The involvement of retinoic acid receptor-alpha in corticotropin-releasing hormone gene expression and affective disorders

Biol Psychiatry. 2009 Nov 1;66(9):832-9. doi: 10.1016/j.biopsych.2009.05.031. Epub 2009 Jul 12.

Abstract

Background: Corticotropin-releasing hormone (CRH) is considered the central driving force in the stress response and plays a key role in the pathogenesis of depression. Retinoic acid (RA) has been suggested by clinical studies to be associated with affective disorders.

Methods: First, hypothalamic tissues of 12 patients with affective disorders and 12 matched control subjects were studied by double-label immunofluorescence to analyze the expression of CRH and retinoic acid receptor-alpha (RAR-alpha). Second, critical genes involved in the RA signaling pathways were analyzed in a rat model of depression. Finally, the regulatory effect of RAR-alpha on CRH gene expression was studied in vitro.

Results: We found that the expression of RAR-alpha was colocalized with CRH neurons in human hypothalamic paraventricular nucleus (PVN). The density of RAR-alpha-immunoreactive neurons and CRH-RAR-alpha double-staining neurons was significantly increased in the PVN of patients with affective disorders. The ratio of the CRH-RAR-alpha double-staining neurons to the CRH-immunoreactive neurons in affective disorder patients was also increased. Recruitment of RAR-alpha by the CRH promoter was observed in the rat hypothalamus. A dysregulated RA metabolism and signaling was also found in the hypothalamus of a rat model for depression. Finally, in vitro studies demonstrated that RAR-alpha mediated an upregulation of CRH gene expression.

Conclusions: These results suggest that RAR-alpha might contribute to regulating the activity of CRH neurons in vivo, and the vulnerable character of the critical proteins in RA signaling pathways might provide novel targets for therapeutic strategies for depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Arginine Vasopressin / metabolism
  • Cell Line, Tumor
  • Corticotropin-Releasing Hormone / genetics*
  • Female
  • Humans
  • Hypothalamus / metabolism
  • Male
  • Middle Aged
  • Mood Disorders / genetics
  • Mood Disorders / metabolism*
  • Mood Disorders / physiopathology*
  • Neurons / metabolism
  • Rats
  • Receptors, Retinoic Acid / metabolism*
  • Receptors, Retinoic Acid / physiology
  • Retinal Dehydrogenase / metabolism
  • Retinoic Acid Receptor alpha
  • Signal Transduction / genetics
  • Stress, Physiological / physiology
  • Tretinoin / metabolism
  • Up-Regulation*

Substances

  • RARA protein, human
  • Rara protein, rat
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • retinoic acid binding protein I, cellular
  • Arginine Vasopressin
  • Tretinoin
  • Corticotropin-Releasing Hormone
  • Aldehyde Dehydrogenase 1 Family
  • Aldh1a1 protein, rat
  • Aldh1a3 protein, rat
  • Retinal Dehydrogenase