Schaffer/Nishimura Lab

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    Data from: A pilot study investigating the effects of voluntary exercise on capillary stalling and cerebral blood flow in the APP/PS1 mouse model of Alzheimer’s disease
    Falkenhain, Kaja; Ruiz-Uribe, Nancy E.; Haft-Javaherian, Mohammad; Ali, Muhammad; Michelucci, Pietro E.; Schaffer, Chris B.; Bracko, Oliver (2020)
    Exercise exerts a beneficial effect on the major pathological and clinical symptoms associated with Alzheimer’s disease in humans and mouse models of the disease. While numerous mechanisms for such benefits from exercise have been proposed, a clear understanding of the causal links remains elusive. Recent studies also suggest that cerebral blood flow in the brain of both Alzheimer’s patients and mouse models of the disease is decreased and that the cognitive symptoms can be improved when blood flow is restored. We therefore hypothesized that the mitigating effect of exercise on the development and progression of Alzheimer’s disease may be mediated through an increase in the otherwise reduced brain blood flow. To test this idea, we examined the impact of three months of voluntary wheel running in ~1 year old APP/PS1 mice on short-term memory function, brain inflammation, amyloid deposition, and cerebral blood flow. Our findings that exercise led to improved memory function, a trend toward reduced brain inflammation, markedly increased neurogenesis in the dentate gyrus, and no changes in amyloid-beta deposits are consistent with other reports on the impact of exercise on the progression of Alzheimer’s related symptoms in mouse models. Notably, we did not observe any impact of wheel running on overall cortical blood flow nor on the incidence of non-flowing capillaries, the mechanism we recently identified as the cause of cerebral blood flow deficits in mouse models of Alzheimer’s disease. We did, however, note that running mice had, on average, slightly larger diameter capillaries in the cortex. Overall, our results replicate previous findings that exercise is able to ameliorate certain aspects of Alzheimer’s disease pathology, but show that this benefit does not appear to act though increases in cerebral blood flow. The dataset supports the findings of this study.
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    Data from: Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models
    Hernández, Jean C Cruz; Bracko, Oliver; Kersbergen, Calvin J; Muse, Victorine; Haft-Javaherian, Mohammad; Berg, Maxime; Park, Laibaik; Vinarcsik, Lindsay K; Ivasyk, Iryna; Rivera, Daniel A; Kang, Yiming; Cortes-Canteli, Marta; Peyrounette, Myriam; Doyeux, Vincent; Smith, Amy; Zhou, Joan; Otte, Gabriel; Beverly, Jeffrey D; Davenport, Elizabeth; Davit, Yohan; Lin, Charles P; Strickland, Sidney; Iadecola, Costantino; Lorthois, Sylvie; Nishimura, Nozomi; Schaffer, Chris B (2019)
    Cerebral blood flow (CBF) reductions in Alzheimer’s disease (AD) patients and related mouse models have been recognized for decades, but the underlying mechanisms and resulting consequences on AD pathogenesis remain poorly understood. In APP/PS1 and 5xFAD mice we found that an increased number of cortical capillaries had stalled blood flow as compared to wildtype animals, largely due to neutrophils that adhered in capillary segments and blocked blood flow. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to an immediate increase in CBF and to rapidly improved performance in spatial and working memory tasks. This study identified a novel cellular mechanism that explains the majority of the CBF reduction seen in two mouse models of AD and demonstrated that improving CBF rapidly improved short-term memory function. Restoring cerebral perfusion by preventing neutrophil adhesion may provide a novel strategy for improving cognition in AD patients. This dataset supports the above research and conclusions.
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    Data from: Deep convolutional neural networks for segmenting 3D in vivo multiphoton images of vasculature in Alzheimer disease mouse models
    Haft-Javaherian, Mohammad; Fang, Linjing; Muse, Victorine; Schaffer, Chris B; Nishimura, Nozomi; Sabuncu, Mert R (2018)
    The health and function of tissue rely on its vasculature network to provide reliable blood perfusion. Volumetric imaging approaches, such as multiphoton microscopy, are able to generate detailed 3D images of blood vessels that could contribute to our understanding of the role of vascular structure in normal physiology and in disease mechanisms. The segmentation of vessels, a core image analysis problem, is a bottleneck that has prevented the systematic comparison of 3D vascular architecture across experimental populations. We explored the use of convolutional neural networks to segment 3D vessels within volumetric in vivo images acquired by multiphoton microscopy. We evaluated different network architectures and machine learning techniques in the context of this segmentation problem. We show that our optimized convolutional neural network architecture, which we call DeepVess, yielded a segmentation accuracy that was better than both the current state-of-the-art and a trained human annotator, while also being orders of magnitude faster. To explore the effects of aging and Alzheimer's disease on capillaries, we applied DeepVess to 3D images of cortical blood vessels in young and old mouse models of Alzheimer's disease and wild type littermates. We found little difference in the distribution of capillary diameter or tortuosity between these groups, but did note a decrease in the number of longer capillary segments (>75μm) in aged animals as compared to young, in both wild type and Alzheimer's disease mouse models. These data support these findings.
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    Data from: In Vivo Calcium Imaging of Cardiomyocytes in the Beating Mouse Heart with Multiphoton Microscopy
    Jones, Jason Scott; Small, David Machin; Nishimura, Nozomi (2018-06-21)
    Background: Understanding the microscopic dynamics of the beating heart has been challenging due to the technical nature of imaging with micrometer resolution while the heart moves. The development of multiphoton microscopy has made in vivo, cell-resolved measurements of calcium dynamics and vascular function possible in motionless organs such as the brain. In heart, however, studies of in vivo interactions between cells and the native microenvironment are behind other organ systems. Our goal was to develop methods for intravital imaging of cardiac structural and calcium dynamics with microscopic resolution. Methods: Ventilated mice expressing GCaMP6f, a genetically-encoded calcium indicator, received a thoracotomy to provide optical access to the heart. Vasculature was labeled with an injection of dextran-labeled dye. The heart was partially stabilized by a titanium probe with a glass window. Images were acquired at 30 frames per second with spontaneous heartbeat and continuously-running, ventilated breathing. The data were reconstructed into three-dimensional volumes showing tissue structure, vasculature, and GCaMP6f signal in cardiomyocytes as a function of both the cardiac and respiratory cycle. Results: We demonstrated the capability to simultaneously measure calcium transients, vessel size, and tissue displacement in three dimensions with micrometer resolution. Reconstruction at various combinations of cardiac and respiratory phase enabled measurement of regional and single-cell cardiomyocyte calcium transients (GCaMP6f fluorescence). GCaMP6f fluorescence transients in individual, aberrantly-firing cardiomyocytes were also quantified. Comparisons of calcium dynamics (rise-time and tau) at varying positions within the ventricle wall showed no significant depth dependence. Conclusion: This method enables studies of coupling between contraction and excitation during physiological blood perfusion and breathing at high spatiotemporal resolution. These capabilities could lead to a new understanding of normal and disease function of cardiac cells.