Biology subjects

Hollis, F.

Publications and source records attributed to Hollis, F..

6 recordsLinked to original sources

bioRxiv2026

Low testosterone promotes anxiety through astrocytic mitochondrial remodelling at the nucleus accumbens blood-brain barrier

Low testosterone is linked to anxiety in men, but its causal role and underlying brain mechanisms remain unknown. Here, using outbred male rats stratified by natural variation in anxiety-like behaviour, we establish its causal endocrine contribution and uncover an astrocytic mitochondrial mechanism at the nucleus accumbens (NAc) blood-brain barrier (BBB). High-anxiety rats showed a NAc-selective increase in BBB permeability, alongside reduced astrocytic endfoot coverage, disrupted endfoot mitochondrial organisation and mitochondria-endoplasmic reticulum contacts, and lower mitofusin 2 (Mfn2). Testosterone suppression increased anxiety in low-anxiety rats, whereas physiological testosterone restoration reduced anxiety, reconfigured astrocytic mitochondrial and BBB-related transcriptional programmes, increased astrocytic endfoot coverage and Mfn2, recovering BBB permeability, with related effects in aged low-testosterone rats. NAc androgen receptor (AR) knockdown blunted behavioural and neurovascular responses, whereas NAc astrocyte-specific Mfn2 overexpression reduced anxiety. Thus, testosterone-AR signalling engages an astrocytic mitochondrial programme at the NAc neurovascular interface linking low testosterone to anxiety vulnerability.

neuroscience↗

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↗

bioRxiv2024

Associations between prenatal distress, mitochondrial health, and gestational age: findings from two pregnancy studies in the USA and Turkey

ObjectiveThis study examined associations between mitochondrial markers--circulating cell-free mitochondrial DNA (cf-mtDNA) and Growth Differentiation Factor-15 (GDF15)--with maternal distress and pregnancy outcomes. MethodParticipants were drawn from two pregnancy studies, EPI (N=187, USA) and BABIP (N=198, Turkey). Plasma cf-mtDNA and GDF15 levels were quantified using qPCR and ELISA assays. ResultsPlasma cf-mtDNA levels did not significantly vary across pregnancy, while plasma GDF15 levels increased from early to late pregnancy and decreased postpartum. Late 2nd trimester plasma GDF15 was negatively correlated with pre-pregnancy BMI (p=0.035) and gestational age (p=0.0048) at birth. Early 2nd trimester maternal distress was associated with lower cf-mtDNA (p<0.05) and a trend for lower GDF15. Higher pre-pregnancy BMI and late-pregnancy maternal distress were linked to smaller postpartum GDF15 declines in EPI (p<0.05). ConclusionThis study reveals distinct plasma cf-mtDNA and GDF15 patterns during the perinatal period, linking mitochondrial markers to maternal distress and pregnancy outcomes.

physiology↗

bioRxiv2022

Gestational stress decreases postpartum mitochondrial respiration in the prefrontal cortex of female rats

Postpartum depression (PPD) is a major psychiatric complication of childbirth, affecting up to 20% of mothers, yet remains understudied. Mitochondria, dynamic organelles crucial for cell homeostasis and energy production, share links with many of the proposed mechanisms underlying PPD pathology. Brain mitochondrial function is affected by stress, a major risk factor for development of PPD, and is linked to anxiety-like and social behaviors. Considering the importance of mitochondria in regulating brain function and behavior, we hypothesized that mitochondrial dysfunction is associated with behavioral alterations in a chronic stress-induced rat model of PPD. Using a validated and translationally relevant chronic mild unpredictable stress paradigm during late gestation, we induced PPD-relevant behaviors in adult postpartum Wistar rats. In the mid-postpartum, we measured mitochondrial function in the prefrontal cortex (PFC) and nucleus accumbens (NAc) using high-resolution respirometry. We then measured protein expression of mitochondrial complex proteins and 4-hydroxynonenal (a marker of oxidative stress), and Th1/Th2 cytokine levels in PFC and plasma. We report novel findings that gestational stress decreased mitochondrial function in the PFC, but not the NAc of postpartum dams. However, in groups controlling for the effects of either stress or parity alone, no differences in mitochondrial respiration measured in either brain regions were observed compared to nulliparous controls. This decrease in PFC mitochondrial function in stressed dams was accompanied by negative behavioral consequences in the postpartum, complex-I specific deficits in protein expression, and increased Tumor Necrosis Factor alpha cytokine levels in plasma and PFC. Overall, we report an association between PFC mitochondrial respiration, PPD-relevant behaviors, and inflammation following gestational stress, highlighting a potential role for mitochondrial function in postpartum health.

neuroscience↗

bioRxiv2022

Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort

Emerging evidence is implicating mitochondrial function and metabolism in the nucleus accumbens in motivated performance. However, the brain is vulnerable to excessive oxidative insults resulting from neurometabolic processes and whether antioxidant levels in the nucleus accumbens contribute to motivated performance is not known. Here, we identify a critical role for glutathione (GSH), the most important endogenous antioxidant in the brain, in motivation. Using proton magnetic resonance spectroscopy (1H-MRS) at ultra-high field in both clinical and preclinical populations, we establish that higher accumbal GSH levels are highly predictive of better, and particularly steady performance over time in effort-related tasks. Causality was established in preclinical in vivo experiments that, first, showed that down-regulating GSH levels through micro-injections of the GSH synthesis inhibitor buthionine sulfoximine in the nucleus accumbens impaired effort-based reward-incentivized performance. In addition, systemic treatment with the GSH precursor N-acetyl-cysteine (NAC) increased accumbal GSH levels and led to improved performance, potentially mediated by a cell-type specific shift in glutamatergic inputs to accumbal medium spiny neurons. Our data indicate a close association between accumbal GSH levels and individuals capacity to exert reward-incentivized effort over time. They also suggest that improvement of accumbal antioxidant function may be a feasible approach to boost motivation.

neuroscience↗

bioRxiv2019

The glucocorticoid receptor in the nucleus accumbens plays a crucial role in social rank attainment in rodents

Social hierarchy in social species is usually established through competitive encounters with conspecifics. It determines the access to limited resources and, thus, leads to reduced fights among individuals within a group. Despite the known importance of social rank for health and well-being, the knowledge about the processes underlying rank attainment remains limited. Previous studies have highlighted the nucleus accumbens (NAc) as a key brain region in the attainment of social hierarchies in rodents. In addition, glucocorticoids and the glucocorticoid receptor (GR) have been implicated in the establishment of social hierarchies and social aversion. However, whether GR in the NAc is involved in social dominance is not yet known. To address this question, we first established that expression levels of GR in the NAc of high anxious, submissive-prone rats are lower than that of their low anxious, dominant-prone counterparts. Furthermore, virally-induced downregulation of GR expression in the NAc in rats led to an improvement of social dominance rank. We found a similar result in a cell-specific mouse model lacking GR in dopaminoceptive neurons (i.e., neurons containing dopamine receptors). Indeed, when cohabitating in dyads of mixed genotypes, mice deficient for GR in dopaminoceptive neurons had a higher probability to become dominant than wild-type mice. Overall, our results highlight GR in the NAc and in dopaminoceptive neurons as an important regulator of social rank attainment.

neuroscience↗