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Principal Investigator

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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.

21 publication(s) since Septembre 2008:

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30/09/2020 | Curr Biol   IF 9.6
A Novel Cortical Mechanism for Top-Down Control of Water Intake.
Zhao Z, Soria-Gomez E, Varilh M, Covelo A, Julio-Kalajzic F, Cannich A, Castiglione A, Vanhoutte L, Duveau A, Zizzari P, Beyeler A, Cota D, Bellocchio L, Busquets-Garcia A, Marsicano G

Water intake is crucial for maintaining body fluid homeostasis and animals' survival [1-4]. In the brain, complex processes trigger thirst and drinking behavior [1-5]. The anterior wall of the third ventricle formed by the subfornical organ (SFO), the median preoptic nucleus, and the organum vasculosum of the lamina terminalis (OVLT) constitute the primary structures sensing thirst signals and modulating water intake [6-10]. These subcortical regions are connected with the neocortex [11]. In particular, insular and anterior cingulate cortices (IC and ACC, respectively) have been shown to receive indirect innervations from the SFO and OVLT in rats [11] and to be involved in the control of water intake [12-15]. Type-1 cannabinoid receptors (CB1) modulate consummatory behaviors, such as feeding [16-26]. However, the role of CB1 receptors in the control of water intake is still a matter of debate [27-31]. Here, we show that endogenous activation of CB1 in cortical glutamatergic neurons of the ACC promotes water intake. Notably, presynaptic CB1 receptors of ACC glutamatergic neurons are abundantly located in the basolateral amygdala (BLA), a key area in the regulation of water intake. The selective expression of CB1 receptors in the ACC-to-BLA-projecting neurons is sufficient to stimulate drinking behavior. Moreover, chemogenetic stimulation of these projecting neurons suppresses drinking behavior, further supporting the role of this neuronal population in the control of water intake. Altogether, these data reveal a novel cortico-amygdalar mechanism involved in the regulation of drinking behavior.

29/06/2020 | Molecular Brain   IF 4.7
Expression of serotonin 1A and 2A receptors in molecular- and projection-defined neurons of the mouse insular cortex.
Ju A, Fernandez-Arroyo B, Wu Y, Jacky D, Beyeler A

The serotonin (5-HT) system is the target of multiple anxiolytics, including Buspirone, which is a partial agonist of the serotonin 1A receptor (5-HT1A). Similarly, ligands of the serotonin 2A receptor (5-HT2A) were shown to alter anxiety level. The 5-HT1A and 2A receptors are widely expressed across the brain, but the target region(s) underlying the influence of those receptors on anxiety remain unknown. Interestingly, recent studies in human and non-human primates have shown that the 5-HT1A and 5-HT2A binding potentials within the insular cortex (insula) are correlated to anxiety. As an initial step to define the function of 5-HT transmission in the insula, we quantified the proportion of specific neuronal populations of the insula expressing 5-HT1A or 5-HT2A. We analyzed seven neural populations, including three defined by a molecular marker (putative glutamate, GABA or parvalbumin), and four defined by their projections to different downstream targets. First, we found that more than 70% of putative glutamatergic neurons, and only 30% of GABAergic neurons express the 5-HT1A. Second, within insular projection neurons, 5-HT1A is highly expressed (75-80%) in the populations targeting one sub-nuclei of the amygdala (central or basolateral), or targeting the rostral or caudal sections of the lateral hypothalamus (LH). Similarly, 70% of putative glutamatergic neurons and only 30% of insular GABAergic neurons contain 5-HT2A. Finally, the 5-HT2A is present in a majority of insula-amygdala and insula-LH projection neurons (73-82%). These observations suggest that most glutamatergic neurons can respond to 5-HT through 5-HT1A or 5-HT2A in the insula, and that 5-HT directly affects a limited number of GABAergic neurons. This study defines a molecular and neuroanatomical map of the 5-HT system within the insular cortex, providing ground knowledge to identify the potential role of serotonergic modulation of selective insular populations in anxiety.

