For mammals, distinguishing between a dangerous and a safe social stimulus is critical for their survival. The decision to approach or avoid a conspecific depends on its valence. Stimuli with a positive social valence are perceived as appetitive, and individuals tend to approach and interact with them, while negative social stimuli are perceived as aversive and hence avoided. Dysregulation of the neuronal and molecular mechanisms regulating social valence can cause appetitive social stimuli to be perceived as aversive. Such dysregulation can lead to social dysfunction, which is a core feature of several disorders, including social anxiety disorder, autism spectrum disorder, and schizophrenia.
The lateral septum (LS) – a structure of the basal forebrain – receives abundant neocortical and allocortical inputs conveying cognitive information, which it transmits to downstream hypothalamic structures to regulate various social behaviors (Menon et al, 2022) (Figure 1). The LS also receives several subcortical neuromodulatory inputs, which can convey information about the individual's internal state (i.e., the individual's emotional and physiological state). However, the precise LS sub-circuits that compute social valence by integrating the effect of internal state on cognition to drive specific social behaviors remain unclear. A critical feature of the rodent LS is that it receives extensive peptidergic inputs such as vasopressin (AVP), oxytocin (OXT) (Menon et al., 2018; Borie et al., 2024), corticotropin-releasing factor (CRF) (Sakanaka et al., 1988), as well as cholinergic and monoaminergic inputs such as dopamine (Mahadevia et al., 2021) and serotonin (Köhler et al., 1982). The LS is also highly heterogeneous in that it expresses receptors for all the abovementioned ligands (Risold & Swanson, 1997; Menon et al., 2022), and neurons expressing these receptors have very specific distribution patterns and receive topographically organized cortical and hippocampal inputs (Besnard & Leroy, 2022). However, the role of specific neuromodulatory inputs (i.e., OXT, CRF, Dopamine, and Serotonin) and their interaction with each other in regulating the influence of internal states on cognition during social encounters remains unknown.
Current projects:
The first project studies the role of OXTRs in the LS, in the context of its promiscuous coupling to Gq and Gi-coupled GPCR signaling in regulating social valence alterations during social fear extinction. This study uses in vivo Ca2+ imaging, chemogenetics, and pharmacology to identify the precise dynamics of OXTR signaling in the LS during social fear extinction (i.e., social valence reversal).
The LS expresses receptors for CRF (CRFR1 and CRFR2). Another project I supervise studies the role of LS projecting CRF neurons originating from the prefrontal cortex in regulating stress response during the extinction of social fear. Here, I am using pharmacology and chemogenetics to assess the precise response of CRFR1 and CRFR2 expressing neurons in the LS at different stages of extinction (i.e., social valence reversal).
Within the LS, OXTRs are expressed not only in neurons but also in astrocytes. The third project I supervise characterizes the role of OXTR-expressing astrocytes in the LS in regulating social fear expression in male and female mice. I am using a combination of pharmacology and genetic manipulation to characterize the sex-dependent differential influence of OXTR-expressing LS astrocytes on the expression of social fear in mice.
Apart other subnuclei of the septal area, namely the medial setpum (MS) also expresses OXTR. However, the role of OXT signaling within the MS is completely unstudied. In this project, I aim to characterize the biochemical and functional properties of the OXTR expressing neurons in the MS in context of mouse social behavior.
This process of sensing, interpreting, and integrating internal body signals is called interoception. A recent study has shown that in rodents there is a fast pathway for interoception of the heartbeat, in which arterial pressure pulsations in the brain modulate the activity of mitral cells within the olfactory bulb. Changes is heartrate are known to correlate with modulation in social behavior. In this project, I am using a combination of genetic and behavioral analysis, to assess the role of the pathway involved in interoception of heartrate in the olfactory bulb in regulating mouse sexual behavior.
Funding
DFG grant as a principal investigator for the project titled “Role of CRFR2-signaling within the lateral septum in regulating social fear extinction in lactating mice” (ME 5731/2-1; 2025-2028).
DFG grant as a principal investigator within phase 2 and phase 3 of GRK2174 “Neurobiology of Socioemotional Dysfunctions” (2020-2026).
Collaborations
Prof. Dr. Valery Grinevich (Central Institute of Mental Health, University of Heidelberg, Germany)
Prof. Dr. Gunter Meister (Institute of Biochemistry, University of Regensburg, Germany)
Prof. Dr. Katsuhiko Nishimori (Fukushima Medical University, Japan)
Prof. Dr. Markus Muttenthaler (University of Queensland, Australia)
Prof. Dr. Oliver Bosch (Institute of Zoology, University of Regensburg, Germany)
Prof. Dr. Igor Ulitsky (Weizmann Institute of Science, Israel)
Prof. Dr. Felix Leroy (Instituto de Neurociencias, Alicante, Spain)
Dr. Sanja Bauer Mikulovic (Leibniz Institute for Neurobiology, Magdeburg, Germany)