Sex Differences in the Role of CNIH3 on Spatial Memory and Synaptic Plasticity

Frye, Hannah E.; Izumi, Yukitoshi; Harris, Alexis N.; Williams, Sidney B.; Trousdale, Christopher; Sun, Min; Sauerbeck, Andrew D.; Mennerick, Steven; Zorumski, Charles F.; Nelson, Elliot C.; Dougherty, Joseph D.; Morón, José A.

doi:10.1016/j.biopsych.2021.07.014

Cited by 12 publications

(30 citation statements)

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“…Adult (age range 12 - 24 weeks) WT and Cnih3 KO littermates on a C57/BL6j background were used. Genotyping was performed according to methods used by the group publishing the mouse line (Frye et al, 2021). Mice were kept in climate-controlled facilities with a 12-hour light/dark cycle and ad libitum access to food and water.…”

Section: Methodsmentioning

confidence: 99%

“…Procedures were approved by the Institutional Animal Care and Use Committee at [Author University redacted until double blind review is complete]. Adult (age range 12 - 24 weeks) WT and Cnih3 KO littermates, genotyped as described (Frye et al, 2021), on a C57/BL6j background were used. Mice were kept in climate-controlled facilities with a 12-hour light/dark cycle and ad libitum access to food and water.…”

Section: Methodsmentioning

confidence: 99%

“…As prior experiments with Cnih3 have illustrated, male-female differences can be influen the stage of the estrous cycle (Frye et al, 2021). Therefore, we performed comparisons betwe 2b-2e).…”

Section: Gene Expression Between Wild-type Male and Female Bulk Hippo...mentioning

confidence: 99%

“…Outwardly, the impact of sex has been observed in neuropsychiatric diseases and rodent models thereof, including addiction (Kuhn, 2015), potentially via the hippocampus (Kohtz and Aston-Jones, 2017). Indeed, it was recently observed that knockout (KO) of the opioid dependence-associated gene Cnih3 (Nelson et al, 2016) has not only sex-, but estrous stage-specific effects (Frye et al, 2021) in learning and memory, supporting a role for acute sex hormonal effects on addiction-relevant brain circuitry related to learning and memory. Consistent with Cnih3 modulating learning, KO showed severe memory deficits and corresponding synaptic changes, but only in female mice, and limited to particular phases of the estrous cycle (Frye et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, it was recently observed that knockout (KO) of the opioid dependence-associated gene Cnih3 (Nelson et al, 2016) has not only sex-, but estrous stage-specific effects (Frye et al, 2021) in learning and memory, supporting a role for acute sex hormonal effects on addiction-relevant brain circuitry related to learning and memory. Consistent with Cnih3 modulating learning, KO showed severe memory deficits and corresponding synaptic changes, but only in female mice, and limited to particular phases of the estrous cycle (Frye et al, 2021). This suggested the surprising hypothesis that Cnih3 is involved in buffering the female brain against effects of hormones on hippocampal learning, and thus loss of Cnih3 results in these abnormal outcomes in a cycledependent manner.…”

Section: Introductionmentioning

confidence: 99%

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Typical hippocampal transcriptional response across estrous is dysregulated by Cnih3 gene deletion

Mulvey

Frye

Lintz

et al. 2022

Preprint

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The hippocampus is a critical brain region for coordinating learning, memory, and behavior. In females, the estrous cycle alters these functions through steroid hormone activity, with well-characterized effects on cellular physiology and behavior. However, the molecular basis of these outcomes has not been systematically explored. Therefore, we profiled the transcriptome of dorsal hippocampi from female mice in each estrous cycle stage, and contrasted it with that of males. We identify only subtle sex differences in gene expression between the sexes on average, yet comparing males to individual estrous stages reveals up to thousands of genes deviating from male expression patterns at specific estrous stages. These estrous-responsive genes are especially enriched in gene markers of oligodendrocytes and the dentate gyrus, and in functional gene sets relating to estrogen response, potassium channels, and synaptic gene splicing. Next we profiled Cnih3 knockouts across estrous to provide insight into their previously reported estrous-dependent phenotypes in hippocampal synaptic plasticity, composition, and learning and memory behaviors. Surprisingly, Cnih3 knockouts showed far broader transcriptomic differences between estrous cycle stages and males. Moreover, Cnih3 knockout drove subtle but extensive expression changes accenting sex differential expresssion at diestrus and estrus. Altogether, our profiling constitutes both a resource characterizing estrous-specific gene expression patterns in the adult hippocampus, which can provide insights into mechanisms of sex differential neuropsychiatric functions and dysfunctions, while also highlighting roles of Cnih3 as a buffer against transcriptional effects of estrous and providing insights into the molecular mechanisms that may underlie estrous-dependent phenotypes with its loss.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Gene Expression Between Wild-type Male and Female Bulk Hippo...mentioning

confidence: 99%