Analyzing the role of developmental programming of the adult hippocampal neurogenic niche in prenatal stress-induced vulnerability to psychiatric disease

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Maternal stress during pregnancy, which is also termed prenatal stress (PS), is associated with an increased risk of the offspring to develop mental health problems. The pathophysiological mechanisms leading to this increased risk are not fully understood. Current data, however, suggest that PS modifies the development of neural circuits involved in the modulation of stress and emotional behavior, thereby rendering them more vulnerable to insults in later life. The dentate gyrus of the hippocampal formation plays a fundamental role in regulating learning processes and in modulating anxiety states, i.e., functions that are affected in PS-linked psychiatric disorders. In contrast to most other brain structures, the adult dentate gyrus provides a unique signaling environment that allows for the life-long generation of its principal neurons, i.e. the dentate granule neurons (DGNs). As a consequence the dentate gyrus is composed not only of DGNs that are generated during the embryonic and early postnatal period but also of DGNs that are born during adulthood. Importantly, the functional balance between developmentally-born and adult-born neurons is crucial for dentate gyrus information processing. In this highly collaborative project we will investigate in a rodent model the hypothesis that PS disrupts both the maturation of developmentally-born DGNs and of the unique signaling environment necessary for the life-long generation of DGNs, thereby disrupting the functional balance between these neuronal populations and enabling psychiatric disease related behavioral disturbances. To test this hypothesis, we will apply a combination of molecular, genetic, anatomical, optogenetic and behavioral approaches in mice to i) analyze the specific impact of PS on developmentally- vs adult- born dentate granule neurons (DGNs) at a morphological, functional, and behavioral level, ii) decipher the molecular dynamics driving the aberrant postnatal development of the adult dentate gyrus specific signaling environment, and iii) probe dysregulated Wnt/beta-catenin signaling, an essential regulator of DG development and critical signaling pathway in the adult dentate gyrus neurogenic niche, as a candidate to mediate long-term effects of PS on adult neurogenesis and vulnerability to psychiatric disease. We expect that results from this project will significantly further our understanding of the pathophysiological mechanisms of how adverse events during critical periods of brain development establish vulnerability for psychiatric diseases.