The most common neuropsychiatric consequence of traumatic brain injury (TBI) is depression. Early stress exposure has been recognized as an important mechanism for neuropsychiatric disorders in adulthood. In rodents, as in humans, adolescence is a transitional period between child- and adult-hood that is marked by behavioral changes, heightened brain development, and cognitive maturation. Therefore, exposure to adverse environmental conditions during this sensitive period of development could influence TBI psychiatric outcomes. Activation of the endocannabinoid CB1 receptor is thought to suppress the neuroendocrine and behavioral stress response. Although the endocannabinoid system mediates the neuroendocrine stress system, it is unknown how they interact in the pathophysiology underlying emotional behavioral impairments post TBI, or how prior environmental conditions influence these systems, and whether these effects persist in adulthood. The overarching aims are to test the hypothesis that chronic unpredictable stress provided during adolescence will result in deleterious effects on anxiety, depression, and cognition in rats subjected to a TBI as adults. Moreover, the endocannabinoid system may underlie the molecular mechanisms involved in these behavioral changes, and thus treatment with the CB1 agonist ACEA will reduce the deleterious effects of adolescent stress in adults sustaining a TBI. Specifically, the aims are designed to evaluate the long-term effects of chronic unpredictable stress provided during adolescence in adult TBI rats by utilizing a range of tests for social- anxiety- and depression-related behaviors (Aim 1a), and determine whether these behaviors correlate with cognitive impairments, neuroendocrine responses to stress, and levels of markers indicating neuroplastic changes in brain structures mediating emotional and cognitive processes (Aim 1b).
Aim 2 will investigate the influence of agonists (ACEA) and antagonists (AM251) of the CB1 cannabinoid receptor on behavioral and neuroendocrine responses (from Aims 1a,b) post adult TBI. Thus, the proposed research will determine whether exposure to repeated stress during adolescence plays a determinant role in modulating components of the stress system and brain plasticity, as well as behavior following adult TBI, and whether such effects are dependent on the endocannabinoid action in brain regions regulating emotional responses. Understanding the impact of environmental and biochemical factors will help develop effective preventive and therapeutic strategies for TBI patients.
Children and adolescents are at higher risk of emotional disorders after TBI and depression is one of the most frequently reported psychological problems in adult TBI, affecting 30-40% of patients. As a result, an increased understanding about the relationship between depression and cognitive impairments post-TBI is important for understanding individual functional recovery and developing effective personalized treatments. Thus, the aims of this R21 application are to determine if chronic unpredictable stress provided during adolescence will result in deleterious effects on anxiety, depression, and cognition in rats subjected to a TBI as adults, and whether treatment with the endocannabinoid CB1 agonist ACEA will reduce the deleterious effects of adolescent stress in adult sustaining a TBI.
