1. Sleep-sensitive dopamine receptor expression in male mice underlies attention deficits after a critical period of early adversity.
- Author
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Makino, Yuichi, Hodgson, Nathaniel W., Doenier, Emma, Serbin, Anna Victoria, Osada, Koya, Artoni, Pietro, Dickey, Matthew, Sullivan, Breanna, Potter-Dickey, Amelia, Komanchuk, Jelena, Sekhon, Bikram, Letourneau, Nicole, Ryan, Neal D., Trauth, Jeanette, Cameron, Judy L., and Hensch, Takao K.
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SLEEP interruptions ,DOPAMINE receptors ,SLEEP ,CINGULATE cortex ,SLEEP deprivation - Abstract
Early life stress (ELS) yields cognitive impairments of unknown molecular and physiological origin. We found that fragmented maternal care of mice during a neonatal critical period from postnatal days P2–9 elevated dopamine receptor D2R and suppressed D4R expression, specifically within the anterior cingulate cortex (ACC) in only the male offspring. This was associated with poor performance on a two-choice visual attention task, which was acutely rescued in adulthood by local or systemic pharmacological rebalancing of D2R/D4R activity. Furthermore, ELS male mice demonstrated heightened hypothalamic orexin and persistently disrupted sleep. Given that acute sleep deprivation in normally reared male mice mimicked the ACC dopamine receptor subtype modulation and disrupted attention of ELS mice, sleep loss likely underlies cognitive deficits in ELS mice. Likewise, sleep impairment mediated the attention deficits associated with early adversity in human children, as demonstrated by path analysis on data collected with multiple questionnaires for a large child cohort. A deeper understanding of the sex-specific cognitive consequences of ELS thus has the potential to reveal therapeutic strategies for overcoming them. Editor's summary: Early life adversity (ELA) can have cognitive impacts that persist into adulthood, but the underlying brain mechanisms remain elusive. Here, Makino et al. show that fragmented maternal care led to cognitive dysfunction in adult male, but not female, mice. These findings were associated with disrupted sleep patterns and dysregulated dopamine receptor expression in the anterior cingulate cortex. Acute sleep disruption mimicked ELA-induced changes, and pharmacological rebalancing of DR signaling rescued cognitive dysfunction. Analysis of data from a cohort of young children showed that adversity negatively affected attention, and this relationship was mediated by poor sleep, indicating that the coupling of adversity, sleep, and attention is conserved across species. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]
- Published
- 2024
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