Transgenerational Epigenetic Reprogramming of Neuronal Maturation by Early-Life Maternal Sleep Deprivation( I )

Sleep is a vital component to maintain the health of all living organisms which represents the key machinery for individuals to physically and mentally repair itself. The deleterious effect of maternal sleep deprivation experienced during pregnancy that results in impact on fetal neurodevelopment has already been documented extensively. However, the influences by which life-long (either throughout puberty or in adulthood) maternal exposures to environmental challenges are largely been ignored. The brain is a vulnerable and flexible structure that can easily sense the environmental changes and respond dynamically with structural remodeling. And the amygdala and hippocampal complex which control the cognitive and affective performance are extremely susceptible to fetal reprogramming by maternal sleep deprivation. Since recent epidemiological evidence in humans suggested that germ cells are more susceptible to be reprogrammed during the period of “adolescence” and pass the epigenetic information to the next generations. Based on these previous findings, we raised an interesting hypothesis that maternal sleep deprivation throughout her puberty may induce germ cell epigenetic reprogramming which impacts the normal developmental process of cognitive and emotional circuits in their offspring. Our proposal will focus on early life experience suffered during mother’s period of adolescence, and then behavioral and morphological parameters will be collected at P21 or P90 from the second generations. Two brain areas that crucial for cognitive and affective function (hippocampus and amygdalar BLA) will be targeted for answering three specific aims: First, comprehensive analysis of cross-generational impact of maternal sleep deprivation on cognitive and psychological performance in their offspring. To exclude the confounding factor of “over-stressed” by the standard model, we are now establishing an innovative genetic mouse model for sleep deprivation by inducible overexpression of dominant negative Clock in the suprachiasmatic nucleus that temporally alters the sleep-wake rhythm and shortens the sleep duration by doxycycline. By using these models, we will investigate the functional maturation of two critical neuronal domains: cognitive performance and emotional regulation through variety of behavioral analyses. Second, the influence of alteration in maternal sleep homeostasis on neuronal maturation of their progeny will be investigated. Approaches through an in vivo retroviral based labeling of developing neurons will be conducted. Basically, eGFP expressing neurons will be visualized at different precise (birth-dating) developmental stages to analyze their morphological maturation in detail. Besides, the dynamic building of connections between developing neurons with the neighboring cells in vivo (the formation and pruning of synapses) will be studied as well. Furthermore, by focusing on cross-generational epigenetic modifications, we will answer the underlying mechanisms that contribute to these inherited changes. Experimentally, by combining of biochemical analyses, TALEN-based epigenetic tools and in vitro drug screening platform, we will develop innovative approaches to validate the specific inherited epigenetic imprinting that dedicates the behavioral and morphological alterations. Our proposal has the potential to answer the correlation of early-life maternal experience with the risk of neuropsychiatric or mental disorders in their offspring and provide the feasible pharmacological interventions that target the early-life maternal sleep deprivation induced epigenetic modification specifically and eventually reinstate normal neurodevelopment in the suffered offspring.