Anxiety disorders such as posttraumatic stress disorder, generalized anxiety disorder, and panic disorder afflict almost one third of Americans with significant personal, financial and societal costs. Thus, identification of the brain circuits that are disordered in these illnesses would have a major benefit to society. In recent years, it has become appreciated that the hippocampus, in addition to its role in learning and memory, plays an important role in emotional behavior. We have recently shown that acute modulation of neuronal activity in the ventral hippocampus (vHPC) can powerfully and reversibly suppress innate anxiety-related behavior. However, the mechanisms by which the vHPC may control fear, anxiety, and negatively motivated behaviors have remained elusive. In this proposal, we will leverage optical techniques to interrogate the extended vHPC circuit to determine how it may control emotional behavior. We will focus on deconstructing the output from the vHPC to the hypothalamus and amygdala, two subcortical structures involved in the autonomic, neuroendocrine and motivational responses to emotionally charged stimuli. We will first map the extended vHPC network that controls emotional behavior, determining the cell-types types modulated by the vHPC, as well as the behavioral stimuli that recruit these output streams. Then, we will use projection-specific, optical modulation of vHPC terminals in the amygdala and hypothalamus to determine whether vHPC output streams are functionally dissociable in their contribution to innate anxiety, aversion and learned fear. Finally, we will use cell-type specific functional imaging to determine whether there exists a neuronal signature for anxiety state within the activity of populations of vHPC neurons. The ultimate goal of these studies is to develop a functional map of the extended vHPC circuit that modulates innate and learned fear, providing a novel target for therapies aimed at the treatment of these debilitating anxiety disorders.

Public Health Relevance

The proposed experiments aim to identify the distributed neuronal circuits that underlie adaptive fear behavior, so that we may understand how they become disrupted in many anxiety disorders. Identification of these circuits will provide the basis for novel, targeted therapies for the treatment of anxiety disorders such as generalized anxiety disorder and posttraumatic stress disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Vicentic, Aleksandra
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Jimenez, Jessica C; Su, Katy; Goldberg, Alexander R et al. (2018) Anxiety Cells in a Hippocampal-Hypothalamic Circuit. Neuron 97:670-683.e6
Zhou, Pengcheng; Resendez, Shanna L; Rodriguez-Romaguera, Jose et al. (2018) Efficient and accurate extraction of in vivo calcium signals from microendoscopic video data. Elife 7:
Biane, Jeremy S; Kheirbek, Mazen A (2017) Imaging Adult Hippocampal Neurogenesis In Vivo. Neuropsychopharmacology 42:373
Woods, Nicholas I; Kheirbek, Mazen A (2017) The Small World of a Fear Memory. Neuron 94:226-227