Rutkowsky, J. M. | bioRxiv Science

bioRxiv2025

Light and sex modify Snord116 genotype effects on metabolism, behavior, and imprinted gene networks following circadian entrainment

Mammals utilize imprinted and X-linked epigenetic mechanisms in development, metabolism, and behavior. Imprinted genes, including Prader-Willi syndrome Snord116 noncoding RNAs, are implicated in the regulation of sleep and circadian rhythms through poorly understood mechanisms. Utilizing mouse models of Snord116 deficiency and overexpression, we performed an integrated, sex-stratified analysis of free running behaviors, indirect calorimetry, and cortical transcriptomes following entrainment to a 22 hour light:dark T-cycle. We observed significant interactions of sex, entrainment, and Snord116 genotype in period length at baseline and after-effects of post-entrainment. Snord116 deletions effect on respiratory exchange ratio was light sensitive, with sex and entrainment effects dominant under total darkness. Snord116 genotype impacted both rhythmic and non-rhythmic cortical gene networks that integrated sex, light, and entrainment effects with genotype-phenotype correlations. A co-expressed gene network enriched for imprinted, Snord116-target, and Xist-proximal long noncoding RNAs was identified as a light-sensitive regulatory hub of sexual dimorphic responses to a dynamic environment.

animal behavior and cognition↗

bioRxiv2025

Whey Protein Phospholipid Concentrate Supplementation Prevents High-Fat Diet Induced Cognitive Impairment in Wistar Rats by Promoting Brain Neuronal Connectivity and Sphingolipid Clearance

Whey protein phospholipid concentrate (WPPC), a byproduct of whey protein processing, is high in phospholipids and glycoconjugates which serve as substrates for fatty acids and sugar monomers (e.g. sialic acid) critical to neuronal myelin synthesis in the brain. This led us to hypothesize that WPPC will improve cognitive impairment induced by a high fat (HF) diet by promoting myelin turnover and improving myelin-dependent processes associated with encoding and storing memory. Male Wistar rats were randomized to one of four diets starting at weaning to [~]6.5 months on age: a low-fat (LF) diet containing 10% fat by weight, a HF diet containing 45% fat by weight to induce cognitive impairment, and a HF diet containing either 1.6% or 10% WPPC by weight (n=12 per diet). Rats were subjected to cognitive testing after 2 and 4 months of dietary intervention and then implanted with chronic bipolar electrodes to measure axonal evoked responses within the entorhinal cortex-hippocampal circuitry. Phospholipid and sphingolipid components of myelin were quantified in the hippocampus. There were no significant differences in cognition measured by novel object recognition after 2 months of supplementation. At 4 months, rats on the HF diet performed significantly worse than rats on the LF, HF1.6 and HF10 diets. The beneficial effects of WPPC on cognition were due to a partial reversal in evoked response impairments in hippocampal memory storage. Additionally, hippocampus sphingolipids were higher in rats on the HF diet compared to the LF, HF1.6 and HF10 groups. These findings demonstrate that WPPC prevented cognitive impairment induced by a HF diet by regulating entorhinal cortex-hippocampal circuitries associated with memory storage, though modulating myelin turnover.

neuroscience↗