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Neuroscience PhD

Expertise: Electrophysiology, Optogenetics, Fiber photometry, Neuroanatomy, Valence Coding, Amygdala

Anxiety disorders include nine classes of psychiatric diseases and represent the most prevalent psychiatric conditions with an estimated prevalence of 18% among adults, and more than 28% over a lifetime. Despite the high personal and societal costs of anxiety disorders, relatively few therapeutic targets have been identified and current threatments are limited and have side effects. The main reason for these limitation is that we still do not understand the neural substrate underlying these pathologies. A leading hypothesis posits that anxiety disorders are caused by dysfunctions of neural circuits encoding emotional valence. Brain regions encoding emotional valence have been identified in humans and animal models, but the functional role of the circuits including these regions are just starting to be identified.  

The insular cortex, or insula, is a brain region responding to emotional stimulation in healthy individuals, and has been shown to be overactivated in patients with different types of anxiety disorders such as generalized anxiety disorder, social anxiety disorder or specific phobia. However, very few is known regarding the anatomo-functional organization of this brain region, and the circuits involving the insula.

Our research program aims at defining the circuit, cellular and synaptic organization of the insular cortex in healthy conditions using mice models, and to determine whether alterations of this organization is causally linked to pathological level of anxiety. The long term goal of our research is to restore the neural dysfunctions underlying anxiety disorders in pre-clinical models to translate our findings to develop novel strategies to treat anxiety disorders.

17 publication(s) since Septembre 2008:

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The indicated IF have been collected by the Web of Sciences in

2014 | prog mol biol transl sci   IF 2.8
Deciphering memory function with optogenetics.
Beyeler A, Eckhardt CA, Tye KM

Optogenetics has accelerated the field of neuroscience by overcoming many of the spatial, genetic, and temporal limitations of previous techniques to control neural activity. The study of learning and memory has profoundly benefited from these tools mainly from their use in rodents. New insights have been made regarding the involvement of specific cell types or populations of synapses in the acquisition, consolidation, and retrieval of memories. The cellular specificity and temporal precision of optogenetic manipulations have also shown to be useful to study synaptic mechanisms supporting learning and memory including long-term synaptic plasticity. Recently, new light-sensitive molecules have been developed to control intracellular pathways or gene expression, which promise to enhance our understanding of the molecular mechanism of memory function.

21/08/2013 | Neuron   IF 14.4
BLA to vHPC inputs modulate anxiety-related behaviors.
Felix-Ortiz AC*, Beyeler A*, Seo C, Leppla CA, Wildes CP, Tye KM

The basolateral amygdala (BLA) and ventral hippocampus (vHPC) have both been implicated in mediating anxiety-related behaviors, but the functional contribution of BLA inputs to the vHPC has never been directly investigated. Here we show that activation of BLA-vHPC synapses acutely and robustly increased anxiety-related behaviors, while inhibition of BLA-vHPC synapses decreased anxiety-related behaviors. We combined optogenetic approaches with in vivo pharmacological manipulations and ex vivo whole-cell patch-clamp recordings to dissect the local circuit mechanisms, demonstrating that activation of BLA terminals in the vHPC provided monosynaptic, glutamatergic inputs to vHPC pyramidal neurons. Furthermore, BLA inputs exerted polysynaptic, inhibitory effects mediated by local interneurons in the vHPC that may serve to balance the circuit locally. These data establish a role for BLA-vHPC synapses in bidirectionally controlling anxiety-related behaviors in an immediate, yet reversible, manner and a model for the local circuit mechanism of BLA inputs in the vHPC.

