The generation of new neurons in the adult hippocampus is a highly complex process, which is regulated by numerous stimuli and environmental factors. One of the most intriguing regulators of adult neurogenesis is seizure activity, but the functional consequences underlying seizure-induced neurogenesis are unclear. Recently, we showed that adult-born dentate granule cells (DGCs) after pilocarpine-induced status epilepticus (SE) causes more spontaneous, recurrent seizures and abnormal hippocampal-dependent learning and memory. These data helped us formulate a clear objective for this grant proposal: to use optogenetic techniques to explore the cell intrinsic role of adult-born DGCs in epileptogenesis and local neural activity. Our central hypothesis is hyperactive adult-born DGCs cause recurrent, spontaneous seizures by disrupting critical neural circuits. We will test this hypothesis via two specific aims: 1) To inhibit adult-born DGCs with archaerhodopsin and determine whether this reduces chronic seizure frequency and 2) To determine whether hyperactivation of adult-born DGCs with Channelrhodopsin promotes chronic seizures.
Aim 1 will utilize a Nestin-CreERT2-inducible transgenic mouse expressing Archaerhodopsin-3 (Arch) EGFP to selectively silence adult-born DGCs during chronic epilepsy.
Aim 2 will use a Nestin-CreERT2-inducible transgenic mouse expressing Channelrhodopsin (ChR2) tdTomato to selective activate adult-born DGCs during chronic epilepsy. The conceptual framework and approach is innovative because we will apply state-of-the-art optogenetic techniques to a mouse model of temporal lobe epilepsy and dissect underlying cellular- and circuit-level mechanisms of SE-dependent neurogenesis. As our long-term goal is to understand the molecular mechanisms important for how aberrant neurogenesis drives chronic epilepsy, the proposed work is disease- relevant and highly significant. It will advance and expand our basic understanding of seizure activity- dependent molecular networks regulating neural stem cell proliferation, neuronal and glial differentiation, survival and maturation which will advance our understanding of neurogenesis in both basal and pathological states. The proposed study is relevant to NIH's mission as it will allow us to gain fundamental insight regarding the molecular underpinnings of epilepsy and associated comorbidities as well as acquiring knowledge towards new avenues for treating neurological and psychiatric disorders.
Disease, degeneration or traumatic injury of the nervous system are among the greatest public health concerns in the United States and are generally considered irreparable, often causing catastrophic damage to the functional capacity of the individual. Now, however, characterization of neural stem cells residing within specific germinal centers of the brain and in cell culture raises hope that functional regeneration of nervous tissue may be feasible, if we learn to exploit adult neurogenesis for clinical benefit. The research proposal will lead to improved understanding of neural stem cell biology, possibly leading to the development of new drugs for repair and regeneration of the nervous system.
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