Biology subjects

Walker, A. M.

Publications and source records attributed to Walker, A. M..

3 recordsLinked to original sources

bioRxiv2026

Chronic Intermittent Ethanol Exposure Produces Physiological Tolerance and Distinct Behavioral Alterations Across Abstinence in Female Mice

Chronic ethanol consumption produces long-lasting effects on the brain that contribute to persistent behavioral changes. This has been modeled in animals using the chronic intermittent ethanol (CIE) paradigm, which induces escalation of consumption and alterations in affective and cognitive behavior. While this model has been well characterized in male subjects, the effects of CIE in females and long-term effects that persist beyond the acute withdrawal remain relatively underexplored. Here, female C57BL/6J mice were exposed to four weeks of chronic intermittent ethanol (CIE) vapor to induce dependence. Following CIE, mice were evaluated for physiological tolerance to ethanol and alterations in anxiety-like behaviors and memory processing. Using the ethanol responsivity battery (ERB) assay to assess physiological tolerance, we found blunted responsiveness to the intoxicating effects of ethanol in the CIE-exposed females, indicating heightened ethanol tolerance that persists beyond the acute withdrawal phase. A cohort underwent behavioral testing following CIE to characterize changes in anxiety-like behavior, exploration, and memory across abstinence. In early abstinence (<5 days post-CIE), CIE-exposed females showed increased exploratory behavior compared with Air controls. After one week of abstinence, CIE-exposed females displayed impaired object recognition memory. CIE-exposed females also showed increased anxiety-like behavior at protracted abstinence time points, exhibiting hyponeophagia in the novelty-suppressed feeding test at 2 weeks post-CIE. In addition, following cued fear conditioning, we found reduced extinction recall at 4 weeks post-CIE. Together, this work indicates that chronic alcohol exposure leads to increased alcohol tolerance and distinct, persistent alterations in memory and anxiety-like behavior in female mice.

neuroscience↗

bioRxiv2026

Knockdown of the long isoform of the prolactin receptor selectively targets pathogenic immune cells and averts lupus nephritis

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic inflammation in multiple organ systems. While a clinical association between elevated levels of the hormone/cytokine, prolactin (PRL), and exacerbation of SLE has been recognized for some time, little is known about the mechanisms through which PRL affects the course of this disease. Here, we show that immune cells in SLE have aberrant splicing of the prolactin receptor (PRLR) such that the ratio of the long to short splice variants is increased. To determine whether the change in PRLR isoform expression was causal in this disease, we used a splice-modulating oligomer (SMO) that knocked down expression of the long splice variant (LFPRLR). Using patient samples ex vivo, SLE-prone mice in vivo, high-dimensional flow cytometry and single-cell RNA-sequencing, we demonstrate that the aberrant PRLR isoform expression in SLE both directly and indirectly drives production of autoreactive immune cell phenotypes. Thus, LFPRLR knockdown decreased the expression of type I interferon signaling/response genes known to be biomarkers and hub genes for SLE, reduced immunoglobulins with signatures considered autoreactive, and averted glomerular kidney damage in SLE-prone mice. Importantly, LFPRLR knockdown reduced pathogenic B cells and other immune subsets that drive B-cell activation, without negative impact on healthy donor counterparts. Current treatments for SLE adversely affect healthy cells and do not concurrently eradicate multiple pathogenic immune subsets. Since LFPRLR SMO does not share these disadvantages, knockdown of the LFPRLR represents a potential treatment strategy for SLE that merits further investigation. Graphical AbstractThe LFPRLR represents an attractive therapeutic target in SLE. (Left) In addition to increased pituitary/circulating PRL, individuals with SLE exhibit aberrant increases in the production of autocrine/paracrine PRL by immune cells, and in their expression of specifically the long isoform (LF) of the PRLR. (Middle) Expression of the LFPRLR specifically enhances autoreactive immunophenotypes and promotes lupus nephritis. (Right) A splice modulating oligomer (SMO), that prevents synthesis of only the LFPRLR but not the short PRLR isoforms, reduces pathogenic immunophenotypes without affecting the normal counterparts of immune cells.

immunology↗

bioRxiv2021

Extensive introgression among North American wild grapes (Vitis) fuels biotic and abiotic adaptation

Introgressive hybridization can introduce adaptive genetic variation into a species or population. To evaluate the evolutionary forces that contribute to introgression, we studied six Vitis species that are native to the Southwestern United States and potentially useful for breeding grapevine (V. vinifera) rootstocks. By creating a reference genome from one wild species, V. arizonica, and by resequencing 130 accessions, we focused on identifying putatively introgressed regions (pIRs) between species. We found that up to ~8% of extant genome is attributable to introgression between species. The pIRs tended to be gene poor, located in regions of high recombination and enriched for genes implicated in disease resistance functions. To assess potential pIR function, we explored SNP associations to bioclimatic variables and to bacterial levels after infection with the causative agent of Pierces Disease. pIRs were enriched for SNPs associated with both climate and bacterial levels, suggesting potential drivers of adaptive events. Altogether, this study yields insights into the genomic extent of introgression, potential pressures that shape adaptive introgression, and the history of economically important wild relatives of a critical crop.

evolutionary biology↗