Scientific
experience : Activity patterns and synaptic plasticity in the developing and
adult cortical networks
Cortical networks, including the hippocampal circuit, often express
spontaneous, physiological patterns of activity which strongly influence
neuronal synchonisation. The relative timing of neuronal discharges is a
critical factor for the induction of activity-dependent synaptic plasticity,
that may support cognitive functions such as learning and memory in the adult,
circuit maturation during the early stages of development, or even cell death
during pathological synchronisations. GABAergic inhibition mediated by various
categories of interneurons with both divergent and dense axonal projections
plays a central role in the control of neuronal synchronisation and global
excitability of the network. Using various electrophysiological (sharp
electrodes, patch clamp, extracellular unit and multi-unit recordings using
simple of more elaborate multi-site recording probes) and imaging (confocal
Ca2+ imaging) techniques in rodent preparations (slices, intact neonatal
septo-hippocampal complex in vitro, anesthetized and freely moving animals), we
investigate the expression, mechanisms of generation and consequences of
spontaneous patterns of activity expressed by cortical structures in various
behavioral situations in the adult and neonatal rat, with a particular emphasis
on the interactions between GABAergic and glutamatergic neuronal
circuits.
1)
Activity patterns in the immature rat hippocampal network in vitro (PhD :
development, slices; with Vadim Tseeb and Rustem Khazipov (PhD supervisor) in
Ben-Ari's lab)
During my PhD, I have used a combination of imaging (confocal microscopy with
the fluorescent Ca2+ sensors Fluo3 and Fluo3-AM) and electrophysiological
(patch clamp in whole cell and cell attached configurations) techniques and
observed that during the first postnatal week (P0-5), rat hippocampal neurons
displayed synchronous intracellular Ca2+ oscillations mediated by synaptically
generated Giant Depolarising Potentials (GDPs). In fact, we have shown that
interactions between immature neurons had very different properties than in
adult: 1) GABA, which is the principal inhibitory transmitter of the adult
brain, has excitatory effects in neonatal neurons due to a reverse Cl-
gradient, and facilitates the activation of NMDA receptors at a time when
excitatory transmission via AMPA receptors is quiescent; 2) this GABA-NMDA
synergy provides simultaneous presynaptic firing, postsynaptic Ca increase and
activation of NMDA receptors during Giant Depolarising Potentials (GDPs) that
are spontaneously expressed by the immature hippocampal network and could
therefore modulate the formation of the neuronal network by activity dependent
synaptic plasticity (hebbian model).
Publications :
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Leinekugel X., Tseeb V., Ben-Ari Y. & Bregestovski Y. (1995): Synaptic
GABAA activation induces Ca2+ rise in pyramidal cells and interneurons from rat
neonatal hippocampal slices. Journal of Physiology (
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Leinekugel X.,
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Khazipov R., Leinekugel X., Khalilov I., Jean-Luc Gaļarsa & Ben-Ari Y.
(1997): Synchronization of GABAergic interneuronal network in CA3 region of
neonatal hippocampus. Journal of Physiology (
2)
Activity patterns in intact immature cortical networks, in vitro and in vivo
(postdoc : development, intact preparations; with Ilgam Khalilov, Rustem
Khazipov and
In order to study the generation and propagation of GDPs in intact networks, we
developped in Dr. Ben-Ari's laboratory a new preparation that allows to record
neuronal activity from intact cortical structures in vitro. Using multiple
simultaneous electrophysiological recordings on this preparation (single or
double patch clamp combined to 4 or 5 extracellular electrodes), I found that
spontaneous Giant Depolarizing Potentials (GDPs) are present and propagate
within the intact septo-hippocampal complex (both hippocampi and septum
functionally connected) in vitro. In fact, the septal pole of hippocampus acts
as a pace maker for the generation of GDPs that subsequently propagate towards
both septal poles and medial septum. Therefore, the maturation of these two
networks that form a functional system in the adult brain may be modulated by a
common pattern of activity.
