(Courtesy of Alex Thomson, Synaptic noise and its consequences University of London, UK) on the integrative properties of cortical neurons Le bruit synaptique et ses conséquences sur les propriétés intégratives des neurones corticaux Alain Destexhe Unité de Neurosciences, Information et Complexité (UNIC), CNRS, Gif-sur-Yvette http://cns.iaf.cnrs-gif.fr Institut de Neurobiologie Alfred Fessard, CNRS, Gif sur Yvette
Complex and seemingly stochastic patterns of neuronal discharge Ensemble activity in the cortex of a behaving rhesus monkey Wessberg Crist & Nicolelis (2002)
Multiscale analysis Characterization of “noisy” Integrative properties of single neurons network activity in vivo: during High-Conductance states High-conductance states EEG Units High-conductance states at the network level
PLAN How stochastic is neuronal activity ?
Human ensemble recordings Utah-array recordings Peyrache et al, PNAS , 2012
Human ensemble recordings RS/FS cells monosynaptic connections Peyrache et al, PNAS , 2012
Human ensemble recordings RS/FS correlations Peyrache et al, PNAS , 2012
Human ensemble recordings RS/FS correlations Peyrache et al, PNAS , 2012
Multiunit extracellular recordings in awake cats Apparent stochastic dynamics! Softky & Koch, J Neurosci. 1993 Bedard et al., Phys Rev Lett 2006
Multiunit extracellular recordings in awake cats Statistics of spike patterns in cat parietal cortex Correlated Uncorrelated Marre et al., Physical Review Letters , 2009
PLAN High-conductance states
Intracellular characterization of network activity in vivo Intracellular recordings in parietal cortex of awake and sleeping cats (Courtesy of Igor Timofeev, Laval University, Canada)
Synaptic “noise” in vivo Intracellular recordings in parietal cortex in different brain states Pare et al. J Neurophysiol . 1998 Steriade et al. J Neurophysiol . 2001 Destexhe et al. Nature Reviews Neurosci. 2003
Conductance measurements in vivo Paré et al., J. Neurophysiol. 1998 Destexhe et al., Nature Reviews Neurosci. 2003
Characterization of up-states in vivo by TTX microdialysis Microperfusion of TTX in cat parietal cortex under ketamine-xylazine anesthesia Paré et al., J. Neurophysiol. 1998 Destexhe et al., Nature Reviews Neurosci. 2003
Characterizing neuronal activity Summary of measurements of neuronal activity in awake animals Synaptic activity is intense and noisy, essentially Gaussian distributed (both for Vm and conductances) Responsible for a “high-conductance state” (3 to 5-fold larger than resting conductance) Statistics of neuronal activity is very close to Poisson processes Destexhe & Rudolph, Neuronal Noise, Springer 2012
PLAN Modeling high-conductance states in cortical neurons
Detailed models of HC states Reconstructed neocortical pyramidal neurons with synaptic densities estimated from morphological measurements Total synapses: 16% inhibitory 84% excitatory Spine density: (dendrites > 40 µ m from soma) 0.6 spines per µ m 2 GABAergic synapses on the soma: 10.6 ± 3.7 per 100 µ m 2 Total GABAergic synapses: 7% on soma 93% in dendrites DeFelipe & Fariñas, Prog. Neurobiol. (1992); Larkman, Comp. Neurol. (1991)
Detailed models of HC states 1. Calibration of the model to miniature synaptic events recorded intracellularly in vivo 2. Adjustment of release rates to active states recorded intracellularly in vivo => Rin, <Vm>, σ V
PLAN Simplified models of high-conductance states
Global synaptic conductances
Simplifed models of HC states Simplified representation of synaptic background activity as a random-walk process [Uhlenbeck & Ornstein (1930)] The “point-conductance” model Destexhe et al., Neuroscience 2001
PLAN Consequences of high-conductance states in cortical neurons
Consequence 1: neurons are probabilistic devices Ho & Destexhe, J Neurophysiol. 2000
Consequence 2: Enhanced responsiveness Quiescent High-conductance noise
Enhanced responsiveness
Enhanced responsiveness at the network level Synaptic background activity enhances the detection of synaptic inputs at the network level Ho & Destexhe, J Neurophysiol. 2000
Consequence 3: Equalization of synaptic efficacies Location independence of cellular response to synaptic stimulation Rudolph & Destexhe, J. Neurosci. 2003
EPSP attenuation during high-conductance states Destexhe et al., Nature Reviews Neuroscience 2003
