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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.

SUBMITTER: Amaya JM

PROVIDER: S-EPMC9287025 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Amaya Jorge Miguel JM Viho Eva M G EMG Sips Hetty C M HCM Lalai Reshma A RA Sahut-Barnola Isabelle I Dumontet Typhanie T Montanier Nathanaëlle N Pereira Alberto M AM Martinez Antoine A Meijer Onno C OC

Journal of neuroendocrinology 20220401 4

Excess glucocorticoid exposure affects emotional and cognitive brain functions. The extreme form, Cushing's syndrome, is adequately modelled in the AdKO<sub>2.0</sub> mouse, consequential to adrenocortical hypertrophy and hypercorticosteronemia. We previously reported that the AdKO<sub>2.0</sub> 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 expr ...[more]

PMID: 35365898

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Project description:BackgroundNeonatal hypoxic-ischemic brain injury (HIBI) results in significant morbidity and mortality despite current standard therapies. MicroRNAs (miRNAs) are a promising therapeutic target; however, there is a paucity of data on endogenous miRNA expression of the brain after HIBI during the primary therapeutic window (6-72 h after injury).MethodsPostnatal day 9 mouse pups underwent unilateral carotid ligation+hypoxia (HIBI), sham surgery+hypoxia, or sham surgery+normoxia (controls). miRNA sequencing was performed on the ipsilateral brain of each of the three groups plus the contralateral HIBI brain at 24 and 72 h after injury. Findings were validated in eight key miRNAs by quantitative polymerase chain reaction.ResultsHypoxia resulted in significant differential expression of 38 miRNAs at both time points. Mir-2137, -335, -137, and -376c were significantly altered by neonatal HIBI at 24 and 72 h, with 3 of the 4 demonstrating multiphasic expression (different direction of differential expression at 24 versus 72 h).ConclusionsOur global assessment of subacute changes in brain miRNA expression after hypoxia or HIBI will advance research into targeted miRNA-based interventions. It will be important to consider the multiphasic miRNA expression patterns after HIBI to identify optimal timing for individual interventions.ImpactThis study is the first to comprehensively define endogenous brain microRNA expression changes outside of the first hours after neonatal hypoxic-ischemic brain injury (HIBI). Mir-2137, -335, -137, and -376c were significantly altered by neonatal HIBI and therefore deserve further investigation as possible therapeutic targets. The expression profiles described will support the design of future studies attempting to develop miRNA-based interventions for infants with HIBI. At 24 h after injury, contralateral HIBI miRNA expression patterns were more similar to ipsilateral HIBI than to controls, suggesting that the contralateral brain is not an appropriate "internal control" for miRNA studies in this model.

Dataset Information

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

Publications

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

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