Moreover, during my postdoc in Pr. Buzsaki laboratory (Rutgers University,
Newark, NJ, USA), I used multi-extracellular and patch
clamp recordings from freely behaving and anesthetized 3-6 day-old pups, which
allowed us to describe recurrent collective bursts of action potentials,
reminiscent of both adult sharp waves and immature in vitro giant depolarizing
potentials. Since these synchronous events provide synchronized
pre- and postsynaptic firing at the CA3-CA1 synapse, they may
contribute to the maturation and maintenance of cortical circuits in the
newborn rat by Hebbian modulation of developing synapses.
After my return to
Publications
(* : equally contributing authors) :
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Khalilov I., Esclapez M., Medina I., Aggoun D., Lamsa K., Leinekugel X.,
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Leinekugel X,
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Leinekugel X.*, Khazipov R.*, Cannon R., Hirase H., Ben-Ari Y. & Buzsaki
G.* (2002) : Correlated bursts of activity in the neonatal hippocampus in vivo.
Science 296 (5575), p. 2049-2052. Leinekugel-et-al-science-2002.pdf
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Khazipov R.*, Sirota A.*, Leinekugel X.*, Holmes G., Ben-Ari Y. & Buzsaki
G. (2004) : Early Motor Activity Drives Spindle-Bursts in the Developing
Somatosensory Cortex, Nature 432 (7018), p.758-761. Khazipov-et-al-nature-2004.pdf
For
review, you can have a look at Leinekugel-J-Physiol-Paris-2003.pdf
Ou pour une revue en franēais, Leinekugel-Neurologies-2006.pdf
3) Activity patterns and synaptic
plasticity in the adult rat (postdoc : adult hippocampus in vivo, with Hajime
Hirase, Andras Czurco, Jozsef Csicsvari,
Information encoding and storage in the
mammalian central nervous structures seem to result from tight interactions
between the basic integrative properties of individual cells and network driven
background oscillations (theta, gamma or Sharp Waves) observed in the behaving
animal. Long term modification of synaptic weights within a circuit is largely
dependent on the discharge type (single action potentials or bursts) and their
synchrony. During my postdoc in Pr. Buzsaki laboratory (
Although the hebbian model of synaptic
plasticity is the main reference as basic cellular mechanism of learning, the
physiological conditions implicated in synaptic plasticity are still unclear.
Using combined intracellular and extracellular recordings in anesthetised adult
rats, we have observed that experimentally pairing the intracellularly recorded
cell with the spontaneous network activity (SPWs), recorded in extracellular,
produced long-term enhancement of the synaptic drive to this cell. Therefore,
spontaneously occuring SPWs represent a relevant pattern for long term synaptic
plasticity induction in the adult rat hippocampus.
I also performed large scale extracellular unit
recordings in freely moving animals using "tetrodes", that allow to
identify the spiking activity of 5 to 10 individual neurons (per tetrode)
simultaneously, together with the field potential collective activity. Using 8
tetrodes simultaneously during various types of behaviour (exploration of
familiar or new environments, wheel-running, sleep...), we made the following
observations :
First, we could provide experimental support to the hypothesis that the firing rate of hippocampal cells during sleep is determined by an
interaction between novelty-induced experience and network regulating
mechanisms that maintain homeostatic population activity. Therefore, any
activity-dependent change in the matrix of synaptic weights would be
compensated by opposite plasticity to maintain constant global activity within
the network.
Second, we found that temporal correlation among neurons depends on the
distance between the recorded neurons as well as on the state of the network.
Therefore, even though the hippocampus does not code
information in a simple topographic format, nearby hippocampal neurons may
discharge together due to the state-dependent participation of different sets
of afferents during various tasks. This would affect the spatial clustering of
neuronal discharges in the hippocampal CA1 region and be responsible for local
clustering of similarly responding neurons.
Third, we found that burst initiation probability and burst length from
hippocampal pyramidal cells were inversely correlated to the last inter-spike
interval. Therefore, bursts length and probability both increased during silent
periods. While crucial involvement of burst firing has been hypothesized in the
induction of synaptic plasticity, the behavioral, network, and cellular
conditions under which a burst will be initiated are not yet clear. Our results
suggest that bursts may function as "conditional synchrony
detectors", signaling strong afferent synchrony after neuronal silence,
and that single spikes triggered by a weak input may suppress the later
induction of a burst by a strong input.
