Studying the effects and mechanisms of deep brain stimulation in Rett syndrome mice

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PROJECT SUMMARY/ABSTRACT Deep brain stimulation (DBS) has expanded therapeutic options in disorders of movement, cognition, and mood. DBS is even beginning to be used to treat both motor and neuropsychiatric disorders in children. Several years ago, inspired by a study showing DBS can improve memory in Alzheimer's disease, my lab tested forniceal DBS in a mouse model of Rett Syndrome (RTT), a severe neurodevelopmental disorder that affects the entire brain, producing intellectual disability, motor, and affective abnormalities. One ramification of MeCP2 loss is the reduction of hippocampal neurogenesis. Importantly, we found that forniceal DBS stimulated neurogenesis in the dentate gyrus and dramatically rescued hippocampal memory in RTT mice. While suggestive, no direct causality has been drawn between DBS-induced neurogenesis and enhanced memory. Moreover, given that new neurons are born daily, and DBS is applied over a two-week period, it is conceivable that DBS is not only stimulating the generation of newborn neurons but also influencing their maturation and integration into the hippocampal circuit. Identifying a link between DBS, neurogenesis and the integration of newborn neurons is critical to understanding how DBS is enhancing hippocampal memory. Furthermore, although DBS induced neurogenesis may account for memory improvements in RTT, it is insufficient to explain how DBS of the nuclei in the basal ganglia, where neurogenesis does not occur, improves motor function. Our preliminary data show that DBS applied to the dorsal striatum improves the motor symptoms of RTT mice. We will capitalize on this progress to understand DBS effects in two different types of neurons and two different neural circuits in the same genetic context. In Aim 1, we will first examine the causation between forniceal DBS induced hippocampal neurogenesis and the memory enhancement. Then, we will determine how forniceal DBS affects the maturation and functioning of the newborn hippocampal neurons. In Aim 2, we will determine the duration of motor benefits induced by chronic striatal DBS and optimize the frequency of DBS treatment. Then we will elucidate the possible mechanisms of striatal DBS on motor benefits at the neuronal and circuit levels as well as the role of midbrain dopaminergic signaling in the benefits. Collectively, these studies will generate proof-of-concept data to validate DBS as an intervention to treat RTT and, potentially, other neurodevelopmental diseases.