Biology subjects

Beaver, J. N.

Publications and source records attributed to Beaver, J. N..

5 recordsLinked to original sources

bioRxiv2025

PMAT enhances sexual dimorphism of fear behaviors and facilitates female mice's generalized contextual fear extinction

Enhanced signaling of dopamine and/or serotonin during highly arousing situations can be reduced or terminated by monoamine transporters. One such transporter, plasma membrane monoamine transporter (PMAT, Slc29a4), attenuates both dopamine and serotonin signaling. An absence of selective pharmacological inhibitors means genetically modified mice constitutively deficient in PMAT remain the best tool with which to study PMATs organism-level functional effects. Fear conditioning is a high arousal process. Generalization of fear is an evolutionarily advantageous process, whereby information learned from one experience is applied to other new but similar encounters. Pathological fear generalization, in contrast, is a core feature of most anxiety disorders. Given our previous findings indicating PMAT function reduces male mices context fear and enhances extinction of female mices cued fear, we hypothesized that PMAT would similarly reduce generalization (i.e., enhance discrimination) of context and cued fear in male and female mice, respectively. Our context and cued fear conditioning experiments in adult PMAT wildtype (+/+) and heterozygous (+/-) male and female mice partially supported our hypotheses. We discovered PMAT functions to facilitate extinction of contextually generalized fear, plus subsequent extinction of context-specific fear, selectively in females. Moreover, when specific fear cues or contexts were temporally presented before cues or contexts that were similar enough to make generalization possible, PMAT enhanced biological sex differences. Growing evidence reports common PMAT polymorphisms elicit measurable effects when PMAT function is reduced. Thus, we suspect future experiments may reveal positive associations between PMAT polymorphisms and risk for anxiety disorder symptoms, particularly in people assigned female at birth. Inclusion of these genetic variations in pharmacogenomic analyses may prove therapeutically beneficial.

neuroscience↗

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↗

bioRxiv2024

Male and female mice respectively form stronger social aversive memories with same and different sex conspecifics

Mice offer a wealth of opportunities for investigating brain circuits regulating multiple behaviors, largely due to their genetic tractability. Social behaviors are translationally relevant, considering both mice and humans are highly social mammals, and human social behavior disruptions are key symptoms of myriad neuropsychiatric disorders. Stresses related to social experiences are particularly influential in the severity and maintenance of neuropsychiatric disorders like anxiety disorders, and trauma and stressor-related disorders. Yet, induction and study of social stress in mice has disproportionately focused on males, influenced heavily by their inherent territorial nature. Social target-instigated stress (i.e., defeat), while ethologically relevant, is quite variable and predominantly specific to males, making rigorous and sex-inclusive studies challenging. In pursuit of a controllable, consistent, high throughput, and sex-inclusive method for social stress elicitation, we modified a paradigm to train male and female F1 129S1/SvlmJ x C57BL/6J mice to associate (via classical conditioning) same or different sex C57BL/6J targets with a mild, aversive stimulus. While further paradigm optimization is required, social interaction testing 24 h after conditioning indicates males socially conditioned better to male targets by exhibiting reduced social interaction, whereas females appeared not to form social stimulus associations. Serum corticosterone levels inversely corresponded to social avoidance after different sex, but not same sex, conditioning, suggesting corticosterone-mediated arousal influences cross-sex interactions. These rigorously controlled null outcomes align with past pursuits limited success in creating a sex-inclusive social stress paradigm. Significance StatementValidated paradigms to study social stress in female mice, and across sexes, are needed. We modified a published male mouse protocol by using classical conditioning to pair an aversive stressor with a target. Our goal was to create a uniform, cross-sex, high-throughput social stress technique to advance future research. Though our modified paradigm requires future improvements, we did acquire evidence that males can be socially conditioned in this way, and female same sex social engagement can be attenuated by a preceding non-social aversive experience. These null findings, while not achieving our goal, provide useful information to advance future sex-inclusive social stress investigations.

neuroscience↗

bioRxiv2023

Heterotypic stressors unmask behavioral influences of PMAT deficiency

Certain life stressors having enduring physiological and behavioral consequences, in part by eliciting dramatic signaling shifts in monoamine neurotransmitters. High monoamine levels can overwhelm selective transporters like the serotonin transporter. This is when polyspecific transporters like plasma membrane monoamine transporter (PMAT, Slc29a4) are hypothesized to contribute most to monoaminergic signaling regulation. Here, we employed two distinct counterbalanced stressors - fear conditioning, and swim stress - in mice to systematically determine how reductions in PMAT function affect heterotypic stressor responsivity. We hypothesized male heterozygotes would exhibit augmented stressor responses relative to female heterozygotes. Decreased PMAT function enhanced context fear expression, an effect unexpectedly obscured by a sham stress condition. Impaired cued fear extinction retention and enhanced context fear expression in males were conversely unmasked by a sham swim condition. Abrogated corticosterone levels in male heterozygotes that underwent swim stress after context fear conditioning did not map on to any measured behaviors. In sum, male heterozygous mouse fear behaviors proved malleable in response to preceding stressor or sham stress exposure. Combined, these data indicate reduced male PMAT function elicits a form of stress-responsive plasticity. Future studies should assess how PMAT is differentially affected across sexes and identify downstream consequences of the stress-shifted corticosterone dynamics.

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↗