Early life stressors~have profound and lasting impact on behavior and neuroendocrine function. Indeed, clinical epidemiological studies have shown that childhood abuse and/or neglect is a significant risk factor for the development of adult psychopathology. These effects are due to changes in brain morphology and neurocircuit function that are only partially documented. Clarification of these changes could lead to new treatment strategies to ameliorate the deficiencies caused by the early life stress or by genetic factors. It has been known for many decades now that CNS catecholaminergic systems play a major role in the regulation of behavior. Depression has long been linked to dysfunction of dopaminergic and/or noradrenergic systems in the brain. This is not surprising as dopaminergic and noradrenergic systems have been linked to reward/motivation and to vigilance, respectively. These circuits also participate in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Clinical depression as well as many animal models of depression-like syndrome are characterized by aberrant vigilance expressed as anxiety, anhedonia, and dysregulation of the HPA axis. The current project will focus on a comparison Of the development and function of these important neural systems in an epigenetic (early life stress) model of depression-like syndrome in rodents. Additionally, a limited number of studies will be performed on a early liter stress nonhuman primate model. Neurochemical, molecular, behavioral, and electrophysiological approaches will be used to characterize these neural systems in these animal models throughout neonatal development and maturity under basal, stress (acute and chronic) conditions, and in response to antidepressant treatment. Both males and females will be used. We hypothesize that alterations in the development and/or function of dopaminergic and/'or noradrenergic neural systems underlie the altered mood, reward, reinforcement, and motor function in these animal models. Further, we postulate that catecholaminergic neurocircuits may become """"""""sensitized"""""""" by early life stress leading to enhanced vulnerability to the effects of later exposure to adverse life events thus increasing their risk of developing major depression or related mood disorders. Multiple interactions with other preclinical and clinical components of the Emory University Center for the Neuroscience of Mental Disease will benefit these studies both in terms of the uniformity of the animal models and their treatment but also in terms of intellectual cross-fertilization.
Showing the most recent 10 out of 146 publications