Fourth, analysis of the firing phase of hippocampal cells in respect to theta
oscillations revealed that the spike phase precession phenomenon is not a
hallmark of spatial behavior, as suggested previously, but rather a
manifestation of a more fundamental principle governing the timing of pyramidal
cell discharge, that involves the interplay between the magnitude of dendritic
excitation and rhythmic inhibition of the somatic region.
Publications
(* equally contributing authors) :
-
King C., Henze D., Leinekugel X. & Buzsaki G. (1999) : Hebbian
modification of a hippocampal population pattern. Journal of Physiology (
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Papp E., Leinekugel X., Henze D.A., Lee J. &
Buzsaki G. (2001) : The apical shaft of CA1 pyramidal cells is under
GABAergic interneuronal control. Neuroscience102(4),
p. 715-721. Papp-et-al-neurosci-2001.pdf
-
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Hirase H., Leinekugel X., Csicsvari J., Czurko A. &
Buzsaki G. (2001) : Behavior-dependent states of the hippocampal network affect
functional clustering of neurons. Journal of Neuroscience
21 (10), RC 145. Hirase-et-al-JN-2001.pdf
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Hirase H.*, Leinekugel X.*, Czurko A.*, Csicsvari J. &
Buzsaki G. (2001) : Firing rates of hippocampal neurons are preserved during
subsequent sleep episodes and modified by novel awake experience. Proc Natl
Acad Sci U S A 98 (16), p. 9386-9390. Hirase-et-al-PNAS-2001.pdf
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Harris K.D.*, Hirase H.*, Leinekugel X.*, Henze D.A. &
Buzsaki G. (2001) : Temporal interaction between single spikes and complex
spike bursts in hippocampal pyramidal cells. Neuron 32 (1), p. 141-149. Harris-et-al-neuron-2001.pdf
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Marshall L., Henze D.A., Hirase H., Leinekugel X., Dragoi G. &
Buzsaki G. (2002) : Hippocampal pyramidal cell-interneuron spike
transmission is frequency dependent and responsible for place modulation of
interneuron discharge. Journal of Neuroscience
22 (2), RC197. Marshall-et-al-JN-2002.pdf
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Harris K.D., Henze D.A., Hirase H., Leinekugel X., Dragoi G., Czurko A.
& Buzsaki G. (2002) : Spike train dynamics predicts theta-related phase
precession in hippocampal pyramidal cells. Nature 417
(6890), p. 738-741. Harris-et-al-nature-2002.pdf
4)
Physiopathology of activity patterns (Principal Investigator : freely moving,
head restrained and anesthetized rats and transgenic mice, with Michele
Pignatelli, Colin Molter, Eva Pastalkova, Hajime Hirase, Gyorgy Buzsaki, Yoon
Cho, Joseph O'Neill, Thibault Maviel, Cyril Dejean, Jialing Liu, Bruno Bontempi,
in CNIC/IMN, Bordeaux)
In normal animals, brain states alternate
between two major segregated patterns: an active state associated with high
cholinergic activity, cortical desynchronization and hippocampal theta rhythm,
and a slow-wave state (SWS) associated with low cholinergic activity,
neocortical slow oscillations and hippocampal sharp-wave ripples. Establishing
my own research group in
It is widely assumed that theta
power reflects the expression of sensory-motor integration underlying
decisional and voluntary motor processes, so that a main function of theta
would be to prepare and control relevant motor behaviour. Using large scale
neuronal population recording with single cell resolution in the freely
behaving rat, we observed the presence of robust rhythmic fluctuations of
hippocampal theta power on a time scale of ~1.3s, expressed in a whole variety
of behaviours such as REM sleep, open-field exploration, wheel and maze running.
