ESPE Yearbook of Paediatric Endocrinology

Transl Psychiatry. 2022; 12(1): 109. PMID: 35296634 https://pubmed.ncbi.nlm.nih.gov/35296634/

Brief Summary: This mouse study identified sex and genotype-dependent effects of oral corticosterone on behavioral and physiological outcomes as well as on gene expression and epigenetics in hippocampal subregions.

Glucocorticoids exert their effects by binding to glucocorticoid receptors (GRs), which regulate up to ~20% of the genome via both direct (by binding to glucocorticoid responsive elements in promoter regions) and indirect mechanisms (by interacting with bound transcription factors and epigenetic modifiers) (1, 2). GRs also play a key role in the feedback regulation of the hypothalamic- pituitary-adrenal (HPA) axis. They are highly expressed in the hippocampus and their distribution is heterogeneous depending on the hippocampal subregion both at baseline and in response to stress (3, 4). The dorsal (dHPC) and the ventral hippocampus (vHPC) are two functionally distinct subregions that differ in their respective neuroanatomical connectivity and in the biological processes they encode. Regional differences in gene expression also contribute to distinguish the function of the dHPC and vHPC in response to environmental stimuli. These two hippocampal circuits also show sex differences in neuronal proliferation (5, 6), indicating that males and females use distinct networks to modulate the function of the HPA axis. However, little is known on the whole-genome profile that underlies sex differences in the dHPC and vHPC, especially in response to glucocorticoids.

These authors gave exogenous GCs (oral corticosterone) to mice that were either wild-type (WT) or heterozygous for the brain-derived neurotrophic factor (BDNF) Val66Met (hMet) allele, a variant associated with genetic susceptibility to stress. They studied the effects of oral corticosterone on genomic differences in the hippocampal subregions, dorsal (dHPC) or ventral (vHPC). Gene expression was analyzed using RNA-sequencing and epigenetic regulation was assessed using reverse transcriptase-quantitative polymerase chain reaction and methyl-DNA-immuno-precipitation assay. Behavioral and physiological responses to corticosterone were also assessed.

Male mice showed increased anxiety- and depression-like behavior, while females showed affective behavior in response to corticosterone. Male mice also showed lower glycemia. Gene expression responses to corticosterone were greater in the vHPC than in the dHPC in males of both genotypes, and larger in the vHPC of males compared to females regardless of genotype. Moreover, differentially expressed genes (DEGs) in the vPHC exhibited sex differences related to glucocorticoid receptor (GR)-binding genes and epigenetic modifiers. DEGs showed differences in expression in the vHPC of females and discordant corticosterone-induced DEGs in both brain regions only in hMet males and females. Interestingly, the pattern of gene expression after corticosterone exposure mirrored the behavioral sex differences, as well as the behavior found in hMet females. Finally, they found differential methylation of exons 1C and 1F of the GR gene (Nr3c1) in hMet females.

This is the first study reporting behavioral sex differences in mice given oral corticosterone, impairing the hypothalamic-pituitary-adrenal axis, as well as hippocampal region-specific genomic expression profiles. The results open new avenues for research regarding the effects of stress and/or GC treatment on mood disorders and behavior.

References: 1. Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E. The human glucocorticoid receptor: molecular basis of biologic function. Steroids. 2010; 75(1):1–12. 2. Gray JD, Kogan JF, Marrocco J, McEwen BS. Genomic and epigenomic mechanisms of glucocorticoids in the brain. Nat Rev Endocrinol. 2017; 13: 661–73. 3. Chao HM, Choo PH, McEwen BS. Glucocorticoid and mineralocorticoid receptor mRNA expression in rat brain. Neuroendocrinology 1989; 50: 365–71. 4. Guidotti G, Calabrese F, Anacker C, Racagni G, Pariante CM, Riva MA. Glucocorticoid receptor and FKBP5 expression is altered following exposure to chronic stress: modulation by antidepressant treatment. Neuropsychopharmacology 2013; 38: 616–27. 5. Yagi S, Splinter JEJ, Tai D, Wong S, Wen Y, Galea LAM. Sex differences in maturation and attrition of adult neurogenesis in the hippocampus. eNeuro. 2020; 7: ENEURO.0468-19.2020. 6. Reich CG, Taylor ME, McCarthy MM. Differential effects of chronic unpredictable stress on hippocampal CB1 receptors in male and female rats. Behav Brain Res. 2009; 203: 264–9.