2013 | PLoS ONE   IF 2.8
Recruitment of Perisomatic Inhibition during Spontaneous Hippocampal Activity
Beyeler A, Retailleau A, Molter C, Mehidi A, Szabadics J, Leinekugel X

It was recently shown that perisomatic GABAergic inhibitory postsynaptic potentials (IPSPs) originating from basket and chandelier cells can be recorded as population IPSPs from the hippocampal pyramidal layer using extracellular electrodes (eIPSPs). Taking advantage of this approach, we have investigated the recruitment of perisomatic inhibition during spontaneous hippocampal activity in vitro. Combining intracellular and extracellular recordings from pyramidal cells and interneurons, we confirm that inhibitory signals generated by basket cells can be recorded extracellularly, but our results suggest that, during spontaneous activity, eIPSPs are mostly confined to the CA3 rather than CA1 region. CA3 eIPSPs produced the powerful time-locked inhibition of multi-unit activity expected from perisomatic inhibition. Analysis of the temporal dynamics of spike discharges relative to eIPSPs suggests significant but moderate recruitment of excitatory and inhibitory neurons within the CA3 network on a 10 ms time scale, within which neurons 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.

2013 | PLoS ONE   IF 2.8
Vestibular lesion-induced developmental plasticity in spinal locomotor networks during Xenopus laevis metamorphosis.
Beyeler A, Rao G, Ladepeche L, Jacques A, Simmers J, Le Ray D

During frog metamorphosis, the vestibular sensory system remains unchanged, while spinal motor networks undergo a massive restructuring associated with the transition from the larval to adult biomechanical system. We investigated in Xenopus laevis the impact of a pre- (tadpole stage) or post-metamorphosis (juvenile stage) unilateral labyrinthectomy (UL) on young adult swimming performance and underlying spinal locomotor circuitry. The acute disruptive effects on locomotion were similar in both tadpoles and juvenile frogs. However, animals that had metamorphosed with a preceding UL expressed restored swimming behavior at the juvenile stage, whereas animals lesioned after metamorphosis never recovered. Whilst kinematic and electrophysiological analyses of the propulsive system showed no significant differences in either juvenile group, a 3D biomechanical simulation suggested that an asymmetry in the dynamic control of posture during swimming could account for the behavioral restoration observed in animals that had been labyrinthectomized before metamorphosis. This hypothesis was subsequently supported by in vivo electromyography during free swimming and in vitro recordings from isolated brainstem/spinal cord preparations. Specifically, animals lesioned prior to metamorphosis at the larval stage exhibited an asymmetrical propulsion/posture coupling as a post-metamorphic young adult. This developmental alteration was accompanied by an ipsilesional decrease in propriospinal coordination that is normally established in strict left-right symmetry during metamorphosis in order to synchronize dorsal trunk muscle contractions with bilateral hindlimb extensions in the swimming adult. Our data thus suggest that a disequilibrium in descending vestibulospinal information during Xenopus metamorphosis leads to an altered assembly of adult spinal locomotor circuitry. This in turn enables an adaptive compensation for the dynamic postural asymmetry induced by the vestibular imbalance and the restoration of functionally-effective behavior.

05/2012 | J Physiol Paris   IF 2.7
Neural circuits underlying the generation of theta oscillations.
Pignatelli M, Beyeler A, Leinekugel X

Theta oscillations represent the neural network configuration underlying active awake behavior and paradoxical sleep. This major EEG pattern has been extensively studied, from physiological to anatomical levels, for more than half a century. Nevertheless the cellular and network mechanisms accountable for the theta generation are still not fully understood. This review synthesizes the current knowledge on the circuitry involved in the generation of theta oscillations, from the hippocampus to extra hippocampal structures such as septal complex, entorhinal cortex and pedunculopontine tegmentum, a main trigger of theta state through direct and indirect projections to the septal complex. We conclude with a short overview of the perspectives offered by technical advances for deciphering more precisely the different neural components underlying the emergence of theta oscillations.

