Role of CRFR2-signaling within the lateral septum in regulating social fear extinction in lactating mice

• Applicant: Rohit Menon, Ph.D.
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 556014747

Social interactions are indispensable for our healthy development. Thus, psychopathologies like social anxiety disorder (SAD) - symptomized by intense fear and avoidance of social situations - are extremely debilitating. However, the lack of specific animal models has rendered the current treatment options for SAD inefficacious and relatively unspecific. We have recently generated an operant conditioning-based model of social fear conditioning (SFC), which induces robust fear and avoidance of conspecifics in mice. We could show that the lateral septum (LS) – a brain region that regulates social behavior and stress responses – critically modulates social fear extinction. Various neuropeptide receptors, including the oxytocin (OXT) receptor (OXTR) and receptors of the corticotropin releasing factor (CRF) system, i.e., CRF receptor 1 (CRFR1) and 2 (CRFR2) are expressed in the LS. An activated OXT signaling within the LS promoted social fear extinction in male and female mice. In support, in lactation, when the brain OXT system is highly activated, we found reduced social fear expression and accelerated fear extinction. CRFR2-expressing neurons within the LS (LS-CRFR2) are known to code for aversive stimuli and mediate stress-induced persistent anxiety. As lactation is also characterized by profound adaptations of the brain CRF system, I hypothesize that LS-CRFR2 signaling is involved in the low level of social fear in lactating SFC mice. In support, our preliminary results show that the CRFR2 ligand urocortin 3 (UCN3) reverses SFC-induced social fear in male mice. In this project I first aim to describe and compare the LS-CRFR2 system in virgin and lactating mice. Subsequently, I aim to establish a causal relationship between LS-CRFR2 signaling and reduced social fear expression during lactation. I will use RNAscope to compare the precise location and biochemical nature of LS-CRFR2 in virgin and lactating mice. Using quantitative real-time PCR, I will first describe the alterations in CRFR2 expression in response to social fear extinction in lactation. I will then use retrograde tracing in UCN3-Cre mice to identify the source of UCN3 in the LS and analyse the dynamic changes in the activity of these inputs and their LS-CRFR2 substrates in response to social fear extinction in lactating and virgin mice. Subsequently, I will pharmacologically manipulate CRFR2 in the LS and monitor its consequences on social fear extinction in both virgin and lactating mice. In dependence on these results I will study the effects of chemogenetic inhibition or activation of LS-CRFR2 and their UCN3 inputs on social fear extinction in virgin and lactating mice. These experiments will substantially extend existing knowledge on the role of CRFR2 signaling specifically within the LS in modulating SFC-induced social fear and its potential buffering effects in lactation.

• DFG Programme: Research Grants