The functional role of the chronic oxytocin-induced soluble CRF receptor 2α splice variant

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Due to its pro-social, anxiolytic and anti-stress effects found after acute treatment, the neuropeptide oxytocin (OXT) is considered a therapeutic option for psychiatric disorders associated with socio-emotional deficits. However, several animal and human studies reported adverse behavioral effects of chronic OXT treatment. During the first funding period we revealed that chronic OXT treatment increases anxiety via activating alternative splicing of the corticotropin releasing factor (CRF) receptor CRFR2α in the hypothalamic paraventricular nucleus (PVN). Whereas CRFR2α mediates anxiolytic effects, the soluble sCRFR2α variant exerts an anxiogenic effect. However, the role of sCRFR2α in other behavioral or neuroendocrine contexts is unknown. In continuation of our results we aim to study, whether sCRFR2α modulates the (re)activity of stress-related neuroendocrine systems (hypothalamo-pituitary-adrenal (HPA) axis, OXT and vasopressin systems) by monitoring hypothalamic gene expression patterns, and secretion into blood and within distinct brain regions. We will further study, whether sCRFR2α is involved in the regulation of social and emotional behaviors under basal conditions, and under conditions of social trauma and chronic psychosocial stress using mouse models of social fear conditioning (SFC) and of chronic subordinate colony housing (CSC), respectively. The relevance of these mouse paradigms in the context of sCRFR2α is given as exposure to SFC as well as CSC results in increased social fear and anxiety-related behavior, respectively, and alterations in the OXT system. Here, we will manipulate alternative splicing and the regional availability of sCRFR2α using specific antisense oligonucleotides (GapmeRs), target site blockers and recombinant sCRFR2α peptide infused into the identified region(s) of interest and assess consequences on emotionality and naturally occurring social preference behavior. We will further monitor the consequences of exposure to either SFC or CSC on sCRFR2α expression, and study the consequences of specific regional sCRFR2α manipulation of SFC- and CSC-induced behavioral alterations.To reveal mechanisms of sCRFR2α signaling we will start with identifying the major cell type(s) of expression and splicing of sCRFR2α in neuronal and astrocytic cell cultures, before we will characterize selected sCRFR2α-signaling cascades and intracellular protein interaction partners of sCRFR2α in primary mouse neurons and astrocytes overexpressing sCRFR2α by co-immunoprecipitation and subsequent analysis using mass spectrometry. The project will contribute to the still limited knowledge regarding the adverse consequences of chronic treatment with OXT including the stimulation of alternative splicing of the CRFR2α, which is causally involved in the chronic OXT-induced increase in anxiety level.