Congratulations to Anna Beyeler, Daniela Cota, et Cyril Herry, award winners “Equipes FRM”
Anna Beyeler
Team Neural circuits of anxiety – Neurocentre Magendie
Abstract
Anxiety is a healthy response guiding daily behaviors. However, more than 25% of humans experience anxiety disorders over their lifetime. Multiple risk factors, including early life adversity, have been identified, and we know that most treatments target the serotonin system. Yet, the neurobiology underlying the vulnerability to develop such a disease remains a mystery.
As functional imaging studies have identified that the insular cortex is dysregulated in patient with anxiety disorder, this research project aims to define the role of serotonergic modulation within insular circuits in the control of anxiety vulnerability and resilience. We will use cutting-edge technologies in mice models to dissect neural circuits at an unprecedented resolution. Our hypothesis is that the structure and activity of serotonergic and insular circuits predict vulnerability and resilience to anxiety phenotypes induced by early life adversity.
First, we will perform whole-brain mapping of DRN and insula anxiety circuits in anxiety-vulnerable and anxiety-resilient mice, and identify the synaptic strength with those circuits. Afterward, we will use RNA-sequencing on neurons of those circuits to characterize their transcriptional signature and dissect serotonin receptor patterns in mice with different levels of anxiety. To assess serotonin function in vivo, we will first record serotonin transmission in insular structures using a genetically encoded serotonin sensor (GRAB-SERT) and fiber photometry technology. Then, based on the serotonin dynamics identified, we will implement chemogenetic manipulations of a selective serotonin-insula pathway in adult individuals in an attempt to reprogram circuits encoding anxiety and restore anxiety levels in vulnerable individuals.
Our findings will provide a fundamental dissection of the serotonergic system in anxiety, which will be key to increasing our understanding of anxiety physiopathology and current pharmacotherapies mechanisms.
Daniela Cota
Team Energy balance and obesity – Neurocentre Magendie
Title
Understanding Brain Responses to Energy Surfeit to Tackle Obesity
Abstract
Obesity is a major health problem worldwide, leading to pathologies like diabetes, cancer, and Alzheimer’s disease. In France, 16% of adults suffer from obesity and this percentage is expected to rise in the future. To better treat obesity, it is essential to understand the biological mechanisms that lead to it. The brain coordinates how our body introduces, uses, and stocks the energy coming from the food we ingest, and it is the main victim of diet-induced changes that favor weight gain. Within the brain, POMC neurons located in the hypothalamus control food intake and body weight. Besides POMC neurons, the microglia, which are the immune cells of the brain, have been recently found to play key roles in the regulation of body weight. The consumption of high-calorie foods, rich in fats and sugars, alters the function of both hypothalamic POMC neurons and microglia, contributing to the development of obesity. Recent studies also suggest the existence of different subpopulations of POMC neurons, whose specific functions are still unclear. The goal of this project will be to pinpoint the impact of energy surfeit on cellular and molecular mechanisms regulating the function of hypothalamic POMC neurons, microglia, and their interaction, and define their relevance for obesity etiology and treatment.
Cyril Herry
Team Neuronal circuits of associative learning – Neurocentre Magendie
Abstract
Generalization is arguably one of the most fundamental principles underlying learning, and despite being a phenomenon accounted since the seminal work of Pavlov, its core mechanisms remain unknown. Although generalization is a fundamental process that promote survival, excessive broad generalization can have strong detrimental consequences. Therefore, understanding the neuronal circuit mechanisms controlling generalization is of clinical interest and the focus of the FRM funding. By combining experimental and computational approaches, this proposal aims to reveal how the dynamic functional organization of interacting microcircuits modulates the expression and inhibition of approach and avoidance generalization behavior in mice. The proposed studies will, for the first time, address some fundamental questions about the internal positive and negative valence influence in the generalization of instrumental behavior. Moreover, our experiments will reveal how large-scale networks involving the medial prefrontal cortex (mPFC), the basolateral amygdala (BLA) and ventral hippocampus (vHPC) microcircuits interact during this process. Finally, identifying neural mechanisms facilitating/inhibiting expression of generalization would make an important breakthrough in the development of new therapeutic strategies to treat the pathological aspects of approach/avoidance generalization.
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