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Reduced activity of hypothalamic corticotropin-releasing hormone neurons in transgenic mice with impaired
I Dijkstra1, F J Tilders, G Aguilera
1Graduate School Neurosciences Amsterdam, Department of Pharmacology, Research Institute Neurosciences Vrije Universiteit, 1081 BT Amsterdam, The Netherlands.
Abstract:
Loss of central glucocorticoid receptor (GR) function is thought to be involved in the development of neuroendocrine and psychiatric disorders associated with corticotropin-releasing hormone (CRH) hyperactivity. The possible causal relationship between defective GR function and altered activity of CRH neurons was studied in transgenic mice (TG) expressing antisense RNA against GR. Immunocytochemical studies showed significant reductions in CRH immunoreactive neurons in the paraventricular nucleus (PVN) and in CRH and vasopressin (AVP) stores in the external zone of the median eminence. Concomitantly, stimulus-evoked CRH secretion from mediobasal hypothalami of TG mice in vitro was reduced significantly. However, CRH mRNA levels in the PVN of TG mice were marginally lower than those in wild-type (WT) mice. 125I-CRH binding autoradiography revealed no differences between WT and TG animals in any of the brain regions that were studied. Basal plasma corticosterone (cort) levels and 125I-CRH binding, CRH-R1 mRNA, POMC mRNA, and POMC hnRNA levels in the anterior pituitary gland were similar in WT and TG mice. Intraperitoneal injection of interleukin-1beta (IL-1beta) increased plasma cort levels, CRH mRNA in the PVN, and anterior pituitary POMC hnRNA similarly in WT and TG mice. The injection of saline significantly reduced anterior pituitary CRH-R1 mRNA levels in WT mice, but not in TG mice, whereas IL-1beta produced a decrease in these mRNA levels in both strains. The data show that long-term GR dysfunction can be associated with reduced activity of CRH neurons in the PVN and decreased sensitivity of pituitary CRH-R1 mRNA to stimulus-induced downregulation. Moreover, the hypothalamic changes observed in this model suggest that impaired GR function, at least if present since early embryonic life, does not necessarily result in CRH hyperexpression characteristics of disorders such as major depression.
Insights
Impaired glucocorticoid receptor (GR) function in mice reduced corticotropin-releasing hormone (CRH) neuron activity and altered pituitary responses. This suggests GR dysfunction may not always cause CRH hyperactivity seen in depression.
Area of Science:
- Neuroendocrinology
- Molecular Psychiatry
- Genetics
Background:
- Central glucocorticoid receptor (GR) dysfunction is linked to neuroendocrine and psychiatric disorders.
- Corticotropin-releasing hormone (CRH) hyperactivity is a hallmark of these conditions.
- The causal link between GR defects and CRH neuron activity requires further investigation.
Purpose of the Study:
- To investigate the relationship between defective GR function and CRH neuron activity.
- To examine the effects of long-term GR dysfunction on the neuroendocrine stress axis.
- To determine if impaired GR function leads to CRH hyperexpression.
Main Methods:
- Used transgenic mice (TG) expressing antisense RNA against GR.
- Conducted immunocytochemical studies to assess CRH and vasopressin (AVP) levels.
- Measured stimulus-evoked CRH secretion in vitro and analyzed gene expression (CRH, POMC, CRH-R1) in the hypothalamus and pituitary.
- Administered interleukin-1beta (IL-1beta) and saline to assess stress responses.
Main Results:
- TG mice showed reduced CRH neurons in the PVN and decreased CRH/AVP stores in the median eminence.
- Stimulus-evoked CRH secretion was significantly reduced in TG mice.
- Pituitary CRH-R1 mRNA showed decreased sensitivity to downregulation in TG mice.
- CRH mRNA levels in the PVN were only marginally lower in TG mice.
- Stress responses (plasma corticosterone, POMC hnRNA) were similar between TG and wild-type (WT) mice.
Conclusions:
- Long-term GR dysfunction is associated with reduced PVN CRH neuron activity.
- Impaired GR function can lead to altered pituitary CRH-R1 mRNA regulation.
- This model suggests GR dysfunction does not invariably cause CRH hyperexpression.
- Findings challenge the notion that GR defects directly cause CRH hyperactivity in conditions like depression.