Anxiety disorders such as post-traumatic stress disorder (PTSD) involve inappropriate inhibitory control over fear after exposure to life-threatening traumatic experiences showing enhanced fear generalization and inability to extinguish acquired fear. Currently available medications for PTSD provide limited relief and there is a need for developing more effective treatments for this disorder. Understanding the neural circuitry involved in fear regulation could help develop more effective treatments for this disorder. The amygdala, with its sub-divisions that include the basolateral (BLA) and central nuclei (CeA), is a crucial part of the fear circuitry. Although BLA is known to be important for fer acquisition and CeA for fear expression, the exact mechanisms through which BLA modulates CeA functions is unclear. A GPCR signaling cascade system, pituitary adenylate cyclase activating peptide (PACAP) and its receptor PAC1 have been shown to modulate fear and is expressed in the neural circuitry of fear and have also been related to PTSD diagnosis and symptom severity. Our findings demonstrate that PACAP neurons in the BLA innervate a cluster of cells known as the intercalated cells (ICCs) that lie at the interface of BLA and CeA, a novel microcircuit that could be important for modulation of fear. ICCs receive excitatory projections from the BLA, send inhibitory projections to the CeA, express PAC1 receptors, and have been shown to be important for extinguishing fear behaviors. Given the putative role of the PACAP/PAC1 system and the ICCs in the fear circuitry and their roles in regulating fear, this proposal seeks to elucidate the role of PACAP within the BLA acting via the PAC1-containing neurons in the ICCs that in turn project to CeA in modulation fear expression, generalization and extinction. This proposal will test this hypothesis by systematically manipulating several aspects of the microcircuit involving the BLA (PACAP)-ICCs (PAC1)-CeA using stress-enhanced fear learning (SEFL), a model designed in our lab to specifically test the effects of traumatic experiences on fear behaviors using fear conditioning procedures. The studies will test 1) how loss of function of PAC1 receptors from the ICCs, and 2) how exciting inhibitory signaling in the ICCs alters SEFL expression, generalization and extinction. The findings from the studies in this proposal could unravel novel information about BLA-ICCs-CeA microcircuit as these pathways involving the PACAP/PAC1 system has not been studied in fear-related behaviors. Importantly, these results may be clinically relevant as abnormalities in any part of this circuitry could contribute to the pathology observed in disorders like PTSD, allowing development of targeted therapies.

Public Health Relevance

Post-traumatic stress disorder (PTSD) is a debilitating and chronic disorder triggered by intense trauma and involves dysregulation of fear. A neuropeptide system known as the pituitary adenylate cyclase activating peptide (PACAP) and its receptor PAC1 have been shown to be important for PTSD diagnosis and symptom severity. PACAP and PAC1 receptors are expressed in amygdala, a brain region important for fear acquisition and expression, and a specific cell population known as intercalated that lie between the major amygdala sub-regions and shown to be important for fear extinction. Therefore, the proposed research aims in this NRSA will seek to understand the role of PACAP/PAC1 signaling within the intercalated cells in modulating conditioned fear behaviors including fear generalization and extinction, providing a therapeutic advantage for characterizing substrates in the brain for developing novel and potentially more effective treatments for reducing the devastating psychological toll of PTSD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Desmond, Nancy L
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Ago, Yukio; Hayata-Takano, Atsuko; Kawanai, Takuya et al. (2017) Impaired extinction of cued fear memory and abnormal dendritic morphology in the prelimbic and infralimbic cortices in VPAC2 receptor (VIPR2)-deficient mice. Neurobiol Learn Mem 145:222-231
Rajbhandari, Abha K; Zhu, Ruoyan; Adling, Cora et al. (2016) Graded fear generalization enhances the level of cfos-positive neurons specifically in the basolateral amygdala. J Neurosci Res 94:1393-1399