Hypothalamic-pituitary-adrenocortical axis changes in a transgenic mouse with impaired glucocorticoid receptor...

Area of Science:

• Neuroendocrinology
• Molecular Biology
• Animal Models

Background:

• Stress-related disorders, such as major depression, involve neuroendocrine changes.
• A transgenic mouse model with impaired glucocorticoid receptor (GR) function was developed to study these changes.

Purpose of the Study:

• To investigate hypothalamic-pituitary-adrenocortical (HPA) axis alterations in transgenic mice with impaired GR function.
• To explore the regulation of ACTH secretion and glucocorticoid feedback at the hypothalamic-pituitary level in vitro.

Main Methods:

• Comparison of basal and stress-induced plasma ACTH and corticosterone levels in normal and transgenic mice.
• In vitro studies using pituitary-hypothalamic complex (PHc) and pituitary (PI) tissues to assess ACTH release.
• Evaluation of corticosterone's negative feedback efficacy on ACTH release in vitro.

Main Results:

• Transgenic mice exhibited enhanced plasma ACTH responses to stress but similar corticosterone levels.
• In vitro, transgenic PHc and PI tissues showed augmented ACTH release upon stimulation (high K+, CRH).
• Corticosterone's negative feedback on ACTH release was impaired in transgenic tissues, particularly at the hypothalamic level.

Conclusions:

• Intrahypothalamic mechanisms fine-tune ACTH responses and facilitate glucocorticoid negative feedback.
• Impaired GR function in transgenic mice leads to augmented ACTH release and defective glucocorticoid feedback, primarily in the hypothalamus.
• This transgenic model offers valuable insights into central nervous system glucocorticoid insufficiency and its pathophysiological consequences.