Carlson, E. R. | Search bioRxiv

bioRxiv2024

Pharmacological depletion of microglia protects against alcohol-induced corticolimbic neurodegeneration during intoxication in male rats

Excessive alcohol use damages the brain, especially corticolimbic regions such as the hippocampus and rhinal cortices, leading to learning and memory problems. While neuroimmune reactivity is hypothesized to underly alcohol-induced damage, direct evidence of the causative role of microglia, brain-resident immune cells, in this process is lacking. Here, we depleted microglia using PLX5622 (PLX), a CSF1R inhibitor commonly used in mice, but rarely in rats, and assessed cell death following binge-like alcohol exposure in male rats. Eleven days of PLX treatment depleted microglia >90%. Further, PLX treatment prevented alcohol-induced neuronal death in the hippocampus and rhinal cortices, as the number of FluoroJade-B-positive cells (dying neurons) was reduced to control diet levels. This study provides direct evidence that alcohol-induced microglial reactivity is neurotoxic in male rats. Improved understanding of alcohol-microglia interactions is essential for developing therapeutics that suppress pro-cytotoxic and/or amplify protective microglia activity to relieve alcohol-related damage.

neuroscience↗

bioRxiv2019

Grandpaternal effects are lineage- and sex-specific in threespined sticklebacks

O_LITransgenerational plasticity (TGP) occurs when the environment encountered by one generation (F0) alters the phenotypes of one or more future generations (e.g. F1 and F2). Sex selective TGP, via specific lineages or to only male or female descendants, has been underexplored in natural systems, and may be adaptive if it allows past generations to fine-tune the phenotypes of future generations in response to sex-specific life history strategies. C_LIO_LIWe sought to understand if exposing males to predation risk can influence grandoffspring via sperm in threespined stickleback (Gasterosteus aculeatus). We specifically tested the hypothesis that grandparental effects are transmitted in a sex-specific way down the male lineage, from paternal grandfathers to F2 males. C_LIO_LIWe reared F1 offspring of unexposed and predator-exposed F0 males under control conditions and used them to generate F2s with control grandfathers, a predator-exposed maternal grandfather (i.e., predator-exposed F0 males to F1 daughters to F2 offspring), a predator-exposed paternal grandfather (i.e., predator-exposed F0 males to F1 sons to F2 offspring), or two predator-exposed grandfathers. We then assayed male and female F2s for a variety of traits related to antipredator defense. C_LIO_LIWe found little evidence that transgenerational effects were mediated to only male descendants via the paternal lineage. Instead, grandpaternal effects depended on lineage and were mediated largely across sexes, from F1 males to F2 females and from F1 females to F2 males. When their paternal grandfather was exposed to predation risk, female F2s were heavier and showed a reduced change in behavior in response to a simulated predator attack relative to offspring of control, unexposed grandparents. In contrast, male F2s showed reduced antipredator behavior when their maternal grandfather was exposed to predation risk. However, these patterns were only evident when one grandfather, but not both grandfathers, was exposed to predation risk, suggesting the potential for non-additive interactions across lineages. C_LIO_LIIf sex-specific and lineage effects are common, then grandparental effects are likely underestimated in the literature. These results draw attention to the importance of sex-selective inheritance of environmental effects and raise new questions about the proximate and ultimate causes of selective transmission across generations. C_LI

evolutionary biology↗