Neuronal mechanisms underlying social fear conditioning in mice

社交焦虑障碍（SAD）的终生患病率约为12%;然而，与广泛性焦虑障碍相比，SAD的特定治疗方案缺失，主要是由于缺乏社交恐惧的相关动物模型，因此缺乏对潜在机制的了解。我们最近建立了SAD的第一个特定动物模型，即社会恐惧条件反射（SFC），并证明亲社会和抗焦虑神经肽催产素（OXT）能够逆转雄性和雌性小鼠的社会恐惧。基于这些发现，我们的目标是详细研究社交恐惧背后的神经机制，以及大脑OXT的参与。具体来说，我们的目标是（i）比较区域神经元活动模式对社交与非社交的反应，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通路的贡献，和他们的目标神经元内的外侧隔和杏仁核亚核，社会恐惧收购和灭绝，及（iii）交配诱导激活的内源性OXT系统对社会与线索恐惧的影响。在这种情况下，我们将抑制交配诱导的OXT神经元激活或使用药物遗传学抑制（DREADD）或刺激投射到外侧隔的OXT神经元来模拟局部OXT释放。 我们进一步的目的是表征（iv）下游连接的OXT受体表达神经元内的隔AD杏仁核参与逆转社会恐惧的OXT。最后（v），我们将研究神经肽促肾上腺皮质激素释放因子（CRF）对社会与线索恐惧的影响，以及OXT和CRF的相互作用，特别是在中央杏仁核内有助于巩固和消除社会恐惧。在这种情况下，我们将采用离体电生理学（合作），药物遗传学沉默和刺激CRF神经元内的杏仁核在CRF-CRE小鼠。因此，将现有的和创新的实验方法与新建立的SFC范式相结合，我们将能够解剖与社会恐惧有关的特定神经肽能神经元通路，并有助于识别可能的治疗干预的特定脑靶点。伤心.

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.