QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, August 15, 2007, 27(33):8836-8844; doi:10.1523/JNEUROSCI.0910-07.2007

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Wei, Q. Articles by Akil, H. Search for Related Content PubMed PubMed Citation Articles by Wei, Q. Articles by Akil, H.

 Previous Article  |  Next Article 

Neurobiology of Disease
Overexpressing the Glucocorticoid Receptor in Forebrain Causes an Aging-Like Neuroendocrine Phenotype and Mild Cognitive Dysfunction

Qiang Wei,¹ Elaine K. Hebda-Bauer,¹ Amy Pletsch,¹ Jie Luo,¹ Mary T. Hoversten,¹ Andrew J. Osetek,¹ Simon J. Evans,^1,2 Stanley J. Watson,^1,2 Audrey F. Seasholtz,^1,3 and Huda Akil^1,2

¹Molecular and Behavioral Neuroscience Institute and Departments of ²Psychiatry and ³Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109

Correspondence should be addressed to Dr. Qiang Wei, Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109. Email: qweis{at}umich.edu

Repeated stress enhances vulnerability to neural dysfunction that is cumulative over the course of the lifespan. This dysfunction contributes to cognitive deficits observed during aging. In addition, aging is associated with dysregulation of the limbic–hypothalamic–pituitary–adrenal (LHPA) axis, leading to a delayed termination of the stress response. This delay, in turn, increases exposure to glucocorticoids and exacerbates the likelihood of neural damage. Here we asked whether similar effects could emerge at an early age as a result of genetic variations in the level or function of the brain glucocorticoid receptor (GR). We investigated the effect of forebrain-specific overexpression of GR on LHPA axis activity. Transgenic mice with GR overexpression in forebrain (GRov) display normal basal circulating adrenocorticotropic hormone and corticosterone levels. However, young GRov mice exhibit a number of LHPA alterations, including a blunted initial response to acute restraint stress followed by a delayed turn-off of the stress response. This deficit in negative feedback is paradoxical in the face of elevated GR levels, resembles the stress response in aged animals, and continues to worsen as GRov mice age. The neuroendocrine dysregulation in young GRov mice is coupled with a mild cognitive deficit, also consistent with the accelerated aging hypothesis. The molecular basis of this phenotype was examined using microarray analysis of the hippocampus, which revealed a broad downregulation of glutamate receptor signaling in GRov mice. Thus, even in the absence of chronic stress, elevation of GR gene expression can lead to an increased allostatic load and result in an "aging-like" phenotype in young animals.

Key words: glucocorticoid receptor; neuroendocrine; cognitive; aging; stress; hippocampus

---

Received Feb. 28, 2007; revised June 30, 2007; accepted July 1, 2007.

Correspondence should be addressed to Dr. Qiang Wei, Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109. Email: qweis{at}umich.edu

This article has been cited by other articles:

				C. J. Rice, C. A. Sandman, M. R. Lenjavi, and T. Z. Baram A Novel Mouse Model for Acute and Long-Lasting Consequences of Early Life Stress Endocrinology, October 1, 2008; 149(10): 4892 - 4900. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help