Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behavioral anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus

Psychoneuroendocrinology. 2012 Jan;37(1):27-38. doi: 10.1016/j.psyneuen.2011.04.014. Epub 2011 May 26.


Environmental stress has been demonstrated to increase susceptibility for mood and anxiety disorders, and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, the primary endocrine response to stress, is often observed in these patients. HPA axis activation is initiated by corticotropin-releasing factor (CRF) from the hypothalamus, leading to the hypothesis that hypothalamic CRF overexpression contributes to HPA axis hyperactivity in psychiatric patients. In addition, elevated CRF in cerebrospinal fluid is observed in mood and anxiety disorder patients, suggesting that CRF is also being overproduced from extrahypothalamic sources such as the central amygdala (CeA) and overactivity of the amygdala in neuroimaging studies is a consistent finding in anxiety and depression patients. Due to the importance of CRF and the amygdala in the etiology of stress-sensitive psychiatric disorders, the present study sought to further dissect the impact of CRF overexpression (OE) in the amygdala on downstream behavioral, endocrine, and gene-expression changes typically associated with chronic stress. To test the hypothesis that elevated CRF output from the amygdala would reproduce HPA axis hyperactivity and behavioral symptoms of chronic stress, we developed a lentiviral vector in which 3.0kb of the CRF promoter drives overexpression of CRF (LVCRFp3.0CRF). In adult male rats, Experiment-1 examined behavioral consequences of chronic CRF overexpression from the amygdala; the dexamethasone (Dex)/CRF test was used to measure HPA axis reactivity. Experiment-2 focused on HPA axis disruptions; the dexamethasone-suppression and CRF-stimulation tests as well as the Dex/CRF test were used. In both experiments, expression of HPA-axis related transcripts were assessed.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / metabolism
  • Amygdala / physiopathology
  • Animals
  • Anxiety Disorders / genetics
  • Anxiety Disorders / metabolism*
  • Corticotropin-Releasing Hormone / genetics
  • Corticotropin-Releasing Hormone / metabolism*
  • Corticotropin-Releasing Hormone / physiology*
  • Dexamethasone
  • Disease Models, Animal
  • Gene Expression Profiling / methods
  • Gene Expression Profiling / statistics & numerical data*
  • Genetic Vectors
  • Hippocampus / metabolism
  • Humans
  • Hypothalamo-Hypophyseal System / metabolism
  • Hypothalamo-Hypophyseal System / physiology*
  • Lentivirus / genetics
  • Male
  • Paraventricular Hypothalamic Nucleus / metabolism*
  • Pituitary-Adrenal Function Tests / methods
  • Pituitary-Adrenal Function Tests / psychology
  • Pituitary-Adrenal System / metabolism
  • Pituitary-Adrenal System / physiology*
  • Rats
  • Rats, Wistar


  • Dexamethasone
  • Corticotropin-Releasing Hormone