Stress pathway dysregulation is the most pervasive symptom in neuropsychiatric disease. Patients with schizophrenia and autism show heightened stress sensitivity and exacerbated symptoms during stress experience. It has long been postulated that a hyperactive stress system links stress dysregulation to neuropsychiatric disease, which has promoted the pharmaceutical pursuit of therapeutic targets including antagonists of the CRF receptor-1 (CRFR1) that would blunt this response. Utilizing CRF receptor-2 (CRFR2) deficient mice in which disruption of normal stress neurocircuitry prevents the recruitment and promotion of homeostatic mechanisms during stress, we have demonstrated that an inability to adapt to stress has severe consequences, including cell death within the 5-HT producing raphe nucleus, maladaptive physiological and behavioral stress responses, and increased perseverative behaviors. CRFR2-deficient mice showed elevated proinflammatory cytokines and their downstream effectors including proapoptotic caspases, increased markers of microglia infiltration, and a 20-fold increased level of the CRF binding protein (CRF-BP). These alterations likely contribute to the increased cell death and stress-sensitivity phenotype in these mice. Therefore, we hypothesize that cytokine-induced increases in CRF-BP prevent CRF from activating postsynaptic CRFR1, producing a counterintuitive hypoactive response in the raphe and an inhibition of the normal stress-induced 5-HTergic neurotransmission necessary to promote arousal and coping behaviors.

Public Health Relevance

Stress pathway dysregulation is the most pervasive symptom across neuropsychiatric diseases. In a mouse model of stress dysregulation, we have found that CRFR2-deficient mice show elevated proinflammatory cytokines and their downstream effectors including proapoptotic caspases, increased markers of microglia infiltration, and increased levels of the CRF binding protein in the raphe. We hypothesize that neuroinflammatory cytokines and increased CRF binding protein in the raphe prevent CRF from activating postsynaptic CRFR1, producing a counterintuitive hypoactive response and an inhibition of the normal stress- induced 5-HT neurotransmission necessary to promote arousal and coping behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH073030-09
Application #
8578105
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Desmond, Nancy L
Project Start
2004-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
9
Fiscal Year
2014
Total Cost
$360,000
Indirect Cost
$135,000
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Goel, Namni; Bale, Tracy L; Epperson, C Neill et al. (2014) Effects of sex and gender on adaptation to space: behavioral health. J Womens Health (Larchmt) 23:975-86
Howerton, Alexis R; Roland, Alison V; Bale, Tracy L (2014) Dorsal raphe neuroinflammation promotes dramatic behavioral stress dysregulation. J Neurosci 34:7113-23
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Epperson, C Neill; Kim, Deborah R; Bale, Tracy L (2014) Estradiol modulation of monoamine metabolism: one possible mechanism underlying sex differences in risk for depression and dementia. JAMA Psychiatry 71:869-70
Bale, Tracy L; Chen, Alon (2012) Minireview: CRF and Wylie Vale: a story of 41 amino acids and a Texan with grit. Endocrinology 153:2556-61
Goel, Nirupa; Plyler, Kimberly S; Daniels, Derek et al. (2011) Androgenic influence on serotonergic activation of the HPA stress axis. Endocrinology 152:2001-10
Bale, Tracy L (2011) Sex differences in prenatal epigenetic programming of stress pathways. Stress 14:348-56
Goel, Nirupa; Bale, Tracy L (2010) Sex differences in the serotonergic influence on the hypothalamic-pituitary-adrenal stress axis. Endocrinology 151:1784-94
Goel, N; Bale, T L (2009) Examining the intersection of sex and stress in modelling neuropsychiatric disorders. J Neuroendocrinol 21:415-20
McEuen, Jonathan G; Semsar, Katharine A; Lim, Maria A et al. (2009) Influence of sex and corticotropin-releasing factor pathways as determinants in serotonin sensitivity. Endocrinology 150:3709-16

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