.
<div><figcaption class="big">New dendritic spines (white arrows) in rodent pyramidal neurons ~1hr after LTP</figcaption><img src="figs/Neuroscience5e-Fig-08.15-2R_copy_9d9732f.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.15, Engert and Bonhoeffer *Nature* 1999</figcaption></div>
Note:
- organotypic slice cultures of rat hippocampus, 2P imaging, fluorescent dye fills with patch pipette (calcein), and local superfusion technique
- schaffer collateral stimulation to make EPSPs and induce LTP. Transmitter release blocked everywhere (10 mM Cd2+, 0.8mM Ca2+) except a local domain perfused with normal superfusion solution
---
## Long-term synaptic depression (LTD)
<div><img src="figs/Neuroscience5e-Fig-08.16-1R_copy_a980ce0.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.16</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.16-2R_copy_62a434c.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.16, Mulkey *Science* 1993</figcaption></div>
Note:
* at the CA3-CA1 synapse in hippocampus
* low frequency stimulation (1Hz) in Schaffer collaterals induces LTD of synaptic transmission
---
## Long-term synaptic depression (LTD)
<div><img src="figs/Neuroscience5e-Fig-08.16-3R_copy_b0e0f95.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.16</figcaption></div>
Note:
* NMDA-R still required, but a low-amplitude rise in [Ca2+] activates protein phosphatases instead of kinases
* results in internalization of AMPA-R, decreasing glutamate sensitivity and lower EPSC amplitudes
---
## LTD plasticity at Purkinje neuron synapses in cerebellum
LTD at cerebellar synapses.
<div><img src="figs/Neuroscience5e-Fig-08.17-1R_copy_768ab77.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.17</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.17-2R_copy_3c60fba.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.17, Sakurai *J Physiol* 1987</figcaption></div>
Note:
* record purkinje neuron, stim climbing fibers
* pair sitmulus of CF and parallel fibers cuases LTD that reduces parallel fiber induced EPSPs in purkinje neurons
*LTP can also occur at purkinje neuron synapses, but requires endocannabinoid retrograde signaling to presynaptic climbing fibers*
--
## Cerebellar circuits
<figure><img src="figs/Neuroscience5e-Fig-19.10-0_copy_93cfd72.jpg" height="400px"><figcaption>Neurosciencer 5e Fig. 19.10</figcaption></figure>
Note:
- inferior olive
- largest nucleus in medulla
- olivocerebellar fibers refered to as climbing fibers
- collaterals from the reticular formation and from the pyramids enter the inferior olivary nucleus. inputs from rest of ipsilaterl cerebrum
---
## LTD plasticity at Purkinje neuron synapses in cerebellum
<div><img src="figs/Neuroscience5e-Fig-08.17-3R_copy_39d0f01.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.17</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.17-4R_copy_a110b10.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.17</figcaption></div>
Note:
* climbing fiber depolarizes Purkinje neuron Vm
* parallel fiber synapse weakened
* parallel fiber synapse gluatamte transmission is through both AMPA and mGluR receptors. DAG and IP3 acti with Ca2+ flux through climbing fiber activation releasing Ca2+ from ER and activation of PKC which causes internalization of postsynaptic AMPA receptors (weaking the functional conenction between parallel fibers and purkinje neurons)
---
## Spike-timing dependent plasticity (STDP)
<div style="height:250px"><img src="figs/Neuroscience5e-Fig-08.18-1R_copy_a2ed25f.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.18, Bi and Poo *J Neurosci* 1998</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-08.18-2R_copy_c76cb60.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 8.18, Bi and Poo *J Neurosci* 1998</figcaption></div>
Note:
* cultured hippocampal neurons
* pre before post gives a EPSP riding (AP induced)
* post before pre gives a smaller EPSP amplitude
* experiments in Bi and Poo done in the presence or absence of D-AP-5 (NMDA-R antagonist) as a control
* EPSCs induced by test stimuli (0.03 Hz)
* before and after repetitive stimulation of the presynaptic neuron (60 pulses at 1 Hz, marked by the thick arrow), with both neurons held in current clamp
Found in vivo in barrel cortex, optic tectum, cat visual corte (Y. Dan work) multiple species. Thought to be a unifying princple for plasticity. But debate whether an AP must occur or just sub-threshold activity and role of back-propogating APs in vivo. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059710/
STDP in vivo is smaller and more variable than in vitro (more background activity, neuromodulation, intact circuits and physiological milieu) and persists for just 10-15min before begin reversed by ongoing spontaneous activity (Yao and Dan 2001) and evidence for STDP potentiation in cortex is weaker than STDP depression.
[D. Feldmen book on developing circuit neuroscience](https://books.google.com/books?id=BmdzDAAAQBAJ&pg=PA2006&lpg=PA2006&dq=stdp+in+vivo&source=bl&ots=fof09EmRjo&sig=68IvaSI4uoPSSklDB-5uQ2nFI60&hl=en&sa=X&ved=0ahUKEwjclfjyiM_QAhXBECwKHXEHB4wQ6AEIUTAG#v=onepage&q=stdp%20in%20vivo&f=false)
---
## Spike-timing dependent plasticity (STDP)
<div><img src="figs/Neuroscience5e-Fig-08.18-3R_copy_8026f19.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 8.18, Bi and Poo *J Neurosci* 1998</figcaption></div>
---