The long-term goals of our laboratory are to elucidate the molecular pathways involved in the behavioral and neuroendocrine responses to stress, and to determine how these mechanisms affect cognitive changes during development and aging. Importantly, chronic stress often results in alterations in behavior and physiology that are maladaptive, exacerbating both medical and psychiatric diseases. The calcium-stimulated adenylyl cyclases (ACs) provide a critical control point for the regulation of neuronal physiology, and have been implicated in activity-dependent alterations in neural function. To define the molecular pathways involved in the response to stress, we generated mice deficient (KO) in calcium-stimulated adenylyl cyclase type VIII (AC8). AC8 KO mice demonstrate compromise in calcium-stimulated AC activity in the hippocampus, impaired hippocampal CA1 long-term depression (LTD), and failure to activate CREB in the CA1 region after stress. Consistent with these biochemical and electrophysiological alterations in hippocampal function, AC8 KO mice do not demonstrate stress- induced learning. In this proposal, we seek to define the role of AC8 in transduction of stress-induced signals important for hippocampal LTD and alterations in behavior. Integrating molecular genetic, electrophysiological, and behavioral approaches, we will 1) develop an in vivo transgenic system that allows regulated expression of AC8 within the CA1 region of the hippocampus; 2) determine when during brain development and exposure to stress AC8 activation is required to impart stress- induced learning; 3) determine whether the alterations in neuronal function and behavior arise from resistance of CA1 neurons deficient in AC8 to the effects of glucocorticoids. The findings in these studies will serve as the basis for proposing modulation of AC8 action as a novel therapeutic approach to human psychiatric and chronic stress-generated disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG018876-02
Application #
6532551
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Wagster, Molly V
Project Start
2001-08-15
Project End
2006-07-31
Budget Start
2002-08-15
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$269,500
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wieczorek, L; Majumdar, D; Wills, T A et al. (2012) Absence of Ca2+-stimulated adenylyl cyclases leads to reduced synaptic plasticity and impaired experience-dependent fear memory. Transl Psychiatry 2:e126
Kolber, Benedict J; Boyle, Maureen P; Wieczorek, Lindsay et al. (2010) Transient early-life forebrain corticotropin-releasing hormone elevation causes long-lasting anxiogenic and despair-like changes in mice. J Neurosci 30:2571-81
Wieczorek, Lindsay; Maas Jr, James W; Muglia, Lisa M et al. (2010) Temporal and regional regulation of gene expression by calcium-stimulated adenylyl cyclase activity during fear memory. PLoS One 5:e13385
Kolber, Benedict J; Muglia, Louis J (2009) Defining brain region-specific glucocorticoid action during stress by conditional gene disruption in mice. Brain Res 1293:85-90
Zhang, Ming; Moon, Changjong; Chan, Guy C-K et al. (2008) Ca-stimulated type 8 adenylyl cyclase is required for rapid acquisition of novel spatial information and for working/episodic-like memory. J Neurosci 28:4736-44
Kolber, Benedict J; Wieczorek, Lindsay; Muglia, Louis J (2008) Hypothalamic-pituitary-adrenal axis dysregulation and behavioral analysis of mouse mutants with altered glucocorticoid or mineralocorticoid receptor function. Stress 11:321-38
Moulder, Krista L; Jiang, Xiaoping; Chang, Chunyun et al. (2008) A specific role for Ca2+-dependent adenylyl cyclases in recovery from adaptive presynaptic silencing. J Neurosci 28:5159-68
Kolber, Benedict J; Roberts, Marie S; Howell, Maureen P et al. (2008) Central amygdala glucocorticoid receptor action promotes fear-associated CRH activation and conditioning. Proc Natl Acad Sci U S A 105:12004-9
Conti, A C; Maas Jr, J W; Muglia, L M et al. (2007) Distinct regional and subcellular localization of adenylyl cyclases type 1 and 8 in mouse brain. Neuroscience 146:713-29
Boyle, Maureen P; Kolber, Benedict J; Vogt, Sherri K et al. (2006) Forebrain glucocorticoid receptors modulate anxiety-associated locomotor activation and adrenal responsiveness. J Neurosci 26:1971-8

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