Biology subjects

Hill, M. E.

Publications and source records attributed to Hill, M. E..

5 recordsLinked to original sources

bioRxiv2026

Chronic Stress Exacerbates Long-term Microvascular Network Dysfunction Following Brain Trauma

BackgroundPreexisting factors are among the strongest predictors of recovery following traumatic brain injury (TBI), with chronic stress closely associated with permanent disability and worse long-term outcomes. While chronic cerebrovascular dysfunction is linked to these poor trajectories, as impaired blood flow regulation drives secondary disease progression, the mechanisms regulating this vascular failure remain incompletely understood. Crucially, how premorbid chronic stress and TBI disrupt the fundamental coordination of the cerebrovascular network post-injury remains unknown. MethodsTo elucidate this coordination at rest and in response to increased neuronal activity, we used a model of three repeated moderate closed cortical impacts comorbid with chronic stress induced by social isolation (SI) post-weaning. Our previously developed vascular analysis pipeline (NOVAS3D) was employed to estimate changes in vascular radii across cerebrovasculature proximal to neuronal activation. Arteries and veins were annotated in the imaged volumes to allow for blood flow simulations. ResultsUsing graph-based network analysis, we demonstrate that TBI, when compounded with chronic stress, critically disrupts the long-range coordination of the capillary network. Specifically, the functional coordination of radius changes between nearby, non-adjacent capillaries was reduced by 40{+/-}20% in TBI+SI mice relative to controls. Consequently, simulations estimated that the vascular networks in TBI+SI mice experienced a 68{+/-}7% reduction in arterial red blood cell velocity (VRBC) responses to neuronal activation. These network-wide impairments were fundamentally driven by severely blunted vessel reactivity, including a 28{+/-}7% decrease in the magnitude of arteriolar dilations and a 47{+/-}7% decrease in the magnitude of arteriolar constrictions. ConclusionThese findings provide a mechanistic foundation for worse clinical outcomes seen in TBI patients with comorbid chronic stress, identifying arteriolar reactivity and long-range capillary coordination as critical therapeutic targets to mitigate secondary injury and improve long-term recovery.

neuroscience↗

bioRxiv2024

Unveiling the Structural Proteome of an Alzheimer's Disease Rat Brain Model

Studying native protein structures at near-atomic resolution in crowded environment presents a challenge. Consequently, understanding the structural intricacies of proteins within pathologically affected tissues often relies on mass spectrometry and proteomic analysis. In this study, we utilized electron cryomicroscopy (cryo-EM) and a specific method of analysis called Build and Retrieve (BaR) to investigate structural characteristics of protein complexes such as post-translational modification, active site occupancy, and arrested conformational state in Alzheimers Disease (AD) using brain lysate from a rat model (TgF344-AD) of the disease. Our findings reveal novel insights into the architecture of these complexes, which we corroborate through mass spectrometry analysis. Interestingly, it has been shown that the dysfunction of these protein complexes extends beyond AD, implicating them in cancer, as well as other neurodegenerative disorders such as Parkinsons disease, Huntingtons disease, and Schizophrenia. By elucidating the structural details of these complexes, our work not only enhances our understanding of disease pathology but also suggests new avenues for future approaches in therapeutic intervention.

biochemistry↗

bioRxiv2024

Early transatlantic movement of horses and donkeys at Jamestown

Domestic horses and donkeys played a key role in the initial colonization of the Atlantic seaboard of the Americas, a process partially chronicled by historical records. While Spanish colonists brought horses to the Caribbean and southern latitudes earlier, the transport of domestic horses to the English colony at Jamestown, Virginia in 1606 was among the first dispersals to the eastern seaboard. Archaeozoological analysis, isotope analysis, and radiocarbon dating of identifiable domestic equid remains from two contexts associated with the initial occupation of Jamestown demonstrate intense processing and consumption of the first Jamestown horses during the "Starving Time" winter of 1609, while paleopathological data show evidence of their use in transport. Osteological, genetic, and isotopic study of these equid remains reveal the presence of at least one adult domestic donkey with mixed European and West African ancestry, possibly supplied through undocumented exchange during a trans-Atlantic stopover. These results reveal the importance of equids in the survival of early European settlers and the global connectivity of early trans-Atlantic exchange in horses and donkeys, showing Caribbean and African links in the founding livestock populations and pointing towards an important and ecologically-anchored role for donkeys in the early colonial lifeways along the Eastern seaboard.

genetics↗

bioRxiv2024

Obesity differentially effects the somatosensory cortex and striatum of TgF344-AD rats

1Lifestyle choices leading to obesity, hypertension and diabetes in mid-life contribute directly to the risk of late-life Alzheimers disease (AD). However, in late-life or in late-stage AD conditions, obesity reduces the risk of AD and disease progression. To examine the mechanisms underlying this paradox, TgF344-AD rats were fed a varied high-carbohydrate, high-fat (HCHF) diet to induce obesity from nine months of age representing early stages of AD to twelve months of age in which rats exhibit the full spectrum of AD symptomology. We hypothesized regions primarily composed of gray matter, such as the somatosensory cortex (SSC), would be differentially affected compared to regions primarily composed of white matter, such as the striatum. We found increased myelin and oligodendrocytes in the somatosensory cortex of rats fed the HCHF diet with an absence of neuronal loss. We observed decreased inflammation in the somatosensory cortex despite increased AD pathology. Compared to the somatosensory cortex, the striatum had fewer changes. Overall, our results suggest that the interaction between diet and AD progression affects myelination in a brain region specific manner such that regions with a lower density of white matter are preferentially effected. Our results offer a possible mechanistic explanation for the obesity paradox.

neuroscience↗

bioRxiv2024

Obesity Facilitates Sex-Specific Improvement In Cognition And Neuronal Function In A Rat Model Of Alzheimer's Disease

Obesity reduces or increases the risk of developing Alzheimers disease (AD) depending on whether it is assessed in mid-life or late-life. There is currently no consensus on the relationship between obesity and AD or the mechanism or their interaction. Here, we aim to differentiate the cause-and-effect relationship between obesity and AD in a controlled rat model of AD. We induced obesity in 9-month-old TgF344-AD rats, that is pathology-load wise similar to early symptomatic phase of human AD. To more accurately model human obesity, we fed both TgF344-AD and non-transgenic littermates a varied high-carbohydrate-high-fat diet consisting of human food for 3 months. Obesity increased overall glucose metabolism and slowed cognitive decline in TgF344-AD rats, specifically executive function, without affecting non-transgenic rats. Pathological analyses of prefrontal cortex and hippocampus showed that obesity in TgF344-AD rats produced varied effects, with increased density of myelin and oligodendrocytes, lowered density and activation of microglia that we propose contributes to the cognitive improvement. However, obesity also decreased neuronal density, and promoted deposition of amyloid-beta plaques and tau inclusions. After 6 months on the high-carbohydrate-high-fat diet, detrimental effects on density of neurons, amyloid-beta plaques, and tau inclusions persisted while the beneficial effects on myelin, microglia, and cognitive functions remained albeit with a lower effect size. By examining the effect of sex, we found that both beneficial and detrimental effects of obesity were stronger in female TgF344-AD rats indicating that obesity during early symptomatic phase of AD is protective in females.

neuroscience↗