Anxiety disorders are some of the most common emotional disorders, cause considerable morbidity, and represent a significant economic burden. At least three key influences appear to be involved in the etiology of anxiety disorders: a) constitutive genetic differences, b) adverse early life event-mediated epigenetic changes, and c) chronic stress-induced plasticity. Our hypothesis for the present proposal will focus on two types of severe anxiety disorders, panic disorder (PD) and social anxiety disorder (SAD). We propose to study two components of the 'serotonergic dorsal raphe nucleus (DRN)-extended amygdala anxiety network': 1) the DRN-basolateral amygdala (BLA) and 2) the DRN-bed nucleus of the stria terminalis (BNST) pathways, which may be critical components in the pathophysiology of PD and SAD, respectively. We will systematically elucidate the behavioral, cellular and molecular effects of a) repeated stress neurotransmitter corticotropin- releasing factor (CRF)-induced plasticity, and b) two forms of genetic vulnerability, specifically, variations in serotonin transporter (SERT) expression using SERT and rats, and locally silencing the 5HT1A receptor gene in the BLA and BNST in the pathophysiology of PD and SAD in the current proposal. Our future studies will address the three-way interactions of stress plasticity and genetic vulnerability with early life stress (maternal separation)-induced epigenetic effects.
In SPECIFIC AIM I, we will test the role of repeated stress- induced long-term plasticity in the BLA-DRN circuit in PD.
In SPECIFIC AIM II, the role of long-term plasticity in the BNST-DRN circuit and SAD will be studied.
SPECIFIC AIM III will determine the effects of reduced expression of SERT and vulnerability to stress-induced plasticity, whereas SPECIFIC AIM IV will study the role of reduced 5HT1A receptor gene expression in the vulnerability to stress-induced plasticity and pathophysiology of PD and SAD. Thus, the work proposed in this competitive renewal will a) characterize 'stress'and 'gene'interaction models of human anxiety disorders such as PD and SAD, b) study the putative disruption in the 'anxiety'circuitry of the BLA and BNST involved in the transition from adaptive panic and social responses to pathological states, and c) elucidate the molecular changes within the BLA and BNST that occur in anxiety disorders. The results of this project could help develop novel genetically targeted treatments and prevention strategies for disabling illnesses such as PD and SAD.

Public Health Relevance

This work will a) study the genetic and molecular mechanisms in the 'anxiety'circuitry in the brain that results in the pathological anxiety states such as panic disorder and social anxiety disorder, and b) characterize stress neuropeptide corticotropin-releasing factor-induced long-term changes and known abnormal serotonin gene interaction models of human panic and social anxiety disorders. The results of these studies could position us to develop novel genetically-targeted treatments and prevention strategies for chronic disabling illnesses such as panic and social anxiety disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH065702-09
Application #
8294817
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Meinecke, Douglas L
Project Start
2002-03-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$340,252
Indirect Cost
$60,143
Name
Indiana University-Purdue University at Indianapolis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Federici, Lauren M; Roth, Sarah Dorsey; Krier, Connie et al. (2016) Anxiogenic CO2 stimulus elicits exacerbated hot flash-like responses in a rat menopause model and hot flashes in postmenopausal women. Menopause 23:1257-1266
Hickman, Debra L; Fitz, Stephanie D; Bernabe, Cristian S et al. (2016) Evaluation of Low versus High Volume per Minute Displacement COâ‚‚ Methods of Euthanasia in the Induction and Duration of Panic-Associated Behavior and Physiology. Animals (Basel) 6:
Johnson, Philip L; Molosh, Andrei; Fitz, Stephanie D et al. (2015) Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning. Pharmacol Biochem Behav 138:174-9
Stamper, Christopher E; Hennessey, Patrick A; Hale, Matthew W et al. (2015) Role of the dorsomedial hypothalamus in glucocorticoid-mediated feedback inhibition of the hypothalamic-pituitary-adrenal axis. Stress 18:76-87
Bonaventure, Pascal; Yun, Sujin; Johnson, Philip L et al. (2015) A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects. J Pharmacol Exp Ther 352:590-601
Rook, Graham A W; Lowry, Christopher A; Raison, Charles L (2015) Hygiene and other early childhood influences on the subsequent function of the immune system. Brain Res 1617:47-62
Johnson, Philip L; Federici, Lauren M; Fitz, Stephanie D et al. (2015) OREXIN 1 AND 2 RECEPTOR INVOLVEMENT IN CO2 -INDUCED PANIC-ASSOCIATED BEHAVIOR AND AUTONOMIC RESPONSES. Depress Anxiety 32:671-83
Rook, Graham A W; Raison, Charles L; Lowry, Christopher A (2014) Microbiota, immunoregulatory old friends and psychiatric disorders. Adv Exp Med Biol 817:319-56
Paul, Evan D; Johnson, Philip L; Shekhar, Anantha et al. (2014) The Deakin/Graeff hypothesis: focus on serotonergic inhibition of panic. Neurosci Biobehav Rev 46 Pt 3:379-96
Rook, G A W; Raison, C L; Lowry, C A (2014) Microbial 'old friends', immunoregulation and socioeconomic status. Clin Exp Immunol 177:1-12

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