Folk, C. | bioRxiv Science

bioRxiv2025

Sex-specific effects of chronic unpredictable stress on mitochondrial function in the HPA axis in mice

Stress, whether real or perceived, activates physiological and behavioral responses via the hypothalamic- pituitary-adrenal (HPA) axis and sympathetic nervous system activation. Under chronic stress, however, these adaptive responses become dysfunctional leading to pathological changes in behavior and health. Mitochondria are dynamic organelles essential for cellular energy production and for initiating glucocorticoid synthesis and release from adrenal glands during stress. Thus, mitochondria may represent a first line of response to environmental challenges. However, the effects of chronic stress on mitochondrial function within the HPA axis, particularly regarding sex differences, are unexplored. We exposed adult male and female C57BL6/J mice to four weeks of chronic unpredictable stress and examined behavioral and mitochondrial responses in the hypothalamus and adrenal glands - two key HPA axis regions. As previous reports indicated sex differences in stress responsivity, we hypothesized that chronic stress would differentially impact mitochondrial respiration within HPA axis regions in a sex-specific manner. Chronic stress increased avoidance behavior in males and passive coping behavior in females, indicating sex-specific behavioral responses. In females, stress significantly decreased mitochondrial respiration in both the hypothalamus and adrenal glands, while males were not significantly affected. In males, stress increased adrenal expression of mitochondrial complex II protein, which may have served a compensatory role to preserve mitochondrial function. Mitochondrial respiration significantly correlated with behavioral measures in stressed animals, highlighting a relationship between metabolism and stress-induced impairments. These findings reveal sex-specific metabolic adaptations to chronic stress and suggest that females may be more vulnerable to stress-induced mitochondrial dysfunction within the HPA axis. Clinical PerspectivesO_LIChronic stress is widely prevalent, associated with neuropsychiatric disease that affect women at a rate twice as high as men, and mediated by mitochondria, yet sex differences in the effects of chronic stress on mitochondrial function have not been characterized. C_LIO_LIDespite similar behavioral outcomes, chronic unpredictable stress exposure significantly decreases mitochondrial respiration only in the hypothalamus and adrenal glands from females, in association with stress-induced behavioral alterations. C_LIO_LIFemales may have increased vulnerability to metabolic effects of chronic stress and therapies targeting mitochondrial function may be more efficacious in preventing behavioral impacts of stress in females. C_LI

neuroscience↗

bioRxiv2018

Conceptual content in images triggers rapid shifts of covert attention

The visual system can use conceptual information to search for targets even in the absence of clear featural signifiers1, and visual saccades are often directed at target objects defined by conceptual content2. These abilities are a core component of our facility with the visual world. Here, we evaluate whether contingent mechanisms of visual attention, known to trigger in response to target features such as motion, color or luminance3, are also triggered by visual patterns that match conceptually specified categories. These pre-registered experiments provide convergent behavioral and electrophysiological support that covert spatial attention is rapidly triggered by natural image exemplars from superordinate conceptually described target sets such as dinner food or four-legged animal, even when each target was viewed only once. In the behavioral experiment when two targets were presented with onsets separated by only 167ms, subjects reported the second target more often when it was in the same spatial location as the first. In the EEG experiment, images elicited clear N2pc and P3 components only when they matched the conceptually specified target set. The latency of the N2pc peaked at roughly 250ms, which is comparable to that commonly found in other N2pc studies for simpler stimulus types. These results suggest that vision quickly decodes conceptual information from natural images and selectively deploys spatial attention to locations containing information that matches current search goals.

neuroscience↗