Infusion of CRHR1 agonists in the lateral septum to rescue social preference in a mouse model of schizophrenia

Description du projet

Une stratégie innovante contre les troubles d’anxiété sociale

La schizophrénie et les troubles d’anxiété sociale altèrent les interactions sociales, souvent responsable d’isolement, de perte d’emploi ou de l’incapacité à nouer des relations. En dépit du nombre croissant de cas, il n’existe aucun médicament spécifique pour traiter l’introversion extrême. Le projet SocialPref, financé par le CER s’appuie sur la découverte d’un circuit neuronal entre le cortex préfrontal et le septum latéral qui contribue à réguler le comportement social. Dans les modèles de schizophrénie, cette voie implique le récepteur de l’hormone corticotrope (CRHR1) et est perturbée, ce qui induit une préférence anormale pour la nouveauté sociale. Le projet souhaite définir si les agonistes de la CRHR1 peuvent restaurer le comportement social dans un modèle murin de schizophrénie. Ces découvertes pourraient accélérer le développement de thérapies innovantes pour plusieurs troubles mentaux invalidants.

Objectif

"Patients affected with schizophrenia or social anxiety disorders such as separation anxiety or avoidant personality disorders often exhibit difficulties to socially interact, particularly with novel individuals. Altered social interactions impair their day-to-day life and often prevent them from having families or holding on to their jobs. In addition, the number of individuals living as recluses and suffering from the Hikkimori syndrome has sharply increased since the COVID pandemic. Currently, there is no dedicated medication to treat the crippling introversion associated with these disorders.

We discovered a neuronal circuit regulating social preferences through the activation of the corticotropin-related hormone receptor 1 in the lateral septum (LS). Specifically, we demonstrated through a combination of electrophysiological, chemogenetic, optogenetic, calcium recording and gene silencing techniques that the release of CRH from prefrontal cortex (PFC) neurons into LS suppresses social interaction with familiar mice. This circuit therefore contributes to the social novelty preference exhibited by adult mice. based on these results, we presented a patent titled ""CRHR1 agonists for use in the treatment of social anxiety disorders"". In addition, preliminary data shows that social novelty preference as well as CRH signaling from the PFC to LS is dysregulated in the Df16(A)+/- mouse model of schizophrenia.

In order to further interest for our patent from pharmaceutical companies, we would like to conduct a pre-clinical study testing whether infusion of CRHR1 agonists in the septum of Df16(A)+/- mice can rescue social novelty preference and improve social interactions in this model. Our overarching goal is to facilitate the development of new treatments for mental health disorder patients suffering from extreme introversion."