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定义的发育时间窗内单一短暂或慢性应激事件的影响。然而，在“正常”的生活中，个人在一生中“收集”了许多压力、创伤和忽视的经历。因此，在一个“自上而下”的方法，使用连续压力暴露的动物模型（新生儿和青春期），我们将解决的问题，包括：连续的压力源在关键的发展阶段积累和连续加强其影响，从而增加个人的脆弱性，导致严重功能失调的大脑和行为？或者，连续的ELS事件是否可以引导大脑的可塑性和行为，使个体在以后的生活中更有弹性，更好地科普不利的环境（“压力接种”）？在机制层面上，我们将解决两个互补的ELS诱导的大脑可塑性的假设。首先，我们假设a）mPFC-杏仁核-神经元回路在理解脆弱性与弹性方面是中心的，因为它在青少年时期持续而显著地成熟（即我们第二次命中的时间点）; B）ELS诱导的“应激接种”相对于脆弱性的长期效应是由特定神经元系综内突触可塑性蛋白表达的活动诱导的变化赋予的，其赋予c）突触连接、神经元功能和可塑性的结构长期变化，和d）存在性别特异性差异。其次，我们假设ELS诱导的恢复力是由内源性大麻素CB 1受体的变化赋予的，其表达f）由ELS表观遗传重新编程。使用芯片测序，我们将筛选新的基因靶点，包括潜在的蛋白质，这是CB 1激活的下游信号级联的一部分。在治疗水平上，我们还将阐明，如果和以何种方式药理干预“正常化”的行为病理学和ELS诱导的神经元和突触功能和可塑性的变化大脑。尽管许多临床研究提供了大量证据，证明在ELS诱发的精神障碍的患病率方面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，因此本项目的另一个重点将放在易感性和恢复力的性别特异性差异上。

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.