I1 + I2 - integration Flashcards
(31 cards)
can you explain the methods of Liu et al 2022’s investigation of DA actions beyond the AIS?
- GRABDA & tdTomato signals measured, aligned to movement initiation and velocity in mice
- heatmaps of average GRABDA and ACh fluctuations produced
- described nAChR activation-evoked response, disrupted by DHbE (antagonist) or 6-OHDA lesion of DA axons: suggests response originates from axons + mediated by nAChRs
what is coincidence detection?
computational process performed within dendrites, refers to ability of a neuron to detect precise timing of synaptic activation
what are key aspects of coincidence detection?
- generation of dendritic spikes allows neurons to perform it
- allows neurons to be sensitive to spatial and temporal information of firing
- can perform non-linear integration
- this form of computation where synchronised synaptic input onto dendritic branch -> dendritic spike = simple AND operation & a coincidence detector
- acuity depends on time course of EPSPs, influenced by degree of synchrony of NT release. synchrony supports narrow tuning, asynchrony -> broad tuning
what is non-linear integration in the context of coincidence detection?
- activating 2 inputs of medium strength in quick succession on the same dendrite -> NMDA spike -> supralinear summation of responses
- weak inputs and those arriving on different dendrites sum linearly
- coincidence inputs on the same branch are preferentially amplified: plasticity
what is another name for an NMDA spike?
NMDAR-mediated plateau potential
what is sequence discrimination?
the integration of APs in active dendrites also depends on precise timing of synaptic activation
amplitude of NMDA spike response depends on the order in which spines are activated. a seq towards the soma = greater response than away from it [Branco 2010], 2p uncaging of glut over multiple spine heads on the same dendritic branch
what is STDP?
form of plasticity dependent on precise temporal correlation between firing of pre-syn neuron and post-syn neuron
- more physiologically plausible mechanism for long term changes
- represents biological mechanism rather than experimental stimuli
what is the key concept of STDP?
the direction and magnitude of synaptic modification are determined by relative timing of presyn and postsyn APs
- window of 10s of ms
what happens if pre fires before post?
( pre -> post, +ve time interval)
- if pre fires before post within the critical window, generally leads to timing-dependent LTP (tLTP), strengthening synapse
- aligns w Hebbian principle
what happens if post fires before pre?
( post -> pre, -ve time interval)
generally leads to timing-dependent LTD (tLTD), weaking the synapse
- activity occur after the generation of an AP is irrelevant to generation of post-syn AP and therefore leads to weakening of synapse
how can the direction of STDP be reliably predicted?
levels of intracellular Ca generated in post-syn compartment upon activation
what factors complicate STDP?
- depends on dendritic location
- involves non-linear integration of synaptic modifications induced by complex spike trains
- is modulated by inhibitory + neuromodualtory inputs
what is the assymetric window of STDP?
refers to pattern of synaptic plasticity that occurs depending on precise timing + order of APs
its called asymmetry because the difference in outcome (LTP or LTD) is entirely dependent on which neuron fires first within the critical time frame
looks like a y = 1/x graph w synaptic change on y and spike timing on x
what differs about STDP on excitatory inputs onto inhibitory neurons (sometimes)?
opposite polarity
pre -> post induces LTD and post -> pre induces LTP
what factors can influence the asymmetric window?
- if input is onto inhibitory neuron
- GABAergic input (can have symmetrical windows)
- dendritic location of the synapse
- presence of neuromodulators e.g. DA
- complex firing patterns i.e. not single spike pairs
how is STDP induced for LTP?
- relies on precise temporal incidence detection mediated by NMDARs -> generates Ca in the post-syn compartment
- also bAPs provide necessary post-syn depol at synapse to alleviate NMDAR block, but only if they coincide with presyn glut release
- if presyn glut coincides with bAP, NMDARs activate, Ca influx to postsyn spine (supralinear) -> LTP
- Ca -> CaMKII activated -> PKA activated -> trigger functional + morphological changes underlying LTP
how is STDP induced for LTD?
- if bAP arrives at synapse before presyn glut release, leads to moderate or lower level of postsyn Ca influx compared to tLTP
- OR early vAP can induce Ca influx through VDCCs, leads to inactivation of NMDARs [Rosenmund 1995], then reduced Ca influx -> activate protein phosphatases (PP1, calcineurin) -> tLTD
- supported by observations that tLTD induction requires VDCC activation [Froemke 2005, Nevian & Sakmann 2006] and that pairing EPSPs and bAP at -ve intervals -> sublinear Ca summation influx [Nevian & Skamann 2004]
how does NMDAR act as a coincidence detector for STDP?
requires simultaneous:
* presyn activation + glutamate
* postsyn depol + removal of Mg block
[Mayer 1984]
what did Malenka & Bear find in 2004?
- high freq stimulation -> fast, large Ca2+ influx
- low freq stimulation -> prolonged, modest Ca2+ rise
propose this causes activation of separate molecular pathways (kinase vs phosphatase)
are LTP and LTD experimental phenomena?
- yes, but they demonstrate the long-lasting modifications which synapses are capable of
- whether the same modifications underly a form of LTP/D in vivo is difficult
- though there are clear computational advantages to them, the brain must take advantage of the neuron’s ability to express long-lasting synaptic modifications to modify circuit behaviour
when was STDP demonstrated in vivo?
- Zhang 1998
- retinotectal projection of developing xenopus
- repetitive electrical stimulation of presyn retinal ganglion cells within 20ms before postsyn spiking -> LTP
- pairings at -ve intervals -> LTD
- temporal window similar to STDP windows measured in vitro [Markram paradigm mirrored]
later by Schuett et al 2001 in kitten visual cortex, pairing visual stimuli at a given orientation with electrical stimulation -> changes in orientation map
what can influence non-linear integration of multiple spikes in STDP?
the subthreshold postsyn membrane potential between spikes
can influence amount of LTP induced by pairign protocols
what can modulate STDP induction?
- dendritic location: location of postsyn neuron’s dendrite can influence type/polarity of plasticity induced by SAME spike-timing protocol [Caporale & Dan 2008]
- proximal synapses may favour LTD with the same pre-post pairing (due to bAP attenuation??)
- neuromodulators: DA, ACh, NA can affect magnitude, temporal window + polarity. DA can widen tLTP window or covnert tLTD from post-pre to tLTP (even if applied after pairing protocol) [Zhang 2009]
- inhibitory activity: timing + location of inhib inputs alters postsyn depol
what did Froemke and Dan 2002 find?
STDP can be induced by physiologically relevant stimuli
- recorded visual cortical neuron activity patterns when animals watch movie
- prepared brain slies + replayed patterns of APs between cellsusing these real spike trains -> plasticity
- could predict type of plasticity
- physiological relevancy to idea
