Anxiety disorders are a leading cause of disability, afflicting 5-10% of individuals worldwide with no existing cure. Fear generalization, in which conditioned fear responses occur in an altered, unconditioned context, is a primary symptom in many anxiety disorders such as phobia, panic disorder, and post-traumatic stress disorder (PTSD). Patients and animal models of PTSD consistently show altered activity in brain circuits such as the prefrontal cortex (PFC) and hippocampus, but precise circuit mechanisms and their causal role in fear generalization remain largely unclear. Furthermore, very little is known about the genetic factors that predispose individuals to PTSD. Here, I provide preliminary data that increased activity in PFC to hippocampus projections can recruit fear memory in an unconditioned context (fear generalization), and also preliminary data to suggest that genetic variability in two genes - fibroblast growth factor 13 (Fgf13) and potassium channel tetramerization domain 3 (Kctd3) - are significantly associated with variability in the fear generalization phenotype. I propose to further dissect the role of these circuit and genetic mechanisms as causal contributors to the fear generalization behavior. I will first test whether activating a PFC-HPC circuit (with optogenetic stimulation) is sufficient for fear-generalization (Aim 1). I will then determine whether haplotype knock-in or knock-out at the Fgf13 and Kctd3 locus (with Crispr-Cas9 technology) is sufficient to cause fear generalization (Aim 2). Research during the independent phase (Aim 3) will build on these results to determine whether local hippocampal network dynamics in Fgf13/Kctd3 mouse models of fear generalization have ensemble features, such as the emergence of hub motifs, that are associated with increased fear generalization behavior (using two-photon calcium imaging). In the process, I will become proficient in the use of the tools described above (Crispr-Cas9 technology and two-photon in vivo calcium imaging), leveraging prior experience with similar genome-scale and systems- level techniques and analysis methods. This will be accomplished under the supervision of a team of mentors and consultants (Karl Deisseroth, Feng Zhang, David Tank, Conor Liston, Carla Shatz) who pioneered these methods and have extensive experience training others to use them. They also have highly successful track records in preparing junior investigators for the transition to independence. I anticipate that this project will yield novel insights regarding the genetic and circuit underpinnings of fear memory generalization, and more broadly, of memory representations in the brain. Finally, this work will also provide a foundation for similar approaches (bearing a confluence of systems genetics and systems neuroscience approaches) to the study of other neuropsychiatric diseases.

Public Health Relevance

It is thought that dysfunctions in the communication of two brain regions named the prefrontal cortex and the hippocampus underlie symptoms in human post-traumatic stress disorder (PTSD). I have directly demonstrated for the first time that increased activation of the prefrontal cortex to hippocampus projection indeed leads to increased fear memory generalization, a critical feature of PTSD. I now propose a multilevel mapping of these long-range and local circuits, along with the underlying genetic factors, that together will provide crucial insights for our understanding of PTSD. The long-term goal is to enable the detection of at-risk individuals, with potential for prevention or early intervention an therapy.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Career Transition Award (K99)
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Special Emphasis Panel (ZMH1-ERB-S (01))
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Desmond, Nancy L
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Stanford University
Biomedical Engineering
Schools of Medicine
United States
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Rajasethupathy, Priyamvada; Ferenczi, Emily; Deisseroth, Karl (2016) Targeting Neural Circuits. Cell 165:524-34