Taking into account the phase of spikes relative to this Slow Modulation of
Theta Power (TPSM) provided an up to 2-fold increase in single spike information
content. While previous reports have mainly considered theta power modulation
as fluctuations of brain state or attention level, our results provide the
first demonstration that theta power modulation might be used as a carrier for
spatial and behavioural information encoding. Our observation that changes in
theta power occur in a cyclic manner during a whole variety of behaviours is also
intriguing because it might suggest that the rat's behaviour is controlled or
updated on a predefined time schedule. Moreover, the phenomenon we report of
encoding of information within a second order brain rhythm (i.e. using the
rhythmic modulation of EEG power in a given frequency band) is the first of the
kind.
Attention
was recently driven towards the potential contribution of sleep disorders to
the various deficits affecting patients and animal models of
Huntington's disease (HD). By performing
electrophysiological recordings from the hippocampus and neocortex of freely
moving, head restrained and anesthetized R6/1 mice, we report evidence for a
global dysregulation of brain activity in HD, including systematic background
interictal activity and altered brain states segregation. More specifically, we
observed that the Slow-Wave state was invaded and disorganized by
atropine-sensitive "ectopic" theta oscillations that entrained
interictal spikes and phase-locked hippocampal sharp-wave ripples. These
results point to major cholinergic-system dependent alterations of neuronal
activity during rest in Huntington's disease, a crucial period for off-line
processing and memory consolidation. This is to our knowledge the
first time that the segregation of brain states, one of the most robust and
conserved property of brain functioning, is proven to be altered in a pathology.
Moreover, this is the first electrophysiological investigation at the system's
level of neuronal activity related to Huntington's disease. The potential
involvement of cholinergic systems seems to be both important for the basic
understanding and potential therapeutic approaches to this pathology.
Publications
:
- M.
Pignatelli, A. Beyeler & X. Leinekugel (2012) : Neural circuits underlying
the generation of theta oscillations. J. Physiol.
Paris 106 (3-4):81-92. Pignatelli-et-al-J-Physiol-Paris-2012.pdf
- C. Molter, J. O'Neill, Y. Yamaguchi, H. Hirase &
X. Leinekugel (2012) : Rhythmic modulation of theta oscillations supports
encoding of spatial and behavioural information in the rat hippocampus. Neuron, 2012.06.036 (in press). Molter-et-al-Neuron-2012.pdf
- M. Pignatelli, F. Lebreton, Y. H. Cho & X.
Leinekugel (2012) : "Ectopic" theta oscillations and interictal
activity during slow-wave state in the R6/1 mouse model of Huntington's
disease. Neurobiol. Dis. 48 (3), p. 409-417. Pignatelli-et-al-NBD-2012.pdf
5) synaptic interactions in the CA3
hippocampal circuit (PI : adult hippocampus in vitro and in vivo, with Anna
Beyeler, Aude Retailleau, Hajime Hirase, Janos Szabadics, Colin Molter, in
CNIC/IMN, Bordeaux)
Feedback
inhibition is considered to be of primary importance in the CA3 hippocampal
circuit to support network oscillations as well as to avoid
hyper-synchronisation (which ultimate form is seizures) due to recurrent
excitation by pyramidal cells local collaterals. However, basic parameters
regarding the integration of excitation and perisomatic inhibition in this
circuit have not been described during spontaneous activity. Taking advantage
of an original approach which consists in the extracellular detection of
perisomatic inhibitory events from their target population (extracellular
inhibitory post-synaptic potentials, eIPSPs), in combination with intracellular
and extracellular multi-unit activity recordings, we could quantify the
probabilities that CA3 pyramidal neurons recruit each other and recruit
perisomatic inhibition. In addition to the powerful time-locked inhibition of
CA3 spontaneous activity expected from perisomatic inhibition, analysis of the
temporal dynamics of spike discharges relative to eIPSPs suggests that the CA3 recurrent
excitatory/inhibitory loop operates on a 10 ms time scale, within which
pyramidal cells recruit each other through recurrent collaterals and trigger
powerful feedback inhibition. Such quantified parameters of neuronal
interactions in the hippocampal network may serve as a basis for future
characterisation of pathological conditions potentially affecting the
interactions between excitation and inhibition in this circuit.