Biology subjects

Kenwood, M.

Publications and source records attributed to Kenwood, M..

7 recordsLinked to original sources

bioRxiv2026

Spatially resolved single-cell atlas reveals cortical glial reactivity associated with regions of neuronal growth programs in both hemispheres after stroke

Post-stroke recovery relies on structural remodeling of neuronal circuits in both the spared ipsilesional and contralesional cortices. RNA sequencing studies have identified distinct states of glial reactivity after stroke, but how these states are spatially organized at the single-cell level in relation to neuronal responses remains unknown. Consequently, it remains unclear which reactive states are lesion-restricted versus remote regions, such as the contralesional cortex, and how remote glial responses relate to the neuronal growth programs that support circuit repair. To address this, we used imaging-based subcellular spatial transcriptomics to profile ~650,000 cells across both hemispheres in male and female mice 7 days after cortical ischemic stroke, a critical timepoint for neuroplasticity. Reactive glial states differed significantly in their spatial organization from the lesion: scar-forming astrocytes and infiltrating pro-inflammatory myeloid cells were confined to the perilesional rim, whereas a reactive microglial state and a reactive astrocyte state extended into remote gray and white matter of the contralesional hemisphere. Mapping neuronal growth-associated gene expression across the entire cortex, we found substantial activation in both the perilesional and homotopic contralesional cortex, and these same regions showed significantly increased proportions of reactive microglia and astrocytes. Together, these findings identify spatially organized neuronal growth and glial activation states in both hemispheres after stroke and nominate regions for investigating spatial relationships between complex cell types and functional recovery.

neuroscience↗

bioRxiv2026

Stress-induced motivational impairment is marked by diminished frontocortical cellular communication and neuropeptide signaling

BackgroundRepeated stress is a risk factor for developing motivational deficits which are common across a variety of disease states including depression and are particularly resistant to treatment with conventional pharmacotherapies. Amotivation is multifaceted and can be caused by impairments in value learning, reward anticipation, and cost-benefit decision-making. Importantly, not all individuals who experience chronic stress develop motivational symptoms, suggesting there may be neurobiological signatures of resilience. MethodsWe developed a novel head-restrained effortful reinforcement task in which anticipatory and consummatory behavior can be tracked. Chronic non-discriminatory social defeat stress combined with behavioral analysis and spatially resolved RNA sequencing were used to determine the transcriptional signatures of stress in the anterior cingulate cortex of mice with varying levels of motivational impairment as well as unstressed controls. ResultsWhile stress led to a general impairment in effortful reward seeking, animals differed in the extent of behavioral deficit, with increased susceptibility marked by a unique set of differentially expressed genes within the anterior cingulate cortex (ACC). By leveraging the spatial component of our data, we were further able to identify altered interactions from inhibitory neurons and astrocytes to excitatory pyramidal cells, which correlated with intact or impaired motivated responding following stress exposure. ConclusionsChronic psychosocial stress results in divergent effects on motivated behavior and distinct ACC transcriptional signatures that are concentrated in excitatory pyramidal neurons. Cell interaction analysis implicates enhanced inhibitory neuropeptide signaling and reduced astrocytic contact signaling as upstream markers of motivational resilience and point toward ACC hyperexcitability as a targetable feature of stress susceptibility.

neuroscience↗

bioRxiv2026

CNS-resident B cells develop locally into a pro-inflammatory age-associated phenotype during aging and after stroke

Aging and age-related diseases like ischemic stroke induce chronic lymphocyte recruitment into the central nervous system (CNS). Conflicting effects on post-stroke functional recovery, however, are secondary to the differences in responding lymphocyte populations that shift immunophenotype with both ischemic injury and age. To better define CNS-localized B cell subsets, we used flow cytometry, single-cell RNA sequencing, and B cell receptor sequencing on B cells isolated from uninjured and post-stroke brains of aged male and female mice. We identified a novel B1b cell progenitor pool distinct from canonical pleural and peritoneal B1 niches. Trajectory analysis showed B1b progenitors transition into age-associated B cell (ABC) subsets, and clonal expansion of IgM+ ABCs (ABC/B1b) and plasma cells following ischemic stroke. We also confirmed analogous ABCs and developing B cell populations in post-mortem human parenchymal tissue isolated from aged brain donors. These studies reveal unique B cell populations that proliferate within the aging CNS and are associated with impaired post-stroke functional recovery in mice. Identification of inflammatory, CNS-resident ABC/B1b cells that are conserved across species is critical as they have the potential to be sequestered from peripheral immunotherapies and/or contribute to age-related neurodegenerative diseases.

neuroscience↗

bioRxiv2026

Shared Transcriptomic Signatures in Perilesional and Contralesional Cortex

Stroke induces a transient period of heightened plasticity during which functional recovery is most pronounced. Work in rodent models of stroke has identified key mechanisms in both the ipsilesional and contralesional cortex that contribute to functional and structural post-stroke plasticity. To date, most gene expression studies have focused on the infarct core and the immediately surrounding tissue, peri-lesional cortex (PLC). We sought to understand whether the contralesional cortex (CLC), a region that shows robust structural and molecular remodeling despite its distance from the lesion, mounts a distinct transcriptional response to stroke. Direct comparisons of molecular pathways governing these regions, particularly across sexes, are limited. To address this gap, we performed bulk RNA sequencing of the PLC and CLC at 7 days post-stroke, a critical time point for initiating repair, in male and female mice. Our results indicate that despite distinct positions from the lesion, both regions share a robust upregulation of inflammatory signaling, with Gene Ontology enrichment indicating activation of cytokine signaling, leukocyte activation, and gliogenesis pathways. Further analysis of this shared gene expression signature revealed reactive microglia signaling as the dominant pathway. Surprisingly, the CLC did not show a distinct transcriptional response. These findings were consistent across males and females, which also showed similar CLC-derived corticospinal tract axonal sprouting at 6 weeks post-stroke. Together, these findings support a shared microglia-centered neuroinflammatory transcriptional response in the PLC and CLC and suggest that microglial reactivity is a key early process for post-stroke cortical plasticity in both male and female mice.

