Anxiety disorders are the most prevalent psychiatric disorders and affect over 40 million American adults over the age of 18 every year. Significantly, ~ 20% of individuals who seek treatment for independent anxiety disorders also have a current drug use disorder. The extended amygdala is thought to play a critical role in adaptive motivational behavior, and has been implicated in the pathophysiology of maladaptive fear, anxiety, and addiction. Two key elements of the extended amygdala are the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). Notably, evidence from clinical and preclinical studies suggests that differences in BNST activity determine individual differences in trait anxiety levels and also anticipatory anxiety (AA). Activity of corticotropin release factor (CRF) containing neurons in the BNST plays a central role in the normal adaptive response to stress. However, chronic release of CRF also plays a critical role in several psychopathologies, including anxiety disorders, posttraumatic stress disorder (PTSD), stress-induced drug recidivism, all of which have excessive AA as a core symptom. To date the cellular mechanisms underlying the switch from a normal adaptive response to a psychopathological state remain unknown. However, evidence from imaging studies suggests that activation of a circuit comprising the insular cortex (IC), amygdala, BNST, and ventrolateral periaqueductal grey (vlPAG) plays a key role in regulating the expression of AA. Using a transgenic CRF-Cre mouse line, we now have exciting pilot data showing that cell type-selective inhibition of CRF neurons in the BNST blocks the development of AA. The proposed work will use a multidisciplinary approach to define a functional circuit by testing the hypothesis that BNSTov CRF neurons act to integrate viscerosensory and emotional information from the IC and amygdala and relay this information to the vlPAG to regulate the expression of AA. The long-term objectives of this proposal are to delineate the cellular mechanisms contributing to the pathological switch in BNST function, with the hope of identifying novel targets for clinical intervention.
Three Specific Aims will test the hypothesis:
Aim 1 will examine the necessity / sufficiency of BNSTov CRF neuron activation in the expression of AA.
Aim 2 will examine the role of the insular cortex (IC) and posterior basolateral amygdala (BLAp) in activating BNSTov CRF neurons during AA and their downstream connection with the vlPAG, and Aim 3 will examine the effects of chronic stress on the functioning of the proposed pathway.

Public Health Relevance

Hyper-vigilance and excessive anticipatory avoidance are core symptoms of multiple anxiety disorders including PTSD, panic disorder, generalized anxiety, and phobias. This proposal will delineate the function of a key neural circuit that is thought to mediate the expression of anticipatory anxiety, and then examine the effect of chronic stress on this circuit. Understanding the role of this circuit in mediating anticipatory anxiety ma uncover novel approaches for treating anxiety disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH072908-11A1
Application #
9056205
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nadler, Laurie S
Project Start
2005-04-01
Project End
2021-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
11
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Emory University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Daniel, Sarah E; Guo, Jidong; Rainnie, Donald G (2017) A comparative analysis of the physiological properties of neurons in the anterolateral bed nucleus of the stria terminalis in the Mus musculus, Rattus norvegicus, and Macaca mulatta. J Comp Neurol 525:2235-2248
Dabrowska, J; Martinon, D; Moaddab, M et al. (2016) Targeting Corticotropin-Releasing Factor Projections from the Oval Nucleus of the Bed Nucleus of the Stria Terminalis Using Cell-Type Specific Neuronal Tracing Studies in Mouse and Rat Brain. J Neuroendocrinol 28:
Daniel, Sarah E; Rainnie, Donald G (2016) Stress Modulation of Opposing Circuits in the Bed Nucleus of the Stria Terminalis. Neuropsychopharmacology 41:103-25
Rainnie, Donald G; Hazra, Rimi; Dabrowska, Joanna et al. (2014) Distribution and functional expression of Kv4 family ? subunits and associated KChIP ? subunits in the bed nucleus of the stria terminalis. J Comp Neurol 522:609-25
Dabrowska, Joanna; Hazra, Rimi; Guo, Ji-Dong et al. (2013) Striatal-enriched protein tyrosine phosphatase-STEPs toward understanding chronic stress-induced activation of corticotrophin releasing factor neurons in the rat bed nucleus of the stria terminalis. Biol Psychiatry 74:817-26
Dabrowska, Joanna; Hazra, Rimi; Guo, Ji-Dong et al. (2013) Central CRF neurons are not created equal: phenotypic differences in CRF-containing neurons of the rat paraventricular hypothalamus and the bed nucleus of the stria terminalis. Front Neurosci 7:156
Hazra, R; Guo, J D; Dabrowska, J et al. (2012) Differential distribution of serotonin receptor subtypes in BNST(ALG) neurons: modulation by unpredictable shock stress. Neuroscience 225:9-21
Gafford, Georgette M; Guo, Ji-Dong; Flandreau, Elizabeth I et al. (2012) Cell-type specific deletion of GABA(A)?1 in corticotropin-releasing factor-containing neurons enhances anxiety and disrupts fear extinction. Proc Natl Acad Sci U S A 109:16330-5
Guo, Ji-Dong; Hazra, Rimi; Dabrowska, Joanna et al. (2012) Presynaptic muscarinic M(2) receptors modulate glutamatergic transmission in the bed nucleus of the stria terminalis. Neuropharmacology 62:1671-83
Dabrowska, Joanna; Hazra, Rimi; Ahern, Todd H et al. (2011) Neuroanatomical evidence for reciprocal regulation of the corticotrophin-releasing factor and oxytocin systems in the hypothalamus and the bed nucleus of the stria terminalis of the rat: Implications for balancing stress and affect. Psychoneuroendocrinology 36:1312-26

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