1. Disengagement of somatostatin neurons from lateral septum circuitry by oxytocin and vasopressin restores social-fear extinction and suppresses aggression outbursts in Prader-Willi syndrome model.
- Author
-
Dromard Y, Borie AM, Chakraborty P, Muscatelli F, Guillon G, Desarménien MG, and Jeanneteau F
- Subjects
- Animals, Mice, Aggression drug effects, Aggression physiology, Male, Social Behavior, Septal Nuclei drug effects, Septal Nuclei metabolism, Optogenetics, Mice, Inbred C57BL, Intracellular Signaling Peptides and Proteins, Intrinsically Disordered Proteins, Oxytocin pharmacology, Somatostatin pharmacology, Somatostatin metabolism, Fear drug effects, Fear physiology, Extinction, Psychological drug effects, Extinction, Psychological physiology, Neurons drug effects, Neurons metabolism, Prader-Willi Syndrome physiopathology, Prader-Willi Syndrome drug therapy, Mice, Knockout, Disease Models, Animal, Vasopressins metabolism
- Abstract
Background: Responding to social signals by expressing the correct behavior is not only challenged in autism, but also in diseases with high prevalence of autism, like Prader-Willi Syndrome (PWS). Clinical evidence suggests aberrant pro-social behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, what neuronal mechanisms underlie impaired behavioral responses in a socially-aversive context, and how can they be corrected, remains largely unknown., Methods: Using the Magel2 knocked-out (KO) mouse model of PWS (crossed with CRE-dependent transgenic lines), we devised optogenetic, physiological and pharmacological strategies in a social-fear-conditioning paradigm. Pathway specific roles of OXT and AVP signaling were investigated converging on the lateral septum (LS), a region which receives dense hypothalamic inputs., Results: OXT and AVP signaling promoted inhibitory synaptic transmission in the LS, which failure in Magel2 KO mice disinhibited somatostatin (SST) neurons and disrupted social-fear extinction. The source of OXT and AVP deficits mapped specifically in the supraoptic nucleus→LS pathway of Magel2 KO mice disrupting social-fear extinction, which could be corrected by optogenetic or pharmacological inhibition of SST-neurons in the LS. Interestingly, LS SST-neurons also gated the expression of aggressive behavior, possibly as part of functional units operating beyond local septal circuits., Conclusions: SST cells in the LS play a crucial role in integration and expression of disrupted neuropeptide signals in autism, thereby altering the balance in expression of safety versus fear. Our results uncover novel mechanisms underlying dysfunction in a socially-aversive context, and provides a new framework for future treatments in autism-spectrum disorders., Competing Interests: Disclosures The authors have nothing to disclose and declare no competing interests.
- Published
- 2024
- Full Text
- View/download PDF