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

Descrizione del progetto

Nuova strategia per il trattamento dei disturbi d’ansia sociale

La schizofrenia e i disturbi d’ansia sociale compromettono l’interazione sociale, portando spesso all’isolamento, alla perdita del lavoro o all’incapacità di instaurare relazioni. Nonostante il numero crescente di casi, non esistono farmaci specifici per curare l’introversione estrema. Il progetto SocialPref, finanziato dal CER, si basa sulla precedente scoperta di un circuito neuronale tra la corteccia prefrontale e il setto laterale che aiuta a regolare il comportamento sociale. Nei modelli di schizofrenia, questo percorso coinvolge il recettore dell’ormone di rilascio della corticotropina (CRHR1) che viene alterato, portando a un’anomala preferenza sociale per la novità. Il progetto verificherà se gli agonisti di CRHR1 possano ripristinare il comportamento sociale in un modello murino di schizofrenia. I risultati potrebbero accelerare lo sviluppo di terapie innovative per contrastare le patologie mentali debilitanti.

Obiettivo

"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."