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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH081968-07
Application #
8667500
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Vicentic, Aleksandra
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
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
O'Neill, Pia-Kelsey; Gordon, Joshua A; Sigurdsson, Torfi (2013) Theta oscillations in the medial prefrontal cortex are modulated by spatial working memory and synchronize with the hippocampus through its ventral subregion. J Neurosci 33:14211-24
Parnaudeau, Sebastien; O'Neill, Pia-Kelsey; Bolkan, Scott S et al. (2013) Inhibition of mediodorsal thalamus disrupts thalamofrontal connectivity and cognition. Neuron 77:1151-62
Lacefield, Clay O; Itskov, Vladimir; Reardon, Thomas et al. (2012) Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus. Hippocampus 22:106-16
Richardson-Jones, Jesse W; Craige, Caryne P; Nguyen, Thanh H et al. (2011) Serotonin-1A autoreceptors are necessary and sufficient for the normal formation of circuits underlying innate anxiety. J Neurosci 31:6008-18
Adhikari, Avishek; Topiwala, Mihir A; Gordon, Joshua A (2011) Single units in the medial prefrontal cortex with anxiety-related firing patterns are preferentially influenced by ventral hippocampal activity. Neuron 71:898-910
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

Showing the most recent 10 out of 14 publications