The current proposal is aimed at understanding the neurobiological mechanisms underlying anxiety disorders. Furthering the understanding of anxiety disorders remains a key public health goal, as these disorders represent a large burden to society in morbidity and related costs. Data from human and animal studies implicate the serotonin system, and specifically one particular serotonin receptor, the 1A receptor (5-HT1AR), in the generation and/or regulation of anxiety. Agents which activate the 5-HT1AR, such as serotonin reuptake inhibitors or 5-HT1AR agonists, are anxiolytic both in humans and in animals. Accordingly, genetic deletion of the 5-HT1AR during development results in a robust adult phenotype of increased anxiety-like behavior. Understanding the precise mechanisms by which 5-HT1AR deficiency results in increased anxiety-related behavior promises to add to our understanding of the neurobiology of anxiety. We have recently found evidence of an anxiety-related increase in hippocampal activity, in the form of increased theta oscillations, in 5-HT1AR knockout mice. These data are in agreement with recent findings demonstrating that lesions of the ventral hippocampus increase anxiety. The proposed experiments will test the resulting hypothesis that the increased hippocampal activity accounts for the phenotype of increased anxiety in 5-HT1AR- deficient mice. In particular, we will combine molecular genetic and in vivo neural recordings in behaving mice to address three key questions. First, we will use tissue- specific expression of the 5-HT1AR to ask whether hippocampal receptors are sufficient to reverse the behavioral and physiological phenotypes seen in the knockouts. Second, we will record simultaneously from the ventral hippocampus and downstream structures in wild-type and knockout mice during anxiety-related tasks, to determine if and how these structures coordinate their activity. Third, we will test whether specifically increasing theta oscillations is necessary and sufficient to cause increased anxiety- related behavior. Addressing these three issues will clarify the mechanisms by which 5- HT1AR deficiency causes increased anxiety. Furthermore, they may identify specific patterns of activity in specific neural areas which generate 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 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)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Winsky, Lois M
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Columbia University (N.Y.)
Schools of Medicine
New York
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Likhtik, Ekaterina; Gordon, Joshua A (2014) Circuits in sync: decoding theta communication in fear and safety. Neuropsychopharmacology 39:235-6
Likhtik, Ekaterina; Stujenske, Joseph M; Topiwala, Mihir A et al. (2014) Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety. Nat Neurosci 17:106-13
Stujenske, Joseph M; Likhtik, Ekaterina; Topiwala, Mihir A et al. (2014) Fear and safety engage competing patterns of theta-gamma coupling in the basolateral amygdala. Neuron 83:919-33
Likhtik, Ekaterina; Gordon, Joshua A (2013) A surprised amygdala looks to the cortex for meaning. Neuron 80:1109-11
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Nason Jr, Malcolm W; Adhikari, Avishek; Bozinoski, Marjan et al. (2011) Disrupted activity in the hippocampal-accumbens circuit of type III neuregulin 1 mutant mice. Neuropsychopharmacology 36:488-96

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