Biology subjects

Lipshutz, A.

Publications and source records attributed to Lipshutz, A..

3 recordsLinked to original sources

bioRxiv2026

Sex-Specific Stress Outcomes Following Acute and Chronic Social Defeat Stress

Stressful experiences are a major risk factor for the development of neuropsychiatric disorders in vulnerable individuals. Identifying features that can distinguish stress-susceptible from resilient individuals remains a central goal in stress neurobiology. Due to the routine exclusion of female subjects from stress research or the use of male-defined criteria in behavioral characterization of subjects post-stress, female stress responses and vulnerability profiles remain poorly understood. This work aimed to gain a better understanding of sex-specific stress responses to social defeat stress. Here, we used a novel paired male-female social defeat paradigm and tracked subjects longitudinally in a ''two-hit'' design to evaluate responses to both acute social defeat stress (ASDS) and chronic social defeat stress (CSDS), and to determine how prior stress exposure influences subsequent vulnerability. We found that both ASDS and CSDS induces changes in social avoidance/approach behavior in males but not females, as measured by a classic social interaction ratio. Prior ASDS exposure enhanced susceptibility to subsequent CSDS most clearly in males, with females displaying specific changes in corner zone occupancy. Furthermore, we observed divergent anxiety profiles between males and females in a post-stress behavioral battery. Finally, females exhibited specific stress-related locomotor responses following ASDS. Together, these findings suggest that females may adopt distinct behavioral strategies following social defeat stress.

neuroscience↗

bioRxiv2023

WNK1 enforces macrophage lineage fidelity

The appropriate development of macrophages, the bodys professional phagocyte, is essential for organismal development, especially in mammals. This dependence is exemplified by the observation that loss-of-function mutations in colony stimulating factor 1 receptor (CSF1R) results in multiple tissue abnormalities owing to an absence of macrophages. Despite this importance, little is known about the molecular and cell biological regulation of macrophage development. Here, we report the surprising finding that the chloride-sensing kinase With-no-lysine 1 (WNK1) is required for development of tissue-resident macrophages (TRMs). Myeloid-specific deletion of Wnk1 resulted in a dramatic loss of TRMs, disrupted organ development, systemic neutrophilia, and mortality between 3 and 4 weeks of age. Strikingly, we found that myeloid progenitors or precursors lacking WNK1 not only failed to differentiate into macrophages, but instead differentiated into neutrophils. Mechanistically, the cognate CSF1R cytokine macrophage-colony stimulating factor (M-CSF) stimulates macropinocytosis by both mouse and human myeloid progenitors and precursor cells. Macropinocytosis, in turn, induces chloride flux and WNK1 phosphorylation. Importantly, blocking macropinocytosis, perturbing chloride flux during macropinocytosis, and inhibiting WNK1 chloride-sensing activity each skewed myeloid progenitor differentiation from macrophages into neutrophils. Thus, we have elucidated a role for WNK1 during macropinocytosis and discovered a novel function of macropinocytosis in myeloid progenitors and precursor cells to ensure macrophage lineage fidelity. Highlights- Myeloid-specific WNK1 loss causes failed macrophage development and premature death - M-CSF-stimulated myeloid progenitors and precursors become neutrophils instead of macrophages - M-CSF induces macropinocytosis by myeloid progenitors, which depends on WNK1 - Macropinocytosis enforces macrophage lineage commitment

immunology↗

bioRxiv2022

A Novel Localized Tracing Technique to Explore Intra-Amygdala Functional and Structural Connectivity Patterns as Mediators of Individual Variability in Stress Response

Neuropsychiatric disorders including anxiety and depression can be induced by stress, but not all individuals exposed to stress develop psychopathology. Therefore, probing the neural substrates that underlie trait vulnerability to stress may open the door for preventive approaches that use biological markers to identify at-risk populations. Here, we developed a novel tracing technique to probe local connectivity patterns as predictors of individual variability in stress responses. Specifically, we combined a retrograde transsynaptic rabies tracing system with cFos colocalization immediately after an acute stressor to elucidate local structural and stress-activated (functional) differences in connectivity within the amygdala complex in female and male mice along a spectrum of social approach/avoidance following acute social defeat stress. While we find no structural or functional connections within the amygdala complex as predictors of individual variability in our behavioral readout, our methods provide a novel approach to investigating cellular and behavioral individual variability in stress responses. Furthermore, we identify overall stress-activation as a predictor of social approach/avoidance in two subregions, medial amygdala and piriform-amygdala area, which may serve as potential biological markers of trait vulnerability, with possible clinical applicability. Significance StatementExposure to stress is ubiquitous, but the outcomes of stress exposure vary greatly between individuals. Our work introduces a novel tracing technique to probe for structural and functional connectivity patterns across a broad spectrum of behavioral responses to social stress. Utilizing pre-clinical classification in conjunction with representative behavioral classification introduces to the field a mechanism to identify potential clinical targets for preventative screening for neuropsychiatric disorders as well as further individualized treatment. Notably, our work identifies two intra-amygdalar neural correlates of social stress, opening the door for future investigation of the role these regions play in mediating social stress.

neuroscience↗