Nicholson, S. | bioRxiv Science

bioRxiv2024

Chronic intermittent alcohol yields sex-specific disruptions in cortical-striatal-limbic oscillations

BackgroundWhile the neurobiology of alcohol use disorder (AUD) has been extensively researched, the vast majority of these studies included only male organisms. However, there are significant sex differences in both the causes and consequences of alcohol misuse and dependence, suggesting sex-specific neurobiological mechanisms. The current study used a rodent model to determine whether chronic alcohol exposure impacts sex-specific neural circuits, and whether these changes contribute to the development of alcohol misuse. MethodsMale and female Sprague-Dawley rats were trained to self-administer 10% alcohol before implanting bilateral electrodes into the infralimbic medial prefrontal cortex (IL), nucleus accumbens shell (NAcSh), and central nucleus of the amygdala (CeA). Half of the rats were then exposed to four weeks of chronic intermittent alcohol (CIA) vapor (14 hours on/10 hours off). During acute withdrawal (6-8 after the vapor turns off), local field potentials (LFPs) were recorded from the IL, NAcSh, and CeA during 30-minute self-administration sessions. Using an unbiased machine learning approach, we built predictive models to determine whether/which LFP features could distinguish CIA-exposed from control rats in each sex, as well as if any of these LFP features correlated with rates of alcohol self-administration. ResultsFemale rats self-administered more alcohol in general compared to males, but only males exposed to CIA showed increased alcohol intake during acute withdrawal. LFPs predicted CIA exposure in both sexes better than chance estimates, but models built on IL and NAcSh oscillations performed the best in males, while models built on IL and CeA LFPs performed best in females. High {gamma} LFPs recorded in the NAcSh correlated with rates of alcohol self-administration in males exposed to CIA, while only left-right NAcSh {beta} coherence correlated with drinking in control females. ConclusionsThese data provide support for the hypothesis that the neural circuits driving alcohol dependence development are sex-specific, and that high frequency oscillations in the NAcSh may be related to the increased drinking observed in males exposed to CIA. Overall, these data add to our understanding of the neurobiological underpinnings behind the sex differences observed in AUD and offer promising biomarkers for future therapeutic research.

neuroscience↗

bioRxiv2023

CD45 limits Natural Killer cell development from common lymphoid progenitors

The clinical development of Natural Killer (NK) cell-mediated immunotherapy marks a milestone in the development of new cancer therapies and has gained traction due to the intrinsic ability of the NK cell to target and kill tumour cells. To fully harness the tumour killing ability of NK cells, we need to improve NK cell persistence and overcome suppression of NK cell activation in the tumour microenvironment. The trans-membrane, protein tyrosine phosphatase CD45, regulates NK cell homeostasis, with genetic loss of CD45 in mice resulting in increased numbers of mature NK cells [1-3]. This suggests that CD45-deficient NK cells might display enhanced persistence following adoptive transfer. However, here we demonstrated that adoptive transfer of CD45-deficiency did not enhance NK cell persistence in mice, and instead, the homeostatic disturbance of NK cells in CD45-deficient mice stemmed from a developmental defect in the common lymphoid progenitor population. The enhanced maturation within the CD45-deficient NK cell compartment was intrinsic to the NK cell lineage, and independent of the developmental defect. CD45 is not a conventional immune checkpoint candidate, as systemic loss is detrimental to T and B cell development [4-6], compromising the adaptive immune system. Nonetheless, this study suggests that inhibition of CD45 in progenitor or stem cell populations may improve the yield of in vitro generated NK cells for adoptive therapy.

cell biology↗