11/08/2010 | Neuroscience   IF 3.2
Stimulation of serotonin2C receptors elicits abnormal oral movements by acting on pathways other than the sensorimotor one in the rat basal ganglia.
Beyeler A, Kadiri N, Navailles S, Boujema MB, Gonon F, Moine CL, Gross C, De Deurwaerdere P

Serotonin2C (5-HT(2C)) receptors act in the basal ganglia, a group of sub-cortical structures involved in motor behavior, where they are thought to modulate oral activity and participate in iatrogenic motor side-effects in Parkinson's disease and Schizophrenia. Whether abnormal movements initiated by 5-HT(2C) receptors are directly consequent to dysfunctions of the motor circuit is uncertain. In the present study, we combined behavioral, immunohistochemical and extracellular single-cell recordings approaches in rats to investigate the effect of the 5-HT(2C) agonist Ro-60-0175 respectively on orofacial dyskinesia, the expression of the marker of neuronal activity c-Fos in basal ganglia and the electrophysiological activity of substantia nigra pars reticulata (SNr) neuron connected to the orofacial motor cortex (OfMC) or the medial prefrontal cortex (mPFC). The results show that Ro-60-0175 (1 mg/kg) caused bouts of orofacial movements that were suppressed by the 5-HT(2C) antagonist SB-243213 (1 mg/kg). Ro-60-0175 (0.3, 1, 3 mg/kg) dose-dependently enhanced Fos expression in the striatum and the nucleus accumbens. At the highest dose, it enhanced Fos expression in the subthalamic nucleus, the SNr and the entopeduncular nucleus but not in the external globus pallidus. However, the effect of Ro-60-0175 was mainly associated with associative/limbic regions of basal ganglia whereas subregions of basal ganglia corresponding to sensorimotor territories were devoid of Fos labeling. Ro-60-0175 (1-3 mg/kg) did not affect the electrophysiological activity of SNr neurons connected to the OfMC nor their excitatory-inhibitory-excitatory responses to the OfMC electrical stimulation. Conversely, Ro-60-0175 (1 mg/kg) enhanced the late excitatory response of SNr neurons evoked by the mPFC electrical stimulation. These results suggest that oral dyskinesia induced by 5-HT(2C) agonists are not restricted to aberrant signalling in the orofacial motor circuit and demonstrate discrete modifications in associative territories.

09/2008 | J Neurophysiol   IF 2.6
Metamorphosis-induced changes in the coupling of spinal thoraco-lumbar motor outputs during swimming in Xenopus laevis.
Beyeler A, Metais C, Combes D, Simmers J, Le Ray D

Anuran metamorphosis includes a complete remodeling of the animal's biomechanical apparatus, requiring a corresponding functional reorganization of underlying central neural circuitry. This involves changes that must occur in the coordination between the motor outputs of different spinal segments to harmonize locomotor and postural functions as the limbs grow and the tail regresses. In premetamorphic Xenopus laevis tadpoles, axial motor output drives rostrocaudally propagating segmental myotomal contractions that generate propulsive body undulations. During metamorphosis, the anterior axial musculature of the tadpole progressively evolves into dorsal muscles in the postmetamorphic froglet in which some of these back muscles lose their implicit locomotor function to serve exclusively in postural control in the adult. To understand how locomotor and postural systems interact during locomotion in juvenile Xenopus, we have investigated the coordination between postural back and hindlimb muscle activity during free forward swimming. Axial/dorsal muscles, which contract in bilateral alternation during undulatory swimming in premetamorphic tadpoles, change their left-right coordination to become activated in phase with bilaterally synchronous hindlimb extensions in locomoting juveniles. Based on in vitro electrophysiological experiments as well as specific spinal lesions in vivo, a spinal cord region was delimited in which propriospinal interactions are directly responsible for the coordination between leg and back muscle contractions. Our findings therefore indicate that dynamic postural adjustments during adult Xenopus locomotion are mediated by local intraspinal pathways through which the lumbar generator for hindlimb propulsive kicking provides caudorostral commands to thoracic spinal circuitry controlling the dorsal trunk musculature.