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 #
5R01MH065702-10
Application #
8494087
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
2013-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2013
Total Cost
$326,642
Indirect Cost
$57,737
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
Yong, Weidong; Spence, John Paul; Eskay, Robert et al. (2014) Alcohol-preferring rats show decreased corticotropin-releasing hormone-2 receptor expression and differences in HPA activation compared to alcohol-nonpreferring rats. Alcohol Clin Exp Res 38:1275-83
Molosh, Andrei I; Johnson, Philip L; Spence, John P et al. (2014) Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase. Nat Neurosci 17:1583-90
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, Graham A W; Raison, Charles L; Lowry, Christopher A (2014) Microbiota, immunoregulatory old friends and psychiatric disorders. Adv Exp Med Biol 817:319-56
Lungwitz, Elizabeth A; Stuber, Garret D; Johnson, Philip L et al. (2014) The role of the medial prefrontal cortex in regulating social familiarity-induced anxiolysis. Neuropsychopharmacology 39:1009-19
Rook, G A W; Raison, C L; Lowry, C A (2014) Microbial 'old friends', immunoregulation and socioeconomic status. Clin Exp Immunol 177:1-12
Paul, Evan D; Lowry, Christopher A (2013) Functional topography of serotonergic systems supports the Deakin/Graeff hypothesis of anxiety and affective disorders. J Psychopharmacol 27:1090-106
Molosh, Andrei I; Sajdyk, Tammy J; Truitt, William A et al. (2013) NPY Y1 receptors differentially modulate GABAA and NMDA receptors via divergent signal-transduction pathways to reduce excitability of amygdala neurons. Neuropsychopharmacology 38:1352-64
Donner, Nina C; Lowry, Christopher A (2013) Sex differences in anxiety and emotional behavior. Pflugers Arch 465:601-26
Johnson, Philip L; Sajdyk, Tammy J; Fitz, Stephanie D et al. (2013) Angiotensin II's role in sodium lactate-induced panic-like responses in rats with repeated urocortin 1 injections into the basolateral amygdala: amygdalar angiotensin receptors and panic. Prog Neuropsychopharmacol Biol Psychiatry 44:248-56

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