EPSP attenuation during high-conductance states Destexhe et al., Nature Reviews Neuroscience 2003
EPSP attenuation during high-conductance states Destexhe et al., Nature Reviews Neuroscience 2003
Equalization of synaptic efficacy Location independence in different cellular morphologies Rudolph & Destexhe, J. Neurosci. 2003
Equalization of synaptic efficacy Reconstruction of location independence from the probabilities of AP initiation and propagation P (AP initiation) Q (AP propagation) P � Q Rudolph & Destexhe, J. Neurosci. 2003
Equalization of synaptic efficacy Reconstruction of location independence from the probabilities of AP initiation and propagation probability for probability that a probability of x = evoking a dendritic AP leads evoking a dendritic AP to soma/axon AP soma/axon AP Rudolph & Destexhe, J. Neurosci. 2003
Consequence 4: Sharper temporal resolution Destexhe et al., Nature Reviews Neurosci. 2003
Consequence 5: noise modulates intrinsic properties The non-linear properties of thalamocortical cells Low threshold Ca 2+(IT) - 61 mV - 63 mV - 66 mV Hyperpolarization Wolfart et al., Nature Neurosci , 2005
PLAN Recreating high-conductance states in cortical neurons in vitro
Interaction between Models and Living Cells g (t) e g (t) i “Recreating synaptic noise”: Real-time injection of stochastic synaptic conductances (dynamic-clamp) V (t) m
The Dynamic-clamp g(t) I inj I = g(t) ( V - E ) inj biol rev V biol Robinson & Kawai, 1993 Sharp et al., 1993
The Dynamic-clamp g(t) I inj RT-NEURON V biol RT-NEURON is developed by Gwen LeMasson, University of Bordeaux
Point-conductance models of SBA ”Recreation” of in vivo-like activity by injection of fluctuating conductances under dynamic-clamp
Point-conductance models of SBA ”Recreation” of in vivo-like activity by injection of fluctuating conductances under dynamic-clamp Destexhe et al., Neuroscience 2001
Point-conductance models of SBA ”Recreation” of in vivo-like activity by injection of fluctuating conductances under dynamic-clamp Natural up state Artificial up state Destexhe et al., Neuroscience 2001; Rudolph et al., J Neurophysiol 2004
Extracting conductances from in vivo activity
Extracting conductances from in vivo activity Conductance measurements in awake cats Excitatory and inhibitory conductances Rudolph, Pospischil, Timofeev & Destexhe, J. Neurosci , 2007
Contrasting low and high conductance states Low-conductance states High-conductance states (excitation ~ inhibition) (inhibition >> excitation)
Spike-triggered averages of conductances Dynamic-clamp
Spike-triggered variances of conductances Rudolph, et al., J. Neurosci , 2007
Spike-triggered averages of conductances Destexhe , Current Opin. Neurobiol. , 2011
PLAN Conductance measurements for sensory-evoked responses
Thalamocortical loops Excitation Inhibition
Auditory cortex Wehr & Zador, Nature, 2003
Somatosensory cortex Wilent & Contreras, Nat Neurosci , 2005
Somatosensory cortex Wilent & Contreras, Nat Neurosci , 2005
PLAN How to reconcile these results ?
STA analysis in models Networks of IF neurons Brunel, J Physiol Paris , 2000 Vogels & Abbott, J Neurosci 2005 El Boustani et al., J Physiol Paris , 2007 Destexhe , Current Opin. Neurobiol. , 2011
STA analysis in models Internal activity External input Destexhe , Current Opinion Neurobiol. , 2011
Interpretation Sensory or external input g e Excitation Inhibition g i Internal (recurrent) activity g e Excitation Inhibition g i
Stochastic analysis of single cortical neurons in vivo Summary of the stochastic analysis of High-conductance States Stochastic analysis of Vm fluctuations reveals dominant inhibitory conductances Two ways to evoke spikes: by excitation (rare) or release of inhibition (more generally seen) Spikes in awake state are essentially evoked by internal activity rather than being evoked by external inputs
Reading material Excitation Inhibition Review material (from our lab), available on http://cns.iaf.cnrs-gif.fr (in “Publications”) Scholarpedia article on "High-conductance states" (open access; many articles available, such as “dynamic-clamp”, “neuronal noise”, etc) Destexhe et al. “High-conductance states”, Nature Reviews Neuroscience 2003 Destexhe, Current Opinion Neurobiology , 2011
2012 2009
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