Biology subjects

Freund, J. R.

Publications and source records attributed to Freund, J. R..

4 recordsLinked to original sources

bioRxiv2026

Exercise Myokine Irisin Enables Behavioral Stress Resistance in Mice

Physical activity produces widespread benefits to physical and mental health, including protection against stress-related behavioral outcomes. However, the peripheral signals through which physical activity is translated into stress resistance remain incompletely understood. Irisin, an exercise-induced myokine cleaved from the transmembrane protein FNDC5 and released into circulation, has been implicated in improved cognition and neuroprotection, but its role in resistance to behavioral consequences of future adversity has not been examined. Here, we tested whether forced peripheral elevation of irisin is sufficient to protect against stress-induced behavioral outcomes. Adult male C57BL/6 mice received adeno-associated viral (AAV)-mediated peripheral expression of irisin or GFP control. AAV-irisin significantly increased circulating irisin levels, and six weeks later, mice were exposed to inescapable stress, a well-characterized model that produces anxiety-like behaviors, including reducing rodents natural inclination toward sociability. Elevated circulating irisin prevented the stress-induced reduction in social preference without altering general locomotor activity. Moreover, circulating irisin levels positively predicted individual differences in sociability. Additionally, peripheral irisin elevation increased brain-derived neurotrophic factor (Bdnf) expression, which also positively correlated with circulating irisin levels. Finally, we identified expression of the irisin receptor subunit integrin V within the dorsal raphe nucleus, a key brain region implicated in the behavioral outcomes of inescapable stress that is modulated by prior exercise. Together, these findings identify peripheral irisin as a mediator sufficient to confer resistance to future stress, even in the absence of physical activity. Significance StatementPhysical activity protects against the anxiety-like behavioral outcomes of future stress, but the peripheral mediators of this effect remain unclear. Here we show that forced peripheral elevation of circulating irisin, an exercise-induced myokine, is sufficient to produce behavioral stress resistance in mice. Irisin prevented the stress-induced reduction in social preference and positively correlated with individual differences in sociability. Forced expression of peripheral irisin also increased Bdnf expression in the brain, consistent with engagement of central neuroplasticity pathways that support adaptive behavioral responses. These findings demonstrate that an exercise-induced circulating factor can confer resistance to future stress, identifying irisin as a potential prophylactic target for stress-related mental health disorders.

neuroscience↗

bioRxiv2026

Ovarian hormonal state at exercise initiation interacts with nigrostriatal circuitry to determine long-term voluntary exercise behavior

Despite the well-established health benefits of exercise, adherence to physical activity remains low, highlighting the need to identify biological factors that regulate the initiation and persistence of exercise behavior. Here, we tested whether ovarian hormone state at the onset of voluntary wheel running (VWR) influences both immediate and long-term exercise behavior in female rats. Females that initiated VWR during proestrus (Pro) ran farther, spent more time running, and ran at higher speeds on the first day of wheel access than females initiating VWR outside of Pro. Remarkably, initiating VWR during Pro also produced persistent increases in running distance, duration, speed, and escalation across subsequent weeks, despite normal cycling through other estrous phases. In contrast, exogenous estradiol (E2) administered at VWR initiation did not alter day-1 behavior, but increased running distance and duration across subsequent weeks without affecting running speed or escalation. To determine whether dorsal striatal dopamine contributes to these effects, we inhibited the substantia nigra (SN) to dorsolateral striatum (DLS) pathway on the first day of VWR. This manipulation reduced the immediate and long-term effects of initiating VWR during Pro on running duration and distance but not speed or escalation. These findings identify behavioral initiation as a critical window during which hormones and nigrostriatal signaling influence future engagement in physical activity. Furthermore, analysis of individual components of VWR architecture reveals that distinct features of VWR behavior can be dissociated mechanistically and thus could be used to investigate separate motivational processes underlying physical activity.

neuroscience↗

bioRxiv2020

Altered polarization of PAR-2 signaling during airway epithelial remodeling

BackgroundProtease-activated receptor 2 (PAR-2) is activated by proteases involved in allergy and triggers airway epithelial secretion and inflammation. PAR-2 is normally expressed basolaterally in differentiated nasal ciliated cells. ObjectiveWe tested if epithelial remodeling during diseases characterized by loss of cilia and squamous metaplasia may alter PAR-2 polarization. MethodsEndogenous PAR-2 responses were measured by live cell calcium and cilia imaging, measurement of fluid secretion, and quantification of cytokines. We utilized airway squamous cell lines, primary differentiated air-liquid interface cultures, and tissue explants. Cells were exposed to disease-related modifiers that alter epithelial morphology, including IL-13, cigarette smoke condensate, and retinoic acid deficiency. We used concentrations and exposure times that altered epithelial morphology without causing breakdown of the epithelial barrier, likely reflecting early disease states. ResultsPAR-2 signaling in airway squamous cells activated calcium and inflammatory responses. Squamous cells cultured at air liquid interface (ALI) responded to PAR-2 agonists applied both apically and basolaterally. Primary well-differentiated nasal epithelial ALI cultures responded only to basolateral PAR-2 stimulation. Primary cultures exposed to IL-13, cigarette smoke condensate, or reduced retinoic acid responded to both apical and basolateral PAR-2 stimulation. Nasal polyp tissue, but not control middle turbinate, exhibited apical calcium responses to PAR-2 stimulation. However, isolated ciliated cells from both polyp and turbinate maintained basolateral PAR-2 polarization. ConclusionsSquamous metaplasia and/or loss of cilia enhances apical PAR-2 responses. Altered PAR-2 polarization in dedifferentiated or remodeled epithelia may contribute to increased sensitivity to inhaled protease allergens in inflammatory airway diseases.

physiology↗

bioRxiv2019

Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling

Bitter taste receptors (T2Rs) are GPCRs involved in detection of bitter compounds by type 2 taste cells of the tongue, but are also expressed in other tissues throughout the body, including the airways, gastrointestinal tract, and brain. These T2Rs can be activated by several bacterial products and regulate innate immune responses in several cell types. Expression of T2Rs has been demonstrated in immune cells like neutrophils; however, the molecular details of their signaling are unknown. We examined mechanisms of T2R signaling in primary human monocyte-derived unprimed (M0) macrophages (M{Phi}s) using live cell imaging techniques. Known bitter compounds and bacterial T2R agonists activated low-level calcium signals through a pertussis toxin (PTX)-sensitive, phospholipase C-dependent, and inositol trisphosphate receptor-dependent calcium release pathway. These calcium signals activated low-level nitric oxide (NO) production via endothelial and neuronal NO synthase (NOS) isoforms. NO production increased cellular cGMP and enhanced acute phagocytosis [~]3-fold over 30-60 min via protein kinase G. In parallel with calcium elevation, T2R activation lowered cAMP, also through a PTX-sensitive pathway. The cAMP decrease also contributed to enhanced phagocytosis. Moreover, a co-culture model with airway epithelial cells demonstrated that NO produced by epithelial cells can also acutely enhance M{Phi} phagocytosis. Together, these data define M{Phi} T2R signal transduction and support an immune recognition role for T2Rs in M{Phi} cell physiology.

physiology↗