Serotonin modulation of Cortical-Basal Ganglia circuits involved in food motivation and Avoidance: Translational and multimodal Brain Imaging Investigation from primate to Anorexic patients. – FoodAvoid-BrainCircuits

New converging evidences shows that the serotonin (5-HT) transmission in the Basal Ganglia (BG) could be involved in different psychiatric disorders such as depression, anxiety and food intake disorders. Combining several dimensions of these psychiatric symptoms, the restrictive form of Anorexia Nervosa (AN), is a major eating disorder that affects mainly young women and is the first cause of death among adolescents in Europe. Unlike isolated depression and anxiety that frequently respond to the pharmacological blockade of the serotoninergic transporter (SERT), AN often resists to such selective serotonin reuptake inhibitors (SSRI) treatments. We believe that an alternative strategy directly targeting 5-HT receptors (5-HTR) at post-synaptic level, could improve therapeutic effects for AN and in all other SSRI-resistant patients. Given the large diversity of 5-HTRs and the ambiguity surrounding the therapeutic effects of SSRI, it appears crucial to determine on which brain region, 5-HT can modulate the processes underlying the control of food intake and anxiety. BG and particularly the striatum, are excellent candidates for regulating the expression of symptoms of AN and anxiety by the 5-HT system. The striatum is densely innervated by 5-HT neurons and expresses a plethora of 5-HT markers such as the SERT and some 5-HTR subtypes, including the 5-HT6 that we have preferentially localized inside striatum, in the non-human primate (NHP), with a ligand developed by Pr Zimmer's team. In addition, our recent results in NHP have highlighted the importance of this anterior striatum in the expression of different behavioural disorders having strong similarities with the disorders expresses in AN patients. Thus, by inducing local disturbances inside this anterior striatum, known to be disturbed in AN patients, we produced maladaptive choices, a loss of food motivation as well as avoidance behaviours, three features of AN. The hypothesis of our project coming from these evidences is that dysfunction of 5-HT transmission inside striatum could be the cause of the symptoms of AN and/or the ineffectiveness of the SSRI in this disease. With novel pharmacological agents, selectively targeting 5-HTRs within the striatum, we believe that we can develop a therapeutic alternative for SSRI-resistant patients. The aims of this translational project are: 1) to identify in AN patients, by coupling functional imaging PET / MRI, a potential deficit in 5-HT system linked to cortico-BG networks underpinning the food intake and the control of anxiety; 2) by study the gaze control of AN patients performing food choice tasks, identify a behavioural marker of food-avoidance and 3) to determine at preclinical level in NHP, the therapeutic effects of a SSRI, the fluoxetine, injected directly into the anterior striatum and 4) to explore the therapeutic potential of new agents targeting the 5-HT6 receptors, mainly located inside the striatum, on motivation and decisional processes underlying food intake and avoidance. The public health benefits of this project are significant since they can lead to the improvement of one of the most serious psychiatric pathologies due to the absence of effective pharmacological treatment as well as the consequences on the health and survival of patients with this disease. Beyond the considerable progress on the understanding of the neural mechanisms of AN as well as the perspective to open new therapeutic avenue for AN patients, this ambitious and unique project will certainly have an impact on other psychiatric disorders, such as depression and anxiety disorders, where 5-HT is also a therapeutic target. In conclusion, this project fits perfectly in the objectives of this ANR committee aiming to support translational research, directed towards human health problems and having a strong potential of innovation (knowledge, methods of investigation and therapy) which can apply to a broad field of the Mental health.