diff --git a/2016-11-03-extra.md b/2016-11-03-extra.md index 8c81371..288dfa1 100644 --- a/2016-11-03-extra.md +++ b/2016-11-03-extra.md @@ -285,4 +285,65 @@ Connor Nature 2005, N&V on Quiroga et al: sparse and non-variant ---- \ No newline at end of file +--- + +## Short-term plasticity of the gill-withdrawal reflex in sea slugs + +Facilitation in the marine mollusk *Aplysia californica* + +
Neuroscience 5e Fig. 8.3
+
Neuroscience 5e Fig. 8.3, Squire and Kandel 1999
+
Neuroscience 5e Fig. 8.3, Squire and Kandel 1999
+
Neuroscience 5e Fig. 8.3, Squire and Kandel 1999
+ +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. + +
Neuroscience 5e Box 8C, Dyro 1989
+ +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 + +
Neuroscience 5e Fig. 8.4
+
Neuroscience 5e Fig. 8.4, Squire and Kandel 1999
+
Neuroscience 5e Fig. 8.4, Squire and Kandel 1999
+ +Note: + +Squire and Kandel. *Memory: From Mind to Molecules* 1999 + +--- + +## Molecular signals underlying short- and long-term sensitization in *Aplysia* + +
Neuroscience 5e Fig. 8.5, Squire and Kandel 1999
+
persistent PKA (green) +unindentified proteins responsible for synaptic growth (yellow) +
Neuroscience 5e Fig. 8.5, Squire and Kandel 1999
+ +Note: + +Squire and Kandel. *Memory: From Mind to Molecules* 1999 + +--- + +## CamKII signaling in a dendritic spine during LTP + +
Neuroscience 5e Fig. 8.11
+
Neuroscience 5e Fig. 8.11, Lee et al., *Nature* 2009
+ +--- diff --git a/2016-11-25-lecture18.md b/2016-11-25-lecture18.md index 28e6d2a..f9305b0 100644 --- a/2016-11-25-lecture18.md +++ b/2016-11-25-lecture18.md @@ -357,7 +357,7 @@ PVN– paraventricular nucleus of hypothalamus. Contains groups of neurons activ --- -## Long term potentiation (LTP) in the amygdala +## Long term potentiation (LTP)
Neuroscience 5e Fig. 8.9
@@ -368,6 +368,8 @@ TODO: review this figure legend NMDA receptor opening leads to strengthening of synapses +**LTP in the amygdala** + --- ## Insertion of more AMPA receptors in synapse diff --git a/2016-11-26-lecture17.md b/2016-11-26-lecture17.md index c02ad77..38c6c37 100644 --- a/2016-11-26-lecture17.md +++ b/2016-11-26-lecture17.md @@ -1 +1,388 @@ -## Synaptic plasticity \ No newline at end of file +## 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 + +
+
+ +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) + +
+ +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: +
Neuroscience 5e Fig. 8.1, Charlton and Bittner *J Gen Physiol* 1978
+
Neuroscience 5e Fig. 8.1, Charlton and Bittner *J Gen Physiol* 1978
+ +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: +
squid giant synapse
Neuroscience 5e Fig. 8.1, Swandulla 1991
+
frog neuromuscular synapse
Neuroscience 5e Fig. 8.1, Betz *J. Physiol* 1970
+ +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): +
Neuroscience 5e Fig. 8.1, Lev-Tov *J. Neurophysiol* 1983
+ +Note: + +--- + +## Short-term plasticity at the neuromuscular synapse + +
Neuroscience 5e Fig. 8.2, Katz and Miledi *J. Physiol* 1966
+
Neuroscience 5e Fig. 8.2, Malenka and Siegelbaum *Synapes* 2001
+ +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. + +
Neuroscience 5e Fig. 8.6
+ +Note: + +--- + +## Potentiation of synaptic responses in hippocampal pyramidal neurons + +
Neuroscience 5e Fig. 8.7, Malinow *Science* 1989
+
Neuroscience 5e Fig. 8.7, Malinow *Science* 1989
+ +Note: + +--- + +## Potentiation of synaptic responses in hippocampal pyramidal neurons + +
Long term potentiation
Neuroscience 5e Fig. 8.7, Malinow *Science* 1989
+
Long term potentiation in vivo
Neuroscience 5e Fig. 8.7, Abraham *J. Neurosci* 2002
+ +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 + +
Neuroscience 5e Fig. 8.8, Gustafsson *J. Neurosci* 1987
+ +Note: + +Lomo and Bliss 1960s in Per Andersen's lab at Oslo. + +--- + +## NMDA receptors open only during depolarization + +
Neuroscience 5e Fig. 8.10, Nicoll 1988
+ +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) + +
Neuroscience 5e Fig. 8.9
+ +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 + +
Neuroscience 5e Fig. 8.12, Matsuzaki *Nature* 2004
+
Neuroscience 5e Fig. 8.12, Matsuzaki *Nature* 2004
+
Neuroscience 5e Fig. 8.12, Liao 1995
+ +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 + +
Neuroscience 5e Box 8B, Liao *Nature* 1995
+ + +
Neuroscience 5e Box 8B
+ +Note: + +--- + +## Molecular signaling mechanisms underlying LTP + +
+
+ +* Ca2+ influx +* Ca2+/Calmodulin kinase II (CaMKII) and protein kinase C (PKC) +* Protein substrate phosphorylation +* Insertion of more AMPA receptors in synapse + +
+ +
Neuroscience 5e Fig. 8.13
+ +Note: + +--- + +## LTP dependends on post-synaptic protein synthesis + +
Neuroscience 5e Fig. 8.14, Frey and Moriss Nature 1997
+ +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. + +
Molecular signaling during early and late phases of LTP induced synapse plasticity
Neuroscience 5e Fig. 8.15, Squire and Kandel 1999
+ +Note: + + +--- + +## Long-lasting synaptic plasticity after LTP + +Spine growth and creation– LTP can induce formation of new synapses between neurons. + +
New dendritic spines (white arrows) in rodent pyramidal neurons ~1hr after LTP
Neuroscience 5e Fig. 8.15, Engert and Bonhoeffer *Nature* 1999
+ +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) + +
Neuroscience 5e Fig. 8.16
+
Neuroscience 5e Fig. 8.16, Mulkey *Science* 1993
+ +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) + +
Neuroscience 5e Fig. 8.16
+ +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. +
Neuroscience 5e Fig. 8.17
+
Neuroscience 5e Fig. 8.17, Sakurai *J Physiol* 1987
+ +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 + +
Neurosciencer 5e Fig. 19.10
+ +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 + +
Neuroscience 5e Fig. 8.17
+
Neuroscience 5e Fig. 8.17
+ +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) + +
Neuroscience 5e Fig. 8.18, Bi and Poo *J Neurosci* 1998
+
Neuroscience 5e Fig. 8.18, Bi and Poo *J Neurosci* 1998
+ +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) + +
Neuroscience 5e Fig. 8.18, Bi and Poo *J Neurosci* 1998
+ +--- +