Stress is a part of life; however, stressors during development can lead to increased adult incidence of depression and PTSD, metabolic syndrome, inflammatory disorders, and cardiovascular disease. Further, evidence over the past decade has demonstrated that adolescence is an additional developmental period of increased risk to prolonged consequences of stress exposure. Both males and females exhibit the adult consequences of chronic adolescent stress exposure in the clinic, and in studies using model animals; however, despite the clear clinical sex differences in adult disorders following early life stress, the question of what mediates these sex differences remains unresolved.
We propose that chronic adolescent stress (CAS) alters regulation and function of transcription factors deferentially in males and females. Given that transcription factors control the flow of genetic information from DNA to mRNA and thereby protein, increased or decreased activity of transcription factors can exert wide-ranging effects on both physiology and behavior and may account for the range of observed sex differences in the effects of CAS. The novel contribution of the proposed research will be identification of the extent to which CAS alters adult regulation and function of the transcription factors related to glucocorticoid receptor activation.
Adolescents living with HIV comprise approximately 12% of the HIV-positive population worldwide. Among the adolescent HIV-positive population is a greater incidence of mental health problems including clinical depression, a greater risk of reckless sexual and drug use behaviors, and a decreased adherence to highly active antiretroviral therapies (HAART). Though the stigma of being HIV-positive is often credited with the increased incidence of depression, evidence fails to support the association between external stimuli and depression in disease states. We use adolescent HIV-1 transgenic (HIV-tg) rats, that display related immune-response alterations and pathologies, to test the hypothesis that developmental expression of HIV-1-related proteins contribute to neurobiological indices of depression and depressive-like behaviors.
Further studies in these rats assess functioning of the HPA axis and the stress response and how HIV related proteins may influence these systems to precipitate disease.
HIV and the HPA Response
Congenital infection by the Human Immunodeficiency Virus (HIV) has been shown to lead to much comorbidity, including higher rates of affective and anxiety disorders. These comorbidities develop during the sensitive period of adolescence and more frequently in females. Depression is also linked to changes seen in the intracellular response system to corticosteroids at the level of the hippocampus (HC) and prefrontal cortex (PFC), with alterations of glucocorticoid receptor (GR) co-chaperones FKBP5 (negative modulator) and FKBP4 (positive modulator). In this project we are investigating the effects of HIV protein expression in HIV-1 transgenic adolescent female rats on the intracellular glucocorticoid receptor machinery, at the critical areas of the HC and PFC, at baseline conditions, after acute restraint stress, and after repeated chronic restraint stress. We use a combination of animal behavioral experiments, ELISA steroid assays, and quantitative PCR methods.
While historically neuropsychiatric disorders like depression have been believed to precede the associated alterations in cerebral metabolism, our lab hypothesizes that cerebral metabolic changes precipitate changes in behavior. This hypothesis is particularly relevant in light of the growing obesity epidemic affecting over a third of American adults and 17% of children, and the potential for this metabolic disease to affect not only cardiovascular health but also neuropsychiatric health. We use a high-fructose diet model that produces hyperglycemia and dyslipidemia to examine the mechanisms whereby shifts in energy allocation alter behavior and stress responses. Current studies that neuroinflammation associated with high fructose consumption may underlie some of these changes. Additional work has also examined the role of glucose transporters, altered cerebrovasculature, and the effects of high-fructose diet in a stroke model.
Small cerebral infarcts are diffuse brain lesions resulting from vascular occlusions. Magnetic resonance imaging studies show that an estimated 60% of individuals with pre-senile onset depression and 94% of people with senile onset depression exhibit these lesions. Although links between ischemia and disrupted mood have long been suggested, neither a causal relationship nor an underlying mechanism has been established. We use a rat microsphere injection model to generate diffuse microembolic (ME) strokes within the rat brain. Using a combination of behavioral, histological, molecular, and imaging techniques we have been able to establish a causal role of ME in the development of disrupted affective behavior and cognition as well as a role of cerebral inflammation in the maintenance of these behaviors. Additional work has examined the stress response, sex differences, and the role of lesion size and laterality in the manifestation of disrupted behavioral states.