The quality of the early-life environment is associated with a risk for depression and anxiety disorders. We refer to specific environmental factors as “clinically-relevant” if they increase or decrease the risk for depression and/or anxiety disorders. Our objective is to understand how clinically-relevant forms of environmental experience influence the activity of specific gene networks in brain regions critical for mood disorders. Our objectives are to 1) associate environmentally-regulated changes in gene network activity to function that includes analyses of behavior and neural circuits (assessed using neuroimaging) and 2) to understand the biological basis for individual differences in susceptibility to environmental influences. Our studies include analyses of data from humans and rodent model systems.
An over-arching goal is to align our research to that of other HDRF teams and to 1) contribute genomic and transcriptional data to the HDRF database and 2) provide the unique capacity for small-animal neuroimaging to collaborative projects. A major focus for innovation is the development of statistical models that allow for the integration of transcriptomic and genomic data sets (gene networks) with those from neuroimaging (neural circuits) analyses.
Our rodent studies focus on specific environmental conditions: 1) variations in maternal care in the rat, which influences the development of brain structure and function over the early postnatal period and 2) environmental enrichment in the mouse, which stably alters brain structure and function over the peripubertal period. Enrichment is associated with resilience in response to chronic stress defined as a decrease in the expression of depression- and or anxiety-like phenotypes in response to chronic stress. Maternal care operates across a continuum to influence stress reactivity and the pattern of neural connectivity that determines the impact of chronic stress on mental health outcomes.
We used a mouse model to show that environmental enrichment enhances resilience to a subsequent exposure to chronic defeat stress, thus aligning our model to that developed by the Nestler lab and now used in multiple HDRF teams. Our previous HDRF neuroimaging studies together with data from multiple HDRF programs identified projections from the ventral dentate gyrus of the hippocampus (vDG) to the nucleus accumbens as a critical in determining individual differences in susceptibility/resilience to chronic social defeat. Transcriptomic analyses of the vDG from resilient vs susceptible animals revealed gene networks implicated in neurogenesis, which is increased by both enrichment and maternal care. We are currently determining if gene networks associated with hippocampal neurogenesis mediate the effects of both enrichment and maternal care on individual differences in susceptibility to stress.
Our studies with human data include genome-wide association analyses of individual differences in susceptibility to stress. The results provided the basis for the development of a polygenic score for susceptibility (PGSsus) that has now been replicated in a number of human cohorts and appears to predict mental health outcomes across multiple ethnic groups among individuals exposed to early life adversity. Informatic analyses of the PGSsus identifies “neurogenesis”-related functions as the top biological process in each of the replicate cohorts. We are refining the existing PGSsus to establish greater predictive validity and integrating this measure into human neuroimaging data sets to define target neural circuits.