Neuronal mechanisms underlying social fear conditioning in mice

• Applicant: Professorin Dr. Inga D. Neumann
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428986325

Social anxiety disorders (SAD) have a life time prevalence of about 12 %; however, in contrast to general anxiety disorders, specific treatment options for SAD are missing largely due to lack of relevant animal models of social fear and, thus, knowledge of underlying mechanisms. We have recently established the first specific animal model for SAD, i.e. social fear conditioning (SFC), and demonstrated that the prosocial and anxiolytic neuropeptide oxytocin (OXT) is capable to reverse social fear in male and female mice. Based on these findings, we aim to study in great detail the neuronal mechanisms underlying social fear, and the involvement of brain OXT.Specifically, we aim to (i) compare the regional neuronal activity patterns in response to social versus non-social, i.e. cued fear acquisition and extinction, (ii) the contribution of OXT pathways originating within the hypothalamic supraoptic and paraventricular nuclei, and their target neurons within the lateral septum and amygdala subnuclei, to social fear acquisition and extinction, and (iii) the effects of mating-induced activation of the endogenous OXT system on social versus cued fear. In that context we will either inhibit mating-induced activation of OXT neurons or mimic local OXT release using pharmacogenetic inhibition (DREADD) or stimulation of OXT neurons projecting to the lateral septum. We further aim to characterize (iv) the downstream connectivity of OXT receptor-expressing neurons within the septum ad amygdala involved in the reversal of social fear by OXT. Finally (v), we will investigate the effects of the neuropeptide corticotropin releasing factor (CRF) on social versus cued fear, and interactions of OXT and CRF specifically within the central amygdala contributing to the consolidation and extinction of social fear. In this context we will employ ex vivo electrophysiology (in collaboration), pharmacogenetic silencing and stimulation of CRF neurons within the amygdala in CRF-CRE mice.Thus, combining established and innovative experimental approaches with the newly established SFC paradigm we will be able to dissect specific neuropeptidergic neuronal pathways involved in social fear and contribute to the identification of specific brain targets for possible therapeutic intervention of SAD.

• DFG Programme: Research Grants