Précis

Our lab's role in this Center grant is to assess the Biological Conequences of Prenatal Stress and/or Antidepressant Exposure (i.e., epigenetics).

Details

Given the reality that human infants can be exposed to stressors and antidepressant drugs in utero as part of life events or appropriate medical treatment of the mother, the long term developmental consequences on the offspring need to be determined as one aspect of planning and monitoring long term health issues. This project focuses upon the biological consequences (biochemical, molecular, physiological and genetic) of the quality of maternal care interacting with prenatal stress and in utero antidepressant exposure on brain function of offspring when these rats become adults of reproductive age (i.e., does prenatal exposure to these factors alter the long term biology of the brain?). This project will focus on three unique aspects of adult brain function. 1) What are the regional brain neurochemical and molecular changes that result (the markers to be examined have all been previously promulgated, but not tested, to be involved in stress responsivity or the mechanisms of action of antidepressants) from maternal care, prenatal stress exposure, and in utero antidepressant exposure? 2) Are there structural changes in the microvascular system supplying blood to the brain or in the angiogenic growth factors that signal new blood vessel formation and retraction? For example, although it is well established that CNS plasticity includes changes in synaptic morphology, neuronal connectivity, glial morphology and function as well as changes in vasculature, the effects of maternal care, early life stressors, and in utero antidepressant treatment on the CNS have only been addressed for neurons and glia. 3) We will attempt to identify genetic loci that are epigenetically altered by the quality of maternal care, prenatal stress, and in utero exposure to antidepressants in rat brains. We will use ChIP-on-chip technology to investigate how the quality of maternal care, prenatal stress, and in utero exposure to SSRI’s alter the epigenetic profiles (both DNA methylation and histone modification) of the promoter regions across the genome in rat brains at birth and in adulthood. In addition, the mRNA expression profiles from the same brain regions will be evaluated and correlated with the epigenetic profiles. These state-of-the-art techniques can offer unique insight into the long term changes, or lack thereof, produced by differences in maternal care, prenatal stress, and in utero antidepressant exposure.

Plasticity of the central nervous system is facilitated through changes in vasculature as well as neurons and glia. Vascular disturbances may manifest as cerebral hypoperfusion and have been implicated in a variety of neurodegenerative diseases and psychiatric disorders including Alzheimer’s disease, depression, alcoholism, and substance abuse. Hypoperfusion impairs nutrient and oxygen delivery to neural tissue and can result in cellular edema, gliosis, and perivascular inflammatory infiltrate. In addition, changes in angiogenesis can alter perfusion of neural tissue which may alter synaptic plasticity. Given the crucial role of neuronal vasculature in the maintenance of neural tissue, an understanding of the effects of the early life experiences such as low maternal behavior and exposure to stress and/or antidepressants on brain vasculature may provide insights into the mechanisms that underlie stress-evoked changes in neural plasticity. Preliminary data suggest that prenatal stress alters the expression of cerebral angiogenic factors in adult rats which manifest as alterations in cerebral vessel density (Neigh et al., 2006). The first goal of this project is to assess the effects of maternal behavior, stress and antidepressant exposure on the cerebral vasculature of the offspring and elucidate the potential protective effect of antidepressant administration during gestation. The second portion of this study is designed to characterize the role of maternal behavior and stress exposure on the function of 5-HT in the neuron-astrocyte-microvessel tripartite unit and to elucidate the effect of antidepressant administration during gestation.