Program Director/Principal Investigator (Last, First, Middle): Sahay, Amar Project Summary Anxiety disorders such as generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD) are characterized by heightened fear reactivity to ambiguous threats. This over generalization of fear may arise from erroneous assessment of cue-associated contingency or failure to distinguish a safe environment from a previously experienced aversive one, which then results in inappropriate retrieval of aversive memories and activation of fear circuits. Since pattern separation in dentate gyrus (DG)-CA3 circuit is thought to minimize interference between similar inputs, it may serve as neural mechanism by which ambiguous threats are processed. The DG is host to ongoing neurogenesis throughout life in both rodents and humans and adult- born neurons have been implicated in pattern separation, suggesting a potential role for these cells in processing of ambiguous threats. However, the local circuit mechanisms and neural pathways by which adult- born neurons process ambiguous threats are poorly understood. Addressing this gap in our knowledge may generate fundamental insights into the neurobiology of fear generalization and fuel strategies to reengineer the DG-CA3 circuit to improve ambiguous threat processing. Here, we will use a multidisciplinary approach involving retro-and lenti-viral gene transduction, optogenetic based neural pathway manipulations, and behavioral analysis to interrogate the causal links between adult-born neuron dependent regulation of feed forward excitation-inhibition balance and DG-CA3 extrinsic circuitry with modulation of fear responses to ambiguous threats. In proof of concept studies, we propose to genetically reengineer excitation-inhibition balance in the DG-CA3 circuit to enhance processing of ambiguous threats and develop a hypothesis driven drug discovery approach to identify small molecule modulators of excitation-inhibition balance and consequently, fear generalization. Together, these studies will generate a scaffold for how adult-born dentate granule neurons dictate fear generalization and demonstrate how modulation of excitation-inhibition balance may be harnessed for treatment of fear generalization in anxiety disorders. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Biographical Sketch Format Page

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The proposed experiments will probe the role of a fundamental neurobiological mechanism, regulation of excitation-inhibition balance, in processing of ambiguous threats and will investigate how this mechanism may be genetically and pharmacologically harnessed for modulating fear generalization, a cardinal feature of anxiety disorders such as post-traumatic stress disorder (PTSD) and panic disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZMH1)
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Vicentic, Aleksandra
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Massachusetts General Hospital
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Guo, Nannan; Soden, Marta E; Herber, Charlotte et al. (2018) Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization. Nat Med 24:438-449
McAvoy, Kathleen M; Sahay, Amar (2017) Targeting Adult Neurogenesis to Optimize Hippocampal Circuits in Aging. Neurotherapeutics 14:630-645
Kaluski, Shai; Portillo, Miguel; Besnard, Antoine et al. (2017) Neuroprotective Functions for the Histone Deacetylase SIRT6. Cell Rep 18:3052-3062
Raam, Tara; McAvoy, Kathleen M; Besnard, Antoine et al. (2017) Hippocampal oxytocin receptors are necessary for discrimination of social stimuli. Nat Commun 8:2001
Widge, Alik S; Sahay, Amar (2016) Closing the Loop in Deep Brain Stimulation for Psychiatric Disorders: Lessons from Motor Neural Prosthetics. Neuropsychopharmacology 41:379-80
Besnard, Antoine; Sahay, Amar (2016) Adult Hippocampal Neurogenesis, Fear Generalization, and Stress. Neuropsychopharmacology 41:24-44
McAvoy, Kathleen M; Scobie, Kimberly N; Berger, Stefan et al. (2016) Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits. Neuron 91:1356-1373
McAvoy, Kathleen; Besnard, Antoine; Sahay, Amar (2015) Adult hippocampal neurogenesis and pattern separation in DG: a role for feedback inhibition in modulating sparseness to govern population-based coding. Front Syst Neurosci 9:120
Wu, Melody V; Sahay, Amar; Duman, Ronald S et al. (2015) Functional differentiation of adult-born neurons along the septotemporal axis of the dentate gyrus. Cold Spring Harb Perspect Biol 7:a018978
McAvoy, Kathleen; Russo, Craig; Kim, Shannen et al. (2015) Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age. Hippocampus 25:1429-46

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