2020 | Handbook of Behavioral Neuroscience
Neuronal diversity of the amygdala and the bed nucleus of the stria terminalis
Beyeler A, Dabrowska J

The amygdala complex is a diverse group of more than thirteen nuclei, segregated in five major groups: the basolateral (BLA), central (CeA), medial (MeA), cortical (CoA) and basomedial (BMA) amygdala nuclei. These nuclei can be distinguished depending on their cytoarchitectonic properties, connectivity, genetic and molecular identity, and most importantly, on their functional role in animal behavior. The extended amygdala includes the CeA, as well as the bed nucleus of the stria terminalis (BNST). Both CeA and the BNST share similar cellular organization, including common neuron types, reciprocal connectivity, and many overlapping downstream targets. In this section, we describe the advances of our knowledge on neuronal diversity in the amygdala complex and BNST, based on recent functional studies, performed at genetic, molecular, physiological and anatomical levels in rodent models, especially rats and mice. Molecular and connection property can be used separately, or in combinations, to define neuronal populations, leading to a multiplexed neuronal diversity supporting different functional roles.

11/2019 | neurobiol stress
Neurobiological links between stress and anxiety.
Daviu N, Bruchas MR, Moghaddam B, Sandi C, Beyeler A

Stress and anxiety have intertwined behavioral and neural underpinnings. These commonalities are critical for understanding each state, as well as their mutual interactions. Grasping the mechanisms underlying this bidirectional relationship will have major clinical implications for managing a wide range of psychopathologies. After briefly defining key concepts for the study of stress and anxiety in pre-clinical models, we present circuit, as well as cellular and molecular mechanisms involved in either or both stress and anxiety. First, we review studies on divergent circuits of the basolateral amygdala (BLA) underlying emotional valence processing and anxiety-like behaviors, and how norepinephrine inputs from the locus coeruleus (LC) to the BLA are responsible for acute-stress induced anxiety. We then describe recent studies revealing a new role for mitochondrial function within the nucleus accumbens (NAc), defining individual trait anxiety in rodents, and participating in the link between stress and anxiety. Next, we report findings on the impact of anxiety on reward encoding through alteration of circuit dynamic synchronicity. Finally, we present work unravelling a new role for hypothalamic corticotropin-releasing hormone (CRH) neurons in controlling anxiety-like and stress-induce behaviors. Altogether, the research reviewed here reveals circuits sharing subcortical nodes and underlying the processing of both stress and anxiety. Understanding the neural overlap between these two psychobiological states, might provide alternative strategies to manage disorders such as post-traumatic stress disorder (PTSD).

12/04/2019 | Science   IF 41
Perspective - Do antidepressants restore lost synapses?
Beyeler A


2019 | Current Opinion in Behavioral Sciences   IF 3.4
Valence Coding in Amygdala Circuits
Pignatelli M, Beyeler A

The neural mechanisms underlying emotional valence are at the interface between perception and action, integrating inputs from the external environment with past experiences to guide the behavior of an organism. Depending on the positive or negative valence assigned to an environmental stimulus, the organism will approach or avoid the source of the stimulus. Multiple convergent studies have demonstrated that the amygdala complex is a critical node of the circuits assigning valence. Here we examine the current progress in identifying valence coding properties of neural populations in different nuclei of the amygdala, based on their activity, connectivity, and gene expression profile.

07/11/2018 | Nature   IF 41.6
Dopamine enhances signal-to-noise ratio in cortical-brainstem encoding of aversive stimuli.
Vander Weele CM, Siciliano CA, Matthews GA, Namburi P, Izadmehr EM, Espinel IC, Nieh EH, Schut EHS, Padilla-Coreano N, Burgos-Robles A, Chang CJ, Kimchi EY, Beyeler A, Wichmann R, Wildes CP, Tye KM

Dopamine modulates medial prefrontal cortex (mPFC) activity to mediate diverse behavioural functions(1,2); however, the precise circuit computations remain unknown. One potentially unifying model by which dopamine may underlie a diversity of functions is by modulating the signal-to-noise ratio in subpopulations of mPFC neurons(3-6), where neural activity conveying sensory information (signal) is amplified relative to spontaneous firing (noise). Here we demonstrate that dopamine increases the signal-to-noise ratio of responses to aversive stimuli in mPFC neurons projecting to the dorsal periaqueductal grey (dPAG). Using an electrochemical approach, we reveal the precise time course of pinch-evoked dopamine release in the mPFC, and show that mPFC dopamine biases behavioural responses to aversive stimuli. Activation of mPFC-dPAG neurons is sufficient to drive place avoidance and defensive behaviours. mPFC-dPAG neurons display robust shock-induced excitations, as visualized by single-cell, projection-defined microendoscopic calcium imaging. Finally, photostimulation of dopamine terminals in the mPFC reveals an increase in the signal-to-noise ratio in mPFC-dPAG responses to aversive stimuli. Together, these data highlight how dopamine in the mPFC can selectively route sensory information to specific downstream circuits, representing a potential circuit mechanism for valence processing.

