Biology subjects

Wellington, C. L.

Publications and source records attributed to Wellington, C. L..

4 recordsLinked to original sources

bioRxiv2026

Chronic trazodone treatment consolidates sleep, improves memory, and reduces amyloid pathology in a mouse model of Alzheimer's disease

Sleep disturbance in Alzheimers disease (AD), particularly the reduction of slow wave sleep (SWS), has been proposed as a novel therapeutic target, with disease-modifying potential. Trazodone, an antidepressant with robust SWS-promoting properties, is currently the most prescribed sleep-promoting medication in the United States. Here, we demonstrate that chronic trazodone administration consolidates sleep in the APPNL-F knock-in mouse model of AD, increasing NREM sleep duration and slow wave power during the rest phase while promoting wake during the active phase. These sleep consolidating effects were accompanied by lower regional glial activation and amyloid burden, particularly in male mice. Most notably, hippocampal amyloid plaque burden was 45% lower in mice treated from 14 to 16 months of age than in vehicle-treated controls. Chronic trazodone treatment was also associated with better short-term and long-term recognition memory. Together, these findings support the potential of repurposing trazodone as a well-tolerated, disease-modifying therapeutic for AD, capable of enhancing sleep quality, improving cognition, and lowering AD-relevant neuropathology.

neuroscience↗

bioRxiv2026

Repeated mild traumatic brain injury does not affect sleep or epileptiform activity one-month post-injury in a knock-in mouse model of Alzheimer's disease

Traumatic brain injuries (TBIs) are associated with increased risk of neurodegenerative disease, including Alzheimers disease (AD); however, the mechanisms by which TBI promotes AD pathogenesis remain poorly understood. It also remains unclear whether post-TBI sequelae, including sleep disturbances and seizures, play a role in driving disease progression. To investigate these relationships, we employed a translational approach using the Closed-Head Injury Model of Engineered Rotational Acceleration (CHIMERA) of repeated mild TBI (rmTBI) and an AD knock-in mouse model to assess sleep, power spectral density, epileptiform activity, and A{beta} pathology one month post-injury. RmTBI caused elevated neurofilament-light and glial fibrillary acidic protein, markers of neuronal damage. Sex differences were observed in acute injury outcomes, sleep measures, and A{beta} plaque size. Specifically, females exhibited longer recovery post-injury, higher mortality, decreased non-rapid eye movement sleep duration, and larger average plaque size than males at equivalent impact energy. These findings highlight the importance of including both sexes when establishing injury severity thresholds. Future studies should incorporate validated TBI biomarkers of neural injury to define equivalent injury parameters across sexes and examine the chronic effects of rmTBI on sleep, epileptiform activity and AD pathology.

neuroscience↗

bioRxiv2024

Age dictates brain functional connectivity and axonal integrity following repetitive mild traumatic brain injuries

Traumatic brain injuries (TBI) present a major public health challenge, demanding an in-depth understanding of age-specific signs and vulnerabilities. Aging not only significantly influences brain function and plasticity but also elevates the risk of hospitalizations and death following repetitive mild traumatic brain injuries (rmTBIs). In this study, we investigate the impact of age on brain network changes and white matter properties following rmTBI employing a multi-modal approach that integrates resting-state functional magnetic resonance imaging (rsfMRI), graph theory analysis, diffusion tensor imaging (DTI), and Neurite Orientation Dispersion and Density Imaging (NODDI). Utilizing the CHIMERA model, we conducted rmTBIs or sham (control) procedures on young (2.5-3 months old) and aged (22-month-old) male and female mice to model high risk groups. Functional and structural imaging unveiled age-related reductions in communication efficiency between brain regions, while injuries induced opposing effects on the small-world index across age groups, influencing network segregation. Functional connectivity analysis also identified alterations in 79 out of 148 brain regions by age, treatment (sham vs. rmTBI), or their interaction. Injuries exerted pronounced effects on sensory integration areas, including insular and motor cortices. Age-related disruptions in white matter integrity were observed, indicating alterations in various diffusion directions (mean, radial, axial diffusivity, fractional anisotropy) and density neurite properties (dispersion index, intracellular and isotropic volume fraction). Inflammation, assessed through Iba-1 and GFAP markers, correlated with higher dispersion in the optic tract, suggesting a neuroinflammatory response in aged animals. These findings provide a comprehensive understanding of the intricate interplay between age, injuries, and brain connectivity, shedding light on the long-term consequences of rmTBIs.

neuroscience↗

bioRxiv2022

Altered tau in rTg4510 mice after a single interfaced CHIMERA traumatic brain injury

Traumatic brain injury (TBI) in an established risk factor for neurodegenerative disease. In this report, we used the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA) to study the effects of a single moderate-severe TBI in rTg4510 mice, a mouse model of tauopathy. Fifteen male rTg4510 mice were impacted at 4.0J at 4-mo of age using interfaced CHIMERA and compared to sham controls. Immediately after injury, moderate-severe TBI induced significant mortality (7/15; 47%), and a prolonged duration of loss of righting reflex. At 2-mo post-injury, surviving mice displayed significant histological evidence of microgliosis (Iba1) and axonal injury (Neurosilver). Western blotting showed that TBI mice had a reduced p-GSK-3{beta} (S9):GSK-3{beta} ratio, suggesting greater tau kinase activity. However, tauopathy in surviving TBI mice showed a divergent response, with 3/8 mice having a very low level of tau protein in brain lysates (i.e. lower than sham), and were thus analyzed separately from the other 5/8 TBI mice that maintained the expected level of total tau. Compared to sham controls, TBI mice with normal tau levels had increased p-tau (PHF1 and AT8), increased autophagolysosome accumulation (p62 and Cathepsin D) and decreased hippocampal size. These findings were not observed in TBI mice with low total tau levels. These observations suggest that TBI leads to chronic white matter injury and altered GSK-3{beta} activity. However, post-injury tauopathy and autophagolysosome accumulation diverged in surviving mice through mechanisms that remain to be defined.

neuroscience↗