My career goal is to train graduate, undergraduate, and medical students, and independently lead a research group that investigates the neural circuitry underlying motivated and mood-related behavior to eventually use this insight for translational research. To achieve this goal, I am proposing a project that provides me with significant training by examining how the dentate gyrus (DG) circuit contributes to anxiety-like behavior. Specifically, I will examine whether the developmental origin or regional position of DG granule cells (GCs) dictates their contribution to emotional behavior. To test this, I will use optogenetic techniques to control the activity of mature and adult-born granule cells in the dorsal or ventral DG to determine their relative contribution to anxiety-like behavior. My primary expertise is in mouse behavior, molecular biology and mouse genetics. My career development plan will expand on this by providing me essential training in patch clamp electrophysiology, in vivo electrophysiology, and in vivo optogenetic neuromodulation during behavior. As my career goal is to lead a research group examining the circuits that underlie affective behavior, and how they go wrong in disease states, these skills are not only required, but also essential to my success in leading a well-rounded, independent research career. In addition, as my previous focus has been on basic research, I have proposed to expand my training in translational neuroscience, so that I may apply my research to successfully collaborate with clinicians. Research Project Identifying the circuit mechanisms that underlie anxiety and depression is of utmost importance for treating psychiatric illness. In this proposal, I will examine how the dentate gyrus (DG) contributes to anxiety-like behavior. While classically studied for its role in spatial learning, there is significant support for a role for the DG in emotional behavior, but the mechanism for this remains unknown. A potential mechanism derives from the observation that emotional state can influence the production of new granule cells (GCs) from stem cells located in the adult DG. In addition, recent studies suggest the hippocampus is functionally segregated along its dorsal-ventral axis, influencing anxiety-like behavior through its ventral pole. This would suggest that GCs represent a functionally heterogeneous pool of neurons determined locally by their developmental origin and regionally by their position along the dorsal-ventral axi of the hippocampus. To test these possibilities, we have selectively expressed the blue light activated cation channel channelrhodopsin-2 (ChR2) and the yellow light activated chloride pump halorhodopsin (eNpHR3.0) in populations of mature and adult-born GCs. Using local circuit mapping in vitro, we will test the hypothesis that adult-born GCs modulate DG output. In vivo, we will test the hypothesis that optical stimulation or inhibition of GCs in the ventral DG preferentially influences anxiety-like behavior, while the dorsal DG impacts spatial learning. Finally, we will dissect the preferential contribution of adult-born GCs to anxiety-like behavior.
This proposal is the first to examine how modulating local circuits in the dentate gyrus can contribute to anxiety-like behavior. Identifying the circuits tht underlie anxiety and depression will provide new avenues for developing novel therapies and treatments that would be beneficial for the treatment of mood disorders.
|Lovett-Barron, Matthew; Kaifosh, Patrick; Kheirbek, Mazen A et al. (2014) Dendritic inhibition in the hippocampus supports fear learning. Science 343:857-63|
|Denny, Christine A; Kheirbek, Mazen A; Alba, Eva L et al. (2014) Hippocampal memory traces are differentially modulated by experience, time, and adult neurogenesis. Neuron 83:189-201|
|Kheirbek, Mazen A; Hen, René (2014) Add neurons, subtract anxiety. Sci Am 311:62-7|
|Kheirbek, Mazen A; Hen, Rene (2013) (Radio)active neurogenesis in the human hippocampus. Cell 153:1183-4|
|Ahmari, Susanne E; Spellman, Timothy; Douglass, Neria L et al. (2013) Repeated cortico-striatal stimulation generates persistent OCD-like behavior. Science 340:1234-9|
|Kheirbek, Mazen A; Drew, Liam J; Burghardt, Nesha S et al. (2013) Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus. Neuron 77:955-68|