The long-term objective of this research is to elucidate mechanisms by which stress causes enduring changes in neural systems that mediate emotional arousal that may be expressed as mental and/or behavioral pathology. Specifically, this research examines how the stress neuromediator, corticotropin-releasing factor (CRF) regulates activity of the locus coeruleus (LC)-norepinephrine (NE) system, a neural system involved in emotional arousal. CRF has been implicated as a neuromodulator that activates the LC-NE system during stress, an effect that facilitates arousal and behavioral responses to stress. Two complementary processes, one cellular and one systems, that ultimately determine the magnitude of response of the LC-NE system to CRF and stress will be examined. Because the cellular localization of the CRF receptor (CRFr) determines LC postsynaptic sensitivity to CRF and to stressors, AIM 1 will characterize the intracellular dynamics of CRFr trafficking in LC neurons using electron microscopy. Temporal and pharmacological determinants of CRFr trafficking will be investigated. Additionally, this process will be examined in a genetic model of CRF dysfunction that may mimic affective disorders, i.e., the CRF overexpressing mouse. In addition to its acute ability to excite LC neurons, CRF promotes extension of LC dendrites, a long-term structural effect that can determine the degree of communication with limbic afferents encoding emotional information.
AIM 2 will identify conditions in which this structural effect occurs in vivo and its functional consequences.
This AIM tests the hypothesis that CRF-induced LC dendritic extension into the peri-LC increases contacts with limbic afferents and the limbic influence over the LC-NE system, thereby translating to enhanced emotional arousal. The developmental dependence of this effect of CRF will be determined. Additionally this effect will be assessed in genetic models of CRF dysfunction. These complementary AIMs integrate cellular, systems and behavioral approaches towards understanding mechanisms that determine the magnitude of response of the LC-NE arousal system. The findings have direct clinical implications by advancing our knowledge of 1) the impact of early life stress on mental health, 2) the impact of social stress on mental health, 3) genetic determinants of stress vulnerability and 4) pharmacologic manipulation of stress-related pathology.

Public Health Relevance

Stress is a major determinant of vulnerability to many debilitating psychiatric disorders, including depression, anxiety and substance abuse. This research is designed to elucidate the mechanisms and pathways by which stress alters activity and/or the structure of brain cells that control arousal, attention and emotion. This knowledge will advance our ability to prevent and/or alleviate these debilitating stress-related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH040008-28
Application #
8269773
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (02))
Program Officer
Desmond, Nancy L
Project Start
1997-01-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
28
Fiscal Year
2012
Total Cost
$359,296
Indirect Cost
$97,698
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Bangasser, Debra A; Valentino, Rita J (2014) Sex differences in stress-related psychiatric disorders: neurobiological perspectives. Front Neuroendocrinol 35:303-19
Retson, T A; Van Bockstaele, E J (2013) Coordinate regulation of noradrenergic and serotonergic brain regions by amygdalar neurons. J Chem Neuroanat 52:9-19
Valentino, Rita J; Van Bockstaele, Elisabeth; Bangasser, Debra (2013) Sex-specific cell signaling: the corticotropin-releasing factor receptor model. Trends Pharmacol Sci 34:437-44
Valentino, Rita J; Reyes, Beverly; Van Bockstaele, Elisabeth et al. (2012) Molecular and cellular sex differences at the intersection of stress and arousal. Neuropharmacology 62:13-20
Devilbiss, David M; Waterhouse, Barry D; Berridge, Craig W et al. (2012) Corticotropin-releasing factor acting at the locus coeruleus disrupts thalamic and cortical sensory-evoked responses. Neuropsychopharmacology 37:2020-30
Bingham, Brian; McFadden, Kile; Zhang, Xiaoyan et al. (2011) Early adolescence as a critical window during which social stress distinctly alters behavior and brain norepinephrine activity. Neuropsychopharmacology 36:896-909
Bangasser, Debra A; Zhang, Xiaoyan; Garachh, Veraaj et al. (2011) Sexual dimorphism in locus coeruleus dendritic morphology: a structural basis for sex differences in emotional arousal. Physiol Behav 103:342-51
Swinny, Jerome D; O'Farrell, Eimear; Bingham, Brian C et al. (2010) Neonatal rearing conditions distinctly shape locus coeruleus neuronal activity, dendritic arborization, and sensitivity to corticotrophin-releasing factor. Int J Neuropsychopharmacol 13:515-25
Valentino, Rita J; Van Bockstaele, Elisabeth (2008) Convergent regulation of locus coeruleus activity as an adaptive response to stress. Eur J Pharmacol 583:194-203
Howard, Owen; Carr, Gregory V; Hill, Tiffany E et al. (2008) Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats. Psychopharmacology (Berl) 199:569-82

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