In this application, we propose to investigate the specific neural systems underlying the mechanisms that may lead to long-term sensitization of one of the 'anxiety regulating networks'. The overall hypothesis for the current proposal is that the state of 'anxiety' (measured by behavioral an physiological responses) in an animal is dependent upon sensitization of a distributed forebrain neural network (that includes the basolateral and central nuclei of the amygdala, bed nucleus of the stria terminalis and others) and a topographically organized serotonergic system in the caudal dorsal raph_ nucleus. The experiments described below have been designed to test this hypothesis under four Specific Aims: 1) To demonstrate that the critical components of the proposed neuronal network, specifically, the corticotropin releasing factor (CRF) containing neurons of BLA, CeA, BNST, and the serotonergic neurons of the dorsal raph_nucleus (DRN), are activated (as measured by c-fos activation) in a variety of 'anxiety' states. 2) To determine that repeated stimulation of CRF receptors, either CRF type 1 or 2 receptors (CRFR1 and CRFR2, respectively) within the above network results in 'priming' of chronic anxiety/stress states. 3) To characterize, using combined anatomical and electrophysiological techniques, the effects of stimulating the CRF receptors on the 5-HT neurons of the caudal DRN in control versus chronically anxious (such as those after repeated CRF stimulation) rate. 4) To determine the effects of early life events such as neonatal lipopolysaccharide (LPS) stress on the BLA, CeA, BNST and DRN network functions. All these studies will be utilizing the following methods: a) whole animal behavioral and physiological responses; b) microinjection and immunohistochemical studies to elucidate pathways; c) patch-clamp studies to determine electrophysiological changes at the neuronal level; as well as d) pharmacological and molecular methods to understand regulation of messenger RNA levels that may contribute to long-term changes in cellular function. This proposal is a direct result of a NIMH research network development grant, HPA Regulation: Cross-Disciplinary Research Networks (RO3 MH 60825) and has provided us with an opportunity to demonstrate the feasibility of this proposed international collaboration. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH065702-05
Application #
7156941
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Vicentic, Aleksandra
Project Start
2002-12-01
Project End
2007-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
5
Fiscal Year
2007
Total Cost
$145,205
Indirect Cost
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
Bonaventure, Pascal; Dugovic, Christine; Shireman, Brock et al. (2017) Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation. Front Pharmacol 8:357
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 CO? Methods of Euthanasia in the Induction and Duration of Panic-Associated Behavior and Physiology. Animals (Basel) 6:
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
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
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; 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
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
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
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

Showing the most recent 10 out of 62 publications