The discovery of adrenal steroid receptors in hippocampus provided a gateway to the ongoing discovery that circulating steroid hormones and other systemic mediators, including metabolic hormones and cytokines, affect cognition, mood and many other neural processes and the further discovery that there is structural and functional plasticity of the healthy adult as well as developing brain, which these hormones mediate. Stress hormones do not work alone and excitatory amino acids play a key role along with other mediators such as BDNF and metabolic hormones such as insulin. However, excess, unregulated glutamate and glucocorticoids also mediate destructive changes in the brain accompanying stroke, seizures and head injury, as well as milder changes that are caused by stressors that inhibit neurogenesis in the mature dentate gyrus and cause neuronal dendrites to shrink. According to the stress-diathesis model, it is these stress-induced changes that are involved in precipitating depression in vulnerable individuals, based on work on both animal models and the human brain.
We are currently evaluating the neural and systemic biology of stress-vulnerable versus stress-resilient animal models with translation to human depression. Stress vulnerability is associated with deficits in a natural substance, acetyl-L-carnitine, that results in epigenetic dysregulation of glutamate in the brain and systemic dysregulation that includes increased inflammatory tone and insulin resistance. Translational studies point to a form of human major depression with these characteristics and new methods are being developed to diagnose and treat this type of depression.
We study genetic factors that contribute to this stress-vulnerability and its brain and systemic consequences as well as how sex differences influences both stress-vulnerability and the treatment of depression and other disorders. We also investigate the role of glucocorticoids as major mediating factors in both stress-vulnerable and resilient individuals. Furthermore, we investigate in animal models how early life abuse and neglect by the mother increase stress-vulnerability and the underlying neural and systemic consequences. Again this involves translation to the human condition where childhood abuse and neglect exacerbate diabetes, cardiovascular disease and the risk for dementia and major depression. In all of these projects we collaborate widely within the HDRF taskforce.