Though the precise etiology of schizophrenia remains unclear, exogenous influences such as childhood adversity, elevated basal stress hormones, and stress reactivity during critical periods increase psychosis risk 2-5 fold. Moreover, emerging evidence indicates that the stress response is modulated by endocannabinoids. Such findings are especially interesting given evidence that adolescent cannabis use hastens psychotic disease onset and exacerbates symptom severity. However, the mechanisms by which childhood adversity affect the endocannabinoid and stress response systems and how adversity-induced perturbations in these systems affect behavior are unknown. Cerebellar circuits and related behaviors are especially well-suited to investigate these effects because the cerebellum is (a) highly susceptible to stress due to its protracted developmental window, (b) densely populated with endocannabinoid receptors, and (c) has been implicated in schizophrenia, as is the endocannabinoid system. In particular, delayed eye-blink conditioning is a sensitive measure of cerebellar function that is modulated, perhaps in a sex-specific manner, by endocannabinoid signaling. Delayed eyeblink conditioning is robustly impaired in individuals with schizophrenia and their relatives, suggesting that this task captures a neural deficit inherent in psychosis. Thus, it is hypothesized that early life stress in rat pups will result in long-term down-regulation of the cerebellar endocannabinoid system and this will be reflected by deficits in delay eyeblink conditioning in adulthood. This question will be addressed through two specific aims, which will: (1) test the hypothesis that limited bedding ELS from PND2-9 leads to long-term down-regulation of cerebellar endocannabinoids at PND70 and (2) will test the hypothesis that ELS-induced endocannabinoid aberrations will predict EBC performance. Rat pups of both sexes will undergo an early life stressor, namely limited bedding at postnatal days 2-9, then be reared normally to adulthood. The cerebellar endocannabinoid system (enzymes, lipids, receptors) will be quantified in adulthood, then used to predict behavioral outcomes of a delayed eyeblink conditioning paradigm. The impact of these results would be significant for the field, as they would (a) link perturbations in a well-defined neural circuit to behavioral deficits (i.e., EBC), demonstrating for the first time that early life stress down-regulates the endocannabinoid system within the cerebellum, inducing deficits in a cerebellar-dependent task and (b) unveil novel therapeutic targets that have sound translational power due to the ecological validity of the animal model chosen and conservation of the circuit under investigation across species. Such research will have broad impacts on our understanding of schizophrenia and future efforts to alleviate its personal and societal burdens.! !
Early life stress can affect neurodevelopment, impacting cognitive outcomes in adulthood and increase the risk for serious mental illness. A major question in the field is how early life stress and the endogenous cannabinoid system interact to produce such deleterious effects. Identifying and understanding the neural mechanisms underlying these interactions will facilitate the identification of novel therapeutic targets for the highly impairing cognitive outcomes of early life stress, like those seen in schizophrenia and other forms of psychopathology. !
