Sex-specific attenuation of constant light-induced memory impairment and Clock gene expression in brain in hepatic Npas2 knockout mice

TL;DR

Removing the Npas2 gene in mice livers affects memory under constant light, especially in females, and changes brain circadian gene expression.

Contribution

This study reveals sex-specific effects of liver Npas2 deletion on memory and brain circadian gene expression under constant light.

Findings

Npas2-/- mice showed resistance to constant light-induced memory impairment, especially in females.

Npas2-/- mice exhibited altered Clock gene expression in the frontal cortex.

Sex differences in circadian gene expression were absent in Npas2-/- mice.

Abstract

NPAS2 (Neuronal PAS Domain Protein 2) is a component of the core circadian clock and the coordinated activity between central brain and peripheral liver clock proteins postulated to be instrumental for linking behaviour and metabolism. We investigated a conditional liver-specific knockout mouse model (Npas2-/- or cKO) to explore its function in activity, circadian rhythms and cognition (novel object recognition-NOR). Circadian rhythms showed no genotype differences. Constant-light reduced NOR in floxxed controls but remarkably not in Npas2-/- mice, particularly females. Consistent with entrainment of systemic and central circadian biology, Npas2-/- mice showed altered expression of circadian gene Clock in frontal cortex. Sex differences independent of genotype were found in expression of circadian genes Clock, Bmal1 and Reverb-b in brain. Sex differences in Clock were absent in Npas2-/- mice. Females showed greater period length and phase response to constant light independently of genotype. The data suggest that a role for peripheral NPAS2 in constant light-induced memory impairment in females, and potential mediation by altered cortical circadian Clock gene expression, merit further investigation. These findings have implications for the interaction between peripheral and central circadian clocks, circadian sex differences and the deleterious effects of constant light on cognition.

The online version contains supplementary material available at 10.1038/s41598-025-92938-1.

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