Adaptive plasticity of brain structure and function in response to consecutive stress exposure: assessing the role of endocannabinoid receptors as mediators of resilience

早期生活逆境和早期生活压力(ELS)是导致青春期和成年期出现的各种精神障碍的主要危险因素。绝大多数关于ELA的动物研究都研究了在特定的发育时间窗口内单一的短暂或慢性应激事件的影响。然而，在“正常”的生活中，个体“收集”了许多生活中的压力、创伤和忽视的经历。因此，在使用连续应激暴露的动物模型(新生儿和青春期前)的“自上而下”方法中，我们将解决以下问题：关键发育阶段的连续应激源是否会累积并连续增强其影响，从而增加个人的S脆弱性，从而导致严重的大脑和行为障碍？或者，连续的ELS发作是否会影响大脑的可塑性和行为，使个人在以后的生活中更有弹性，更好地应对不利环境(“应激接种”)？在机制层面上，我们将阐述ELS诱导的大脑可塑性的两个互补假说。首先，我们假设a)mPFC-杏仁核-伏隔核回路是理解脆弱与韧性的中心，因为它在幼年期(即我们第二次打击的时间点)连续而显著地成熟；b)ELS诱导的“应激-接种”对脆弱的长期影响是由特定神经元集合内突触可塑性蛋白表达的活动诱导的变化所授予的，这使得c)突触连接、神经元功能和可塑性的结构长期变化，以及d)存在性别差异。第二，我们假设ELS诱导的复原力是由内源性大麻素CB1受体的变化引起的，其表达f)是由ELS表观遗传重新编程的。利用芯片测序，我们将筛选新的基因靶点，包括潜在的蛋白质，这些蛋白质是CB1激活的下游信号级联反应的一部分。在治疗水平上，我们还将阐明药物干预是否以及以何种方式使行为病理“正常化”，以及ELS诱导的神经元和突触功能以及可塑性大脑的变化。尽管许多临床研究提供了充足的证据证明ELS引起的精神障碍的流行率存在相当大的性别偏见，但绝大多数动物模型研究都集中在对男性的分析上，因此该项目的另一个重点将放在不同性别在易感性和韧性方面的差异上。

Early life adversity and early life stress (ELS) constitute major risk factors that contribute to the aetiology of various psychiatric disorders which emerge during puberty and adulthood. The vast majority of animal studies on ELA have studied the impact of a single brief or chronic stress episode during defined developmental time windows. However, in “normal” life individuals “collect” many experiences of stress, trauma and neglect throughout life. Hence, in a “top-down” approach using an animal model of consecutive stress exposure (neonatal and periadolescent) we will address questions including: do consecutive stressors during critical developmental phases accumulate and successively potentiate their effects and thereby increase an individual´s vulnerability, resulting in severely dysfunctional brain and behavior? Or can consecutive ELS episodes entrain brain plasticity and behavior to make an individual resilient and better cope with an adverse environment later in life (“stress inoculation”)? On the mechanistic level we will address two complementary hypotheses of ELS-induced brain plasticity. First, we hypothesize that a) the mPFC-amygdala-n.accumbens circuit is central in understanding vulnerability vs resilience due to its continuous and significant maturation during juvenility (i.e. time point of our 2nd Hit); b) the long-term effect of ELS-induced “stress-inoculation” vs vulnerability is conferred by activity-induced changes in the expression of synaptic plasticity proteins within specific neuronal ensembles, which confer c) structural long-term changes in synaptic connectivity, neuronal function and plasticity, and d) that sex-specific differences exist. Second, we hypothesize that ELS-induced resilience is conferred e) by changes in endocannabinoid CB1 receptors, whose expression f) is epigenetically re-programmed by ELS. Using Chip sequencing we will screen for novel gene targets, including potential proteins, which are part of CB1-activated downstream signaling cascades. On the therapeutic level we will also elucidate if and in which way pharmacological interventions “normalize” behavioral pathology and ELS-induced changes in neuronal and synaptic function and plasticity brain. Since - despite the fact that many clinical investigations provide ample evidence for a considerable sex bias in the prevalence of ELS-induced mental disorders - the vast majority of research in animal models has focused on the analysis of males, another focus of this project will be laid on sex-specific differences in susceptibility and resilience.