Mechanisms of stress-enhanced aversive conditioning

描述（由申请人提供）：创伤后应激障碍（PTSD）和自闭症谱系障碍（ASD）的特征是持续和强烈的背景恐惧和焦虑，这些恐惧和焦虑通常由急性社会压力引起（PTSD）或明显加剧（ASD）。另一方面，社会支持可以显著减少这两种疾病的恐惧和焦虑症状。社会刺激对情绪过程的不同影响，特别是对习得性恐惧的增强和减少的影响，其背后的大脑机制尚不清楚。在这里，我们建议确定，在细胞和分子水平上，神经递质受体和受体后信号转导通路，积极和消极的社会互动影响后天的背景恐惧。 分别通过代谢型谷氨酸受体5（mGluR 5）和催产素受体（Oxtr）起作用的多巴胺能和催产素能系统在社会互动期间被有效激活并共同调节社会行为。然而，mGluR 5和Oxtr对情感过程的延迟影响显着不同：mGluR 5的不利影响在负面影响后占主导地位，而Oxtr的有益影响在积极的社会互动后占主导地位。mGluR 5和Oxtr类似地分布在脑中，但可能差异地偶联至鸟嘌呤核苷酸结合（G）蛋白。因此，我们假设mGluR 5和Oxtr的不同作用的机制是在受体后的信号转导水平。我们最近开发了社会失败和社会缓冲范式，以模拟消极和积极的社会互动对情绪的相反影响，并建立：（1）社会失败和社会缓冲如何影响信号转导和情境恐惧条件反射;（2）mGluR 5和Oxtr对这些影响的贡献;以及（3）mGluR 5-和Oxtr下游的哪些蛋白激酶介导了社会交往对恐惧的影响。mGluR 5和Oxtr在外侧隔（LS）中高度表达。该区域在处理社会互动中起着重要作用，并调节海马输出纤维的作用，这些纤维是背景恐惧条件反射所必需的。在此基础上，我们提出，LS神经元内接受海马输入的信号将揭示新的mGluR 5和Oxtr相关的恐惧调节的分子作用。我们的中心假设是，在LS，mGluR 5和Oxtr激活离散子集的G-蛋白偶联蛋白激酶途径介导的不同影响的社会失败和社会缓冲的恐惧。在完成这个项目后，我们希望已经确定：（i）mGluR 5和Oxtr激活信号转导以响应消极和积极的社会互动的细胞和分子机制;以及（ii）这些机制对调节恐惧的贡献。在众多受体激活途径中靶向选定的蛋白激酶将增加特异性，同时最大限度地减少PTSD和ASD中恐惧症状的新兴治疗的副作用。 公共卫生相关性：急性社会应激会加重创伤后应激障碍（PTSD）和自闭症谱系障碍（ASD）患者的恐惧和焦虑。另一方面，社会支持可以显著预防这些症状的发生。我们建议发现消极和积极的社会互动对恐惧产生相反影响的分子机制，从而确定新的治疗靶点PTSD和ASD。

DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) and autism-spectrum disorders (ASD) are marked by persistent and intense contextual fear and anxiety that are often caused (PTSD) or notably exacerbated (ASD) by acute social stress. Social support, on the other hand, significantly reduces fear and anxiety symptoms in both disorders. The brain mechanisms underlying different effects of social stimuli on emotional processes, and specifically on the enhancement and reduction of learned fear are not known. Here we propose to identify, at a cellular and molecular level, the neurotransmitter receptors and post-receptor signal transduction pathways by which positive and negative social interactions affect acquired contextual fear. The glutamatergic and oxytocinergic systems, acting via metabotropic glutamate receptors 5 (mGluR5) and oxytocin receptors (Oxtr), respectively, are potently activated during social interactions and co-regulate social behavior. However, the delayed effects of mGluR5 and Oxtr on affective processes markedly differ: the adverse effects of mGluR5 predominate after negative, whereas the beneficial effects of Oxtr prevail after positive social interactions. mGluR5 and Oxtr are similarly distributed in the brain but may differentially couple to guanine nucleotide-binding (G)-proteins. We therefore hypothesize that the mechanisms underlying different actions of mGluR5 and Oxtr are at a post-receptor, signal transduction level. We recently developed social defeat and social buffering paradigms to model the opposite effects of negative and positive social interactions on emotion and establish: (1) How social defeat and social buffering affect signal transduction and contextual fear conditioning; (2) What is the contribution of mGluR5 and Oxtr to these effects; and (3) Which protein kinases downstream of mGluR5- and Oxtr mediate the effects of social interactions on fear. mGluR5 and Oxtr are highly expressed in the lateral septum (LS). This area plays a prominent role in processing social interactions and modulates the action of hippocampal output fibers required for contextual fear conditioning. On this basis, we propose that signaling within LS neurons receiving hippocampal input will reveal novel molecular actions of mGluR5 and Oxtr relevant for fear regulation. Our central hypothesis posits that, within the LS, mGluR5 and Oxtr activate discrete subsets of G-protein coupled protein kinase pathways mediating the disparate effects of social defeat and social buffering on fear. After completing this program we expect to have identified: (i) the cellular and molecular mechanisms by which mGluR5 and Oxtr activate signal transduction in response to negative and positive social interactions; and (ii) the contribution of these mechanisms to regulation of fear. Targeting selected protein kinases among a multitude of receptor-activated pathways will increase the specificity while minimizing side effects of emerging treatments for fear symptoms in PTSD and ASD. PUBLIC HEALTH RELEVANCE: Acute social stress exacerbates fear and anxiety in patients with post-traumatic stress (PTSD) and autism- spectrum disorders (ASD). Social support, on the other hand, may significantly prevent the occurrence of these symptoms. We propose to discover the molecular mechanisms by which negative and positive social interactions exert opposite effects on fear, and thus identify novel treatment targets PTSD and ASD.