Neuronal mechanisms underlying social fear conditioning in mice

社交焦虑症(SAD)的终生患病率约为12%；然而，与一般焦虑症相比，SAD的具体治疗方案缺乏，主要是因为缺乏相关的社会恐惧动物模型，从而缺乏对潜在机制的了解。我们最近建立了第一个SAD的特定动物模型，即社会恐惧条件反射(SFC)，并证明了亲社会和抗焦虑的神经肽催产素(OXT)能够逆转雄性和雌性小鼠的社会恐惧。基于这些发现，我们的目标是更详细地研究社交恐惧的神经机制和脑OXT的参与。具体地说，我们的目标是(I)比较社交和非社交反应的局部神经元活动模式，即线索恐惧的获得和消退，(Ii)起源于下丘脑视上核和室旁核的OXT通路，以及它们在外侧隔核和杏仁核亚核的靶神经元对社会恐惧获得和消失的贡献，以及(Iii)交配诱导的内源性OXT系统激活对社交恐惧和线索恐惧的影响。在这种情况下，我们将抑制交配诱导的OXT神经元的激活，或者使用药物遗传抑制(DREADD)来模拟局部OXT的释放，或者刺激投射到外侧隔区的OXT神经元。我们的进一步目标是表征(Iv)杏仁隔核内表达oxt受体的神经元的下游连接性，该神经元参与oxt逆转社会恐惧。最后(V)，我们将研究神经肽促肾上腺皮质激素释放因子(CRF)对社交恐惧和线索恐惧的影响，以及OXT和CRF在中央杏仁核内的相互作用有助于巩固和消除社交恐惧。在此背景下，我们将采用体外电生理学(合作)、药物遗传沉默和刺激CRF-CRE小鼠杏仁核内的CRF神经元。因此，将已建立的和创新的实验方法与新建立的SFC范式相结合，我们将能够剖析参与社会恐惧的特定神经肽能神经元通路，并为SAD可能的治疗干预识别特定的大脑靶点。

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.