Gene expression changes in the brain of a Cushing's syndrome mouse model

Abstract

Excess glucocorticoid exposure affects emotional and cognitive brain functions. The extreme form, Cushing's syndrome, is adequately modelled in the AdKO 2.0 mouse, consequential to adrenocortical hypertrophy and hypercorticosteronemia. We previously reported that the AdKO 2.0 mouse brain undergoes volumetric changes that resemble closely those of Cushing's syndrome human patients, as well as changes in expression of glial related marker proteins. In the present work, the expression of genes related to glial and neuronal cell populations and functions was assessed in regions of the anterior brain, hippocampus, amygdala and hypothalamus. Glucocorticoid target genes were consistently regulated, including CRH mRNA suppression in the hypothalamus and induction in amygdala and hippocampus, even if glucocorticoid receptor protein was downregulated. Expression of glial genes was also affected in the AdKO 2.0 mouse brain, indicating a different activation status in glial cells. Generic markers for neuronal cell populations, and cellular integrity were only slightly affected. Our findings highlight the vulnerability of glial cell populations to chronic high levels of circulating glucocorticoids.

Long‐term effects of glucocorticoid excess on the brain

“…For example, AdKO mice showed strongly induced expression of FKBP5 and, in the amygdala and hippocampus, CRH. 51,52 In particular, the latter may be directly linked to anxiety and hyperarousal. It will be interesting to see to what extent the changes in these mouse models will be reversible after adrenalectomy or treatment with, for example, GR antagonists.…”

“…Overall, both neuronal and glia cell populations are affected by the chronic hypercortisolemia. 50,51 The extensive changes in oligodendrocyte markers suggest that white matter changes are the consequence of direct targeting of the GR in these cells, which indeed express high levels of GR. 52 Indeed, Sgk1 mRNA expression in oligodendrocytes is highly responsive to stress or circadian glucocorticoid peaks.…”

“…These findings were later extended by mRNA measurements. Overall, both neuronal and glia cell populations are affected by the chronic hypercortisolemia 50,51 . The extensive changes in oligodendrocyte markers suggest that white matter changes are the consequence of direct targeting of the GR in these cells, which indeed express high levels of GR 52 …”

“…It is important to note that not all psychiatric symptoms of Cushing's patients need to be linked to structural changes that can be found by MRI. For example, AdKO mice showed strongly induced expression of FKBP5 and, in the amygdala and hippocampus, CRH 51,52 . In particular, the latter may be directly linked to anxiety and hyperarousal.…”

Transcriptional glucocorticoid effects in the brain: Finding the relevant target genes

“…Indeed, we recently observed that the astrocyte-specific gene coding for aquaporin 4 (Aqp4) was strongly suppressed in the brains of the AdKO mouse model for Cushing's disease. 10 Aquaporin 4 is the limiting factor for the process of cleaning the brain via "glymphatic flow". 95 Moreover, chronic stress and dexamethasone were both shown to reduce glymphatic flow in the rat, in a GR-dependent manner.…”