31/05/2018 | Cell   IF 31.4
Corticoamygdala Transfer of Socially Derived Information Gates Observational Learning.
Allsop SA, Wichmann R, Mills F, Burgos-Robles A, Chang CJ, Felix-Ortiz AC, Vienne A, Beyeler A, Izadmehr EM, Glober G, Cum MI, Stergiadou J, Anandalingam KK, Farris K, Namburi P, Leppla CA, Weddington JC, Nieh EH, Smith AC, Ba D, Brown EN, Tye KM

Observational learning is a powerful survival tool allowing individuals to learn about threat-predictive stimuli without directly experiencing the pairing of the predictive cue and punishment. This ability has been linked to the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA). To investigate how information is encoded and transmitted through this circuit, we performed electrophysiological recordings in mice observing a demonstrator mouse undergo associative fear conditioning and found that BLA-projecting ACC (ACC-->BLA) neurons preferentially encode socially derived aversive cue information. Inhibition of ACC-->BLA alters real-time amygdala representation of the aversive cue during observational conditioning. Selective inhibition of the ACC-->BLA projection impaired acquisition, but not expression, of observational fear conditioning. We show that information derived from observation about the aversive value of the cue is transmitted from the ACC to the BLA and that this routing of information is critically instructive for observational fear conditioning. VIDEO ABSTRACT.

05/03/2018 | Nat Neurosci   IF 19.9
Nontoxic, double-deletion-mutant rabies viral vectors for retrograde targeting of projection neurons.
Chatterjee S, Sullivan HA, MacLennan BJ, Xu R, Hou Y, Lavin TK, Lea NE, Michalski JE, Babcock KR, Dietrich S, Matthews GA, Beyeler A, Calhoon GG, Glober G, Whitesell JD, Yao S, Cetin A, Harris JA, Zeng H, Tye KM, Reid RC, Wickersham IR

Recombinant rabies viral vectors have proven useful for applications including retrograde targeting of projection neurons and monosynaptic tracing, but their cytotoxicity has limited their use to short-term experiments. Here we introduce a new class of double-deletion-mutant rabies viral vectors that left transduced cells alive and healthy indefinitely. Deletion of the viral polymerase gene abolished cytotoxicity and reduced transgene expression to trace levels but left vectors still able to retrogradely infect projection neurons and express recombinases, allowing downstream expression of other transgene products such as fluorophores and calcium indicators. The morphology of retrogradely targeted cells appeared unperturbed at 1 year postinjection. Whole-cell patch-clamp recordings showed no physiological abnormalities at 8 weeks. Longitudinal two-photon structural and functional imaging in vivo, tracking thousands of individual neurons for up to 4 months, showed that transduced neurons did not die but retained stable visual response properties even at the longest time points imaged.

23/01/2018 | Cell Rep   IF 8
Organization of Valence-Encoding and Projection-Defined Neurons in the Basolateral Amygdala.
Beyeler A, Chang CJ, Silvestre M, Leveque C, Namburi P, Wildes CP, Tye KM

The basolateral amygdala (BLA) mediates associative learning for both fear and reward. Accumulating evidence supports the notion that different BLA projections distinctly alter motivated behavior, including projections to the nucleus accumbens (NAc), medial aspect of the central amygdala (CeM), and ventral hippocampus (vHPC). Although there is consensus regarding the existence of distinct subsets of BLA neurons encoding positive or negative valence, controversy remains regarding the anatomical arrangement of these populations. First, we map the location of more than 1,000 neurons distributed across the BLA and recorded during a Pavlovian discrimination task. Next, we determine the location of projection-defined neurons labeled with retrograde tracers and use CLARITY to reveal the axonal path in 3-dimensional space. Finally, we examine the local influence of each projection-defined populations within the BLA. Understanding the functional and topographical organization of circuits underlying valence assignment could reveal fundamental principles about emotional processing.