Biology subjects

Crockett, A. M.

Publications and source records attributed to Crockett, A. M..

4 recordsLinked to original sources

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

Neurovascular mitochondrial susceptibility impacts blood-brain barrier function and behavior

Maintenance of blood-brain barrier (BBB) integrity is critical to optimal brain function, and its impairment has been linked to multiple neurological disorders. A notable feature of the BBB is its elevated mitochondrial content compared to peripheral endothelial cells, although the functional implications of this phenomenon remain unknown. Here we studied BBB mitochondrial function in the context of the 22q11.2 deletion syndrome (22qDS), a condition associated with a highly increased risk for neuropsychiatric disease. As the 22q11.2 deletion includes 6 mitochondrial genes, and because we have previously identified BBB impairment in 22qDS, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction and impact behavior in this condition. We report mitochondrial impairment in human induced pluripotent stem cell (iPSC)-derived BBB endothelial cells from 22qDS patients, and in BBB endothelial cells from a mouse model of 22qDS. Remarkably, treatment to improve mitochondrial function attenuates mitochondrial deficits and enhances BBB function in both the iPSC and mouse 22qDS models. This treatment also corrected social memory in the mouse model, a deficit previously associated with BBB dysfunction. As BBB integrity correlated with social memory performance, together our findings suggest that mitochondrial dysfunction in the BBB influences barrier integrity and behavior in 22qDS.

neuroscience↗

bioRxiv2023

Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer's Disease

Several microglia-expressed genes have emerged as top risk variants for Alzheimers disease (AD). Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD-risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here we show that microglia form lipid droplets (LDs) upon exposure to amyloid-beta (A{beta}), and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. LD formation is dependent on age and disease progression and is prominent in the hippocampus in mice and humans. Despite differences in microglial LD load between brain regions and sexes in mice, LD-laden microglia exhibited a deficit in A{beta} phagocytosis. Unbiased lipidomic analysis identified a decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. DGAT2, a key enzyme for converting FFAs to TGs, promotes microglial LD formation and is increased in 5xFAD and human AD brains. Inhibition or degradation of DGAT2 improved microglial uptake of A{beta} and drastically reduced plaque load in 5xFAD mice, respectively. These findings identify a new lipid-mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.

neuroscience↗

bioRxiv2019

Disruption of the blood brain barrier in 22q11.2 deletion syndrome

Neuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia (SZ). As the blood brain barrier (BBB) is the immunological interface between the brain and the periphery, we investigated whether the BBB is intrinsically compromised in the most common genetic risk factor for SZ, the hemizygous deletion of chromosome 22q11.2 (22qDS). BBB-like endothelium (iBBB) differentiated from human 22qDS+SZ-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 (ICAM-1) was upregulated in 22qDS+SZ iBBB and 22qDS mice, indicating compromise of the BBB immune privilege. This immune imbalance resulted in increased migration/activation of leukocytes crossing the 22qDS+SZ iBBB. Finally, we found heightened astrocyte activation in murine and human 22qDS, suggesting that the BBB promotes astrocyte-mediated neuroinflammation. Overall, the barrier-promoting and immune privilege properties of the 22qDS BBB are compromised, and this might increase the risk for neuropsychiatric disease.

neuroscience↗