Interaction of Epigenetic and Stress Effects on Brain and Behavior

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DESCRIPTION (provided by applicant): Recently it has been discovered that early experiences can modify regulatory factors affecting gene expression in such a way that the DNA sequence itself is not changed but the individual's physiology and behavior are substantially influenced. In some instances these epigenetic effects can be transmitted across generations via incorporation into the germline where they become permanent and tend to be sex-linked, a relevant point as many affective disorders show gender bias. The proposed work will focus on how stress during a critical life history stage (peripubertal) might interact with the epigenome to influence aggressive and affiliative behaviors, metabolic activity in brain nuclei, and patterns of gene expression in specific brain nuclei. We will use an established male rat model of transgenerational epigenetic imprinting for early onset of multi- organ disease. There will be two groups: daily restraint stress for 6 hours for 21 days beginning at 22 days of age, and unstressed. Prior to sacrifice (120 days) animals will given a battery of behavioral tests. The brains will be sectioned in three alternating sets, the first set for cytochrome oxidase histochemistry, the second set for in situ hybridization, and the third set for the CA1 and CA3 of the hippocampus and basolateral amygdala for microanalysis (obtained using laser-capture microdissection). Specific Aim 1 will evaluate the behavioral phenotype of transgenerationally imprinted rats. Specific Aim II will determine if transgenerationally imprinted rats exhibit different patterns of metabolic activity in a defined network of interconnected limbic and forebrain nuclei known to be involved with agonistic and affiliative behaviors. Specific Aim III will determine if the distinct behavioral profiles exhibited by transgenerationally imprinted rats are reflected in unique patterns of gene expression in relevant brain regions. Within each Specific Aim, three hypotheses will be examined in three basic comparisons. Hypothesis 1: The transgenerational effects of vinclozolin exposure modifies both social and affiliative related behaviors and its related metabolic activity in specific brain nuclei as well as influencing the abundance of specific genes and altering the epigenome in the target brain areas. Hypothesis 2: Peripubertal stress potentiates both social and affiliative behaviors and its related metabolic activity in specific brain nuclei as well as influencing the abundance of specific genes and altering the epigenome in the target brain areas. Hypothesis 3: Peripubertal stress interacts with the environmentally induced, transgenerational epigenetic imprinting in a synergistic fashion to modify social behaviors as well as influencing the abundance of specific genes and altering the epigenome in the target brain areas. PUBLIC HEALTH RELEVANCE: How epigenetic modification can modulate how the environment and genetic constitution interact at the level of the brain, ultimately influencing agonistic and affiliative behaviors is the subject of the proposed work.