neuroscience↗

bioRxiv2024

A novel epigenetic clock for rhesus macaques unveils an association between early life adversity and epigenetic age acceleration

Because DNA methylation changes reliably with age, machine learning models called epigenetic clocks can estimate an individuals age based on their DNA methylation profile. This epigenetic measure of age can deviate from ones true age, and the difference between the epigenetic age and true age, known as epigenetic age acceleration (EAA), has been found to directly correlate with morbidity and mortality in adults. Emerging evidence suggests that EAA is also associated with aberrant health outcomes in children, making epigenetic clocks useful tools for studying aging and development. We developed two highly accurate epigenetic clocks for the rhesus macaque, utilizing 1,008 blood samples from 690 macaques between 2 days and 23.4 years of age with diverse genetic backgrounds and exposure to environmental conditions. The first clock, which is trained on all samples, achieves a Pearson correlation between true age and predicted age of 0.983 and median absolute error of 0.210 years. To study phenotypes during development, the second clock is optimized for macaques younger than 6 years and achieves a Pearson correlation of 0.974 and a median absolute error of 0.148 years. Using the latter clock, we investigated whether epigenetic aging is affected by early life adversity in the form of infant maltreatment. Our data suggests that maltreatment and increased hair cortisol levels are associated with epigenetic age acceleration right after the period of maltreatment.

neuroscience↗

bioRxiv2024

SpinalTRAQ: A novel volumetric cervical spinal cord atlas identifies the corticospinal tract synaptic projectome in healthy and post-stroke mice

Abstract/SummaryDescending corticospinal tract (CST) connections to the neurons of the cervical spinal cord are vital for performance of forelimb-specific fine motor skills. In rodents, CST axons are almost entirely crossed at the level of the medullary decussation. While specific contralateral axon projections have been well-characterized using anatomic and molecular approaches, the field currently lacks a cohesive imaging modality allowing rapid quantitative assessment of the entire, bilateral cervical cord projectome at the level of individual laminae and cervical levels. This is potentially important as the CST is known to undergo marked structural remodeling in development, injury, and disease. We developed SpinalTRAQ (Spinal cord Tomographic Registration and Automated Quantification), a novel volumetric cervical spinal cord atlas and machine learning-driven microscopy acquisition and analysis pipeline that uses serial two-photon tomography-images to generate unbiased, region-specific quantification of the fluorescent pixels of anterograde AAV-labeled CST pre-synaptic terminals. In adult mice, the CST synaptic projectome densely innervates the contralateral hemicord, particularly in laminae 5 and 7, with sparse, monosynaptic input to motoneurons in lamina 9. Motor pools supplying axial musculature in the upper cervical cord are bilaterally innervated. The remainder of the ipsilateral cord has sparse labeling in a distinct distribution compared to the contralateral side. Following a focal stroke of the motor cortex, there is a complete loss of descending corticospinal axons from the injured side. Consistent with prior reports of axon collateralization, the CST spinal projectome increases at four weeks post-stroke and continues to elevate by six weeks post stroke. At six weeks post-stroke, we observed striking synapse formation in the denervated hemicord from the uninjured CST in a homotopic distribution. Additionally, CST synaptic reinnervation increases in the denervated lamina 9 in nearly all motoneuron pools, exhibiting novel patterns of connectivity. Detailed level- and lamina-specific quantification of the bilateral cervical spinal cord synaptic projectome reveals previously undescribed patterns of CST connectivity in health and injury-related plasticity.

neuroscience↗

bioRxiv2019

Integration of contours defined by second-order contrast-modulation of texture

AO_SCPCAPBSTRACTC_SCPCAPBoundaries in the visual world can be defined by changes in luminance and texture in the input image. A \"contour integration\" process joins together local changes into percepts of lines or edges. A previous study tested the integration of contours defined by second-order contrast-modulation. Their contours were placed in a background of random wavelets. Subjects performed near chance. We re-visited second-order contour integration with a different task. Subjects distinguished contours with \"good continuation\" from distractors. We measured thresholds in different amounts of external orientation or position noise. This gave two noise-masking functions. We also measured thresholds for contours with a baseline curvature to assess performance with more curvy targets. Our subjects were able to discriminate the good continuation of second-order contours. Thresholds were higher than for first-order contours. In our modelling, we found this was due to multiple factors. There was a doubling of equivalent internal noise between first- and second-order contour integration. There was also a reduction in efficiency. The efficiency difference was only significant in our orientation noise condition. For both first- and second-order stimuli, subjects were also able to perform our task with more curved contours. We conclude that humans can integrate second-order contours, even when they are curved. There is however reduced performance compared to first-order contours. We find both an impaired input to the integrating mechanism, and reduced efficiency seem responsible. Second-order contour integration may be more affected by the noise background used in the previous study. Difficulty segregating that background may explain their result.

neuroscience↗