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.

Autor: Dromard Y; Institut de Génomique Fonctionnelle, University of Montpellier, INSERM, CNRS, France., Borie AM; Institut de Génomique Fonctionnelle, University of Montpellier, INSERM, CNRS, France., Chakraborty P; Institut de Génomique Fonctionnelle, University of Montpellier, INSERM, CNRS, France., Muscatelli F; Institut de Neurobiologie de la Méditerranée, INSERM, University of Aix-Marseille, Marseille, France., Guillon G; Institut de Génomique Fonctionnelle, University of Montpellier, INSERM, CNRS, France., Desarménien MG; Institut de Génomique Fonctionnelle, University of Montpellier, INSERM, CNRS, France., Jeanneteau F; Institut de Génomique Fonctionnelle, University of Montpellier, INSERM, CNRS, France. Electronic address: freddy.jeanneteau@igf.cnrs.fr.
Jazyk: angličtina
Zdroj: Biological psychiatry [Biol Psychiatry] 2023 Oct 27. Date of Electronic Publication: 2023 Oct 27.
DOI: 10.1016/j.biopsych.2023.10.016
Abstrakt: 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 Magel2KO 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 Magel2KO 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.
(Copyright © 2023. Published by Elsevier Inc.)
Databáze: MEDLINE
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