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

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 2^nd 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.