This preprint reports that forced peripheral elevation of the exercise-induced myokine irisin is sufficient to provide resistance to later stress-induced behavioral outcomes in mice. Irisin is cleaved from the transmembrane protein FNDC5 and released into circulation with physical activity. Although prior work linked irisin to improved cognition and neuroprotection, this study specifically tested whether peripheral irisin alone can protect animals from behavioral consequences of a subsequent adverse experience.
The authors emphasize that the work is a preprint and has not been certified by peer review. Conflict-of-interest disclosures related to patents and commercial activities involving irisin are reported in the source.
Adult male C57BL/6 mice received adeno-associated viral (AAV)-mediated peripheral delivery to express irisin or a GFP control. The AAV-irisin intervention produced a significant increase in circulating irisin levels as measured by the investigators. Behavioral testing occurred six weeks after AAV administration, providing a time window for sustained peripheral expression and elevated systemic irisin prior to stress exposure.
Six weeks after peripheral AAV delivery, mice were subjected to an inescapable stress paradigm that is well characterized to produce anxiety-like behavioral outcomes, including reductions in natural sociability. The primary behavioral finding reported is that mice with elevated circulating irisin did not exhibit the usual stress-induced reduction in social preference observed in control animals. Importantly, the change in social preference occurred without alterations in general locomotor activity, indicating that the effect was not attributable to gross motor differences.
Across individual animals, circulating irisin levels positively predicted measures of sociability. The authors report a positive correlation between the amount of circulating irisin and individual differences in social preference following stress exposure, suggesting a dose–response relationship in this dataset between peripheral irisin concentration and behavioral resilience.
Peripheral elevation of irisin was associated with increased expression of brain-derived neurotrophic factor (Bdnf). The study reports that Bdnf expression also positively correlated with circulating irisin levels across animals. Given prior literature implicating Bdnf in activity-dependent brain plasticity and stress resilience, the authors present increased Bdnf expression as a potential downstream molecular correlate of peripheral irisin’s behavioral effects.
The investigators identified expression of the putative irisin receptor subunit integrin alphaV within the dorsal raphe nucleus. The dorsal raphe is a key brain region implicated in the behavioral sequelae of inescapable stress and is modulated by prior exercise in other studies. The detection of integrin alphaV in this region supports a potential route by which circulating irisin could influence neural circuits involved in stress-related behaviors.
Taken together, the data reported in this preprint indicate that peripheral irisin is sufficient to confer behavioral resistance to future stress in mice, even in the absence of exercise. The authors link systemic irisin elevation to preserved sociability after inescapable stress, increased brain Bdnf, and the presence of a candidate receptor subunit in a relevant raphe nucleus.
Limitations that follow from the source content include that this is a preprint and has not undergone peer review; the report presents results from male C57BL/6 mice and does not, in the provided text, report data from females or other strains. The source does not provide additional mechanistic details beyond the correlations reported nor does it detail whether specific neuronal populations in the dorsal raphe are functionally modulated by circulating irisin. The source also discloses competing interests: one author holds a patent related to irisin and several authors have academic or commercial affiliations tied to companies developing therapeutics based on exercise-induced molecules.
Funding sources declared in the article include the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Alzheimer’s Association, the Cure Alzheimer’s Fund, and the Freedom Together Foundation, with specific grant numbers listed in the source.
These findings support a model in which a circulating exercise-induced myokine can act as a peripheral mediator of behavioral stress resistance, and they provide preclinical rationale for further mechanistic and translational work. Details on replication, sex differences, cellular mechanisms, long-term effects, and relevance to humans were not reported in the provided source material.