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Transcriptional response across estrous in the mouse dorsal hippocampus is dysregulated by Cnih3 mutation

ABSTRACT: The hippocampus is a critical brain region for coordinating learning, memory, and behavior. In adult females, the estrus cycle alters these functions through the activity of steroids hormones, with well-characterized effects on cellular physiology and behavior. However,the molecular genetic basis of these outcomes has not been systematically explored. In order to better understand the role of sex and the estrous cycle in the hippocampus, we profiled the transcriptome of hippocampi from female mice in each stage of the estrus cycle, along with those of males. We identify only subtle sex differences in gene expression between the sexes on average, yet comparing males to individual estrous stages reveals ~100 genes deviating from male expression patterns at one point in their cyclic fluctuations across estrous cycle. These estrus-responsive genes are especially enriched in oligodendrocytes and glycinergic neurons, and are potentially regulated downstream of estrogen receptor repressed pathways. To further understand our previous observations of female- and estrous-specific behavioral outcomes in knockout of Cnih3, we performed the same profiling in the knockout strain. Surprisingly, Cnih3 knockouts showed far broader transcriptomic differences between estrous cycle stages and males, despite very subtle within-group-across-genotype expression changes. We show that Cnih3 knockout drives expression changes in opposing directions between males and all points of the estrous cycle, extensively accentuating the magnitude of sex-differential hippocampal gene expression compared to wild-types. We thus provide a novel resource characterizing estrous-specific gene expression patterns in the adult hippocampus, which can provide insights into mechanisms of sex differential neuropsychiatric functions and dysfunctions, and identify a role for Cnih3 in buffering the female brain against the transcriptional effects of estrous.

ORGANISM(S): Mus musculus

PROVIDER: GSE199722 | GEO | 2023/02/17

REPOSITORIES: GEO

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Project description:Brain structure and function are sexually dimorphic. As neuroscience research has largely focused on the male brain and behavior, the female brain and, in particular, its inherent dynamics have been left underexplored. During the mammalian reproductive period, the female brain is exposed to fluctuating hormone levels over the cycles known as menstrual (in humans) or estrous (in rodents). Variation in estradiol levels has been shown to affect synaptic plasticity in the female brain, including changes in dendritic spine density systematically across the estrous cycle. Female emotionality and cognitive function vary with physiologically fluctuating sex hormone levels. However, the molecular mechanisms underlying the dynamic nature of the female brain structure and function are currently unknown. Here we show that neuronal chromatin organization in the female ventral hippocampus of mouse is dynamic and fluctuates across the estrous cycle. We find changes in chromatin organization associated with the transcriptional activity of nearby genes important for neuronal function, neurotransmission, synapse formation, and behavior. We also link these chromatin dynamics to variation in anxiety-like behavior and to fluctuations in dendritic spine and synaptic density in the ventral hippocampus. In terms of chromatin structure, within-female and between-sex variation are of similar magnitudes, emphasizing the importance of accounting for fluctuating sex-hormone levels in females in the studies of the brain epigenome and behavior. These results provide critical insights into the mechanisms underlying sex-hormone and sex-dependent variation in adult brain structure and function. The study also has implications for better understanding of sex-biased disorders such as depression and anxiety which are strongly associated with sex-hormone status in females and are twice as prevalent in women than in men. This study establishes a foundation for the development of sex-specific approaches to treat sex-biased neuropsychiatric disorders including depression and anxiety disorders.

Project description:The uterus, a female reproductive organ regulated by the sex hormones estrogen and progesterone, undergoes periodic cyclical changes. The estrous cycle refers to the reproductive cycle in non-primate mammalian females. During the mouse estrous cycle, the uterus undergoes various physiological changes as a result of dynamic hormonal changes. Accurate regulation of these changes is crucial for the establishment of a successful pregnancy. Notably, estrogen plays an important role in the regulation of the proestrus and estrus stages of the estrous cycle. Family with sequence similarity 3 (Fam3) is a cytokine-like gene family with four members: Fam3a, Fam3b, Fam3c, and Fam3d. Expression and regulation of the Fam3 family members in mouse uterine physiology remain largely unknown. Therefore, this study aimed to investigate the expression of Fam family members in the uterus during the estrous cycle and evaluate its regulation by estrogen using a mouse model. Analysis of mouse uterine RNA sequencing data revealed upregulated expression of Fam3b, Fam3c, and Fam3d during the proestrus and estrus stages. Fam3d expression was dynamically regulated during the estrous cycle, with high expression levels during the proestrus and estrus stages. To investigate whether Fam3d expression is regulated by estrogen, we administered estradiol (E2) to ovariectomized mice at different time points. Fam3d expression was highest 24 h after E2 injection, suggesting that estrogen plays a crucial role in regulating Fam3d expression. Furthermore, inhibition experiments using the estrogen receptor alpha (ERα) antagonist ICI revealed that estrogen regulates Fam3d expression through the ERα-mediated pathway. Immunofluorescence staining demonstrated that FAM3D was exclusively expressed in the luminal and glandular epithelia but not in the stroma. Additionally, FAM3D was predominantly localized in the cytoplasm, particularly in the apical region, and not in the nucleus. These findings provide valuable insights into the potential role of Fam3d in the uterus and lay the groundwork for future research on its function and significance in uterine physiology.

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Transcriptional response across estrous in the mouse dorsal hippocampus is dysregulated by Cnih3 mutation

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