The current proposal is aimed at understanding the neurobiological mechanisms underlying anxiety disorders. Furthering the understanding of anxiety disorders remains a key unmet public health goal, as these disorders represent a large burden to society in morbidity and related costs. Our previous studies with wild-type and serotonin 1A- receptor knockout (5-HT1AR KO) mice have implicated a circuit consisting of the ventral hippocampus (vHPC), the basolateral amygdala (BLA), and the medial prefrontal cortex (mPFC) in regulating anxiety-like behavior in various paradigms. Most notably, we have shown that these three regions functionally interact during anxiety, and that the strength of these interactions (1) correlates with anxiety and (2) is greater in the highly anxious 5- HT1AR KO mice than in wild-type littermates. Furthermore, our data suggest that the mPFC uses these interactions to construct a map of the aversiveness of the environment, which in turn is used to guide behavior. However, these observations are primarily correlative in nature. In this renewal application, we propose to directly test the hypothesis that the vHPC and BLA drive neural representations of aversiveness and anxiety-related behavior via their interactions with each other and with the mPFC. We will use a variety of pharmacological, optogenetic and pharmacogenetic tools to silence the vHPC and/or BLA, combined with in vivo neurophysiology to probe the role of these regions in the neural representations of aversiveness within the mPFC as well as anxiety-like behavior. In parallel, we will use emerging technologies aimed at silencing specific projections from and between these brain regions to determine whether and how these specific projections are required. These experiments will be performed in both wild-type and 5-HT1AR KO mice to test their relevance to pathological as well as physiological anxiety mechanisms. Addressing these issues will clarify the mechanisms by which these brain structures modulate anxiety-like behavior, and may help identify specific patterns of connectivity and activity that underly anxiety, providing novel functional targets for therapeutic intervention.

Public Health Relevance

This proposal is inherently translational in nature, aimed at elucidating the neurobiological substrates of psychiatric disease. It is aimed at identifying specific patterns of brain connectivity and activity which relate to anxiety. Establishing such relationships would set the stage for a novel approach to anxiolytic therapies, aimed at disrupting these specific patterns.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Vicentic, Aleksandra
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
Harris, Alexander Z; Atsak, Piray; Bretton, Zachary H et al. (2018) A Novel Method for Chronic Social Defeat Stress in Female Mice. Neuropsychopharmacology 43:1276-1283
Garcia-Garcia, A L; Canetta, S; Stujenske, J M et al. (2018) Serotonin inputs to the dorsal BNST modulate anxiety in a 5-HT1A receptor-dependent manner. Mol Psychiatry 23:1990-1997
Lu, Jiangteng; Tucciarone, Jason; Padilla-Coreano, Nancy et al. (2017) Selective inhibitory control of pyramidal neuron ensembles and cortical subnetworks by chandelier cells. Nat Neurosci 20:1377-1383
Garcia-Garcia, Alvaro L; Meng, Qingyuan; Canetta, Sarah et al. (2017) Serotonin Signaling through Prefrontal Cortex 5-HT1A Receptors during Adolescence Can Determine Baseline Mood-Related Behaviors. Cell Rep 18:1144-1156
Padilla-Coreano, Nancy; Bolkan, Scott S; Pierce, Georgia M et al. (2016) Direct Ventral Hippocampal-Prefrontal Input Is Required for Anxiety-Related Neural Activity and Behavior. Neuron 89:857-66
Cambiaghi, Marco; Grosso, Anna; Likhtik, Ekaterina et al. (2016) Higher-Order Sensory Cortex Drives Basolateral Amygdala Activity during the Recall of Remote, but Not Recently Learned Fearful Memories. J Neurosci 36:1647-59
Stujenske, Joseph M; Spellman, Timothy; Gordon, Joshua A (2015) Modeling the Spatiotemporal Dynamics of Light and Heat Propagation for In Vivo Optogenetics. Cell Rep 12:525-34
Gore, Felicity; Schwartz, Edmund C; Brangers, Baylor C et al. (2015) Neural Representations of Unconditioned Stimuli in Basolateral Amygdala Mediate Innate and Learned Responses. Cell 162:134-45
Harris, Alexander Z; Gordon, Joshua A (2015) Long-range neural synchrony in behavior. Annu Rev Neurosci 38:171-94
Spellman, Timothy; Rigotti, Mattia; Ahmari, Susanne E et al. (2015) Hippocampal-prefrontal input supports spatial encoding in working memory. Nature 522:309-14

Showing the most recent 10 out of 25 publications