Anello, A. E. | Search bioRxiv

bioRxiv2025

Voluntary eating of saltier food by mice and acute stress each abrogate reductions in a neuroinflammatory marker across sexes

Both consuming excess salt (NaCl) and experiencing environmental stress can elevate neuroinflammation and enhance risk for non-communicable diseases. Most rodent studies investigating these topics use only males, and assess salt or stress separately. Here, we used adult female and male mice to investigate how the combination of access to food high in salt (4% NaCl, w/w) and experiencing an acute stressor interact to affect levels of a proxy measure for neuroinflammation (Iba1). We hypothesized eating salty food and experiencing stress would each individually augment neuroinflammation, and their combination would be additive. Further, we anticipated salty food consumption would increase active stress coping behaviors, and that all of these effects would be enhanced in female mice. Over 4 or 8 weeks, we further evaluated how mice responded to choice access to low (0.4%) and high salt food simultaneously. Our hypothesis that mice across sexes would eventually prefer high over low salt food was supported, while our expectations regarding neuroinflammation and stress did not consistently align with our findings. Instead, we found modest changes in passive coping behaviors driven by our choice condition, unanticipated reductions in sham stress neuroinflammation by high salt in brain region- and biological sex-specific patterns after 4 weeks, and distinct sex- and salt-selective increases in swim stress neuroinflammation after 8 weeks. Though some of our results were unexpected, they include multiple novel and translationally relevant outcomes. Mice willingly choose to eat saltier food over time, akin to people, and this could sex-specifically decrease (females) or augment (males) passive coping stress strategies while eliciting distinctive stress- and brain region-dependent neuroinflammatory patterns over time. Future studies implementing more complex behavior tests and stress manipulations will advance identification of the hidden ways through which salty food and stressful experiences interact to affect risk for non-communicable diseases.

neuroscience↗

bioRxiv2022

Generalization of contextual fear is sex-specifically affected by high salt intake

A hallmark symptom of many anxiety disorders, and multiple neuropsychiatric disorders more broadly, is generalization of fearful responses to non-fearful stimuli. Anxiety disorders are often comorbid with cardiovascular diseases. One established, and modifiable, risk factor for cardiovascular diseases is salt intake. Yet, investigations into how excess salt consumption affects anxiety-relevant behaviors remains little explored. Moreover, no studies have yet assessed how high salt intake influences generalization of fear. Here, we used adult C57BL/6J mice of both sexes to evaluate the influence of two or six weeks of high salt consumption (4.0% NaCl), compared to controls (0.4% NaCl), on contextual fear acquisition, expression, and generalization. Further, we measured osmotic and physiological stress by quantifying serum osmolality and corticosterone levels, respectively. Consuming excess salt did not influence contextual fear acquisition nor discrimination between the context used for training and a novel, neutral context when training occurred 48 prior to testing. However, when a four week delay between training and testing was employed to induce natural fear generalization processes, we found that high salt intake selectively increases contextual fear generalization in females, but the same diet reduces contextual fear generalization in males. These sex-specific effects were independent of any changes in serum osmolality nor corticosterone levels, suggesting the behavioral shifts are a consequence of more subtle, neurophysiologic changes. This is the first evidence of salt consumption influencing contextual fear generalization, and adds information about sex-specific effects of salt that are largely missing from current literature.

neuroscience↗