BackgroundMicroglia can acquire various phenotypes of activation that mediate their inflammatory and neuroprotective effects. Aging causes microglia to become partially activated towards an inflammatory phenotype. As a result, aged animals display a prolonged neuroinflammatory response following an immune challenge. Currently unknown is whether this persistent neuroinflammation leads to greater reductions in hippocampal neurogenesis. Exercise has been shown to alter microglia activation in aged animals, but the nature of these changes has yet to be fully elucidated. The present study assessed whether aged mice show enhanced reductions in hippocampal neurogenesis following an acute immune challenge with lipopolysaccharide (LPS). Further, we assessed whether voluntary wheel running protects against the effects of LPS.MethodsAdult (4 months) and aged (22 months) male C57BL6/J mice were individually housed with or without a running wheel for a total of 9 weeks. After 5 weeks, mice received a single intraperitoneal LPS or saline injection in combination with four daily injections of bromodeoxyuridine (BrdU) to label dividing cells. Tissue was collected 4 weeks later and immunohistochemistry was conducted to measure new cell survival, new neuron numbers, and microglia activation.ResultsData show that LPS reduced the number of new neurons in aged, but not adult, mice. These LPS-induced reductions in neurogenesis in the aged mice were prevented by wheel running. Further, exercise increased the proportion of microglia co-labeled with brain-derived neurotrophic factor (BDNF) in the aged.ConclusionsCollectively, findings indicate that voluntary wheel running may promote a neuroprotective microglia phenotype and protect against inflammation-induced reductions in hippocampal neurogenesis in the aged brain.

SUMMARYDiffusion plays a prominent role in governing both rates of aerobic metabolic fluxes and mitochondrial organization in muscle fibers. However, there is no mechanism to explain how the non-homogeneous mitochondrial distributions that are prevalent in skeletal muscle arise. We propose that spatially variable degradation with dependence on O 2 concentration, and spatially uniform signals for biogenesis, can account for observed distributions of mitochondria in a diversity of skeletal muscle. We used light and transmission electron microscopy and stereology to examine fiber size, capillarity and mitochondrial distribution in fish red and white muscle, fish white muscle that undergoes extreme hypertrophic growth, and four fiber types in mouse muscle. The observed distributions were compared with those generated using a coupled reaction-diffusion/cellular automata (CA) mathematical model of mitochondrial function. Reaction-diffusion analysis of metabolites such as oxygen, ATP, ADP and PCr involved in energy metabolism and mitochondrial function were considered. Coupled to the reaction-diffusion approach was a CA approach governing mitochondrial life cycles in response to the metabolic state of the fiber. The model results were consistent with the experimental observations and showed higher mitochondrial densities near the capillaries because of the sometimes steep gradients in oxygen. The present study found that selective removal of mitochondria in the presence of low prevailing local oxygen concentrations is likely the primary factor dictating the spatial heterogeneity of mitochondria in a diversity of fibers. The model results also suggest decreased diffusional constraints corresponding to the heterogeneous mitochondrial distribution assessed using the effectiveness factor, defined as the ratio of the reaction rate in the system with finite rates of diffusion to that in the absence of any diffusion limitation. Thus, the non-uniform distribution benefits the muscle fiber by increasing the energy status and increasing sustainable metabolic rates.

SUMMARYThis study investigated the influence of fiber size on the distribution of nuclei and fiber growth patterns in white muscle of black sea bass, Centropristis striata, ranging in body mass from 0.45 to 4840g. Nuclei were counted in 1m optical sections using confocal microscopy of DAPI-and Acridine-Orange-stained muscle fibers. Mean fiber diameter increased from 36±0.87m in the 0.45g fish to 280±5.47m in the 1885g fish. Growth beyond 2000g triggered the recruitment of smaller fibers, thus significantly reducing mean fiber diameter. Nuclei in the smaller fibers were exclusively subsarcolemmal (SS), whereas in larger fibers nuclei were more numerous and included intermyofibrillar (IM) nuclei. There was a significant effect of body mass on nuclear domain size (F118.71, d.f.3, P<0.0001), which increased to a maximum in fish of medium size (282-1885g) and then decreased in large fish (>2000g). Although an increase in the number of nuclei during fiber growth can help preserve the myonuclear domain, the appearance of IM nuclei during hypertrophic growth seems to be aimed at maintaining short effective diffusion distances for nuclear substrates and products. If only SS nuclei were present throughout growth, the diffusion distance would increase in proportion to the radius of the fibers. These observations are consistent with the hypothesis that changes in nuclear distribution and fiber growth patterns are mechanisms for avoiding diffusion limitation during animal growth.

5-Bromo-2′-deoxyuridine (BrdU) is frequently used as a mitotic marker in studies of cell proliferation. Recent studies have reported cytotoxic effects of BrdU on neural progenitor cells in embryonic and neonatal brains in vivo and in adult tissue studied in vitro. The present study was conducted to assess whether BrdU interferes with cell proliferation and neuronal maturation in the rat adult hippocampus in vivo. BrdU effects across a wide range of doses (40 – 480 mg/kg) on cell proliferation and the population of immature neurons in the adult hippocampus were investigated using immunohistochemical labeling methods for the cell cycle marker Ki67 and a marker for immature neurons, doublecortin. BrdU did not influence cell proliferation in the dentate gyrus or the population of immature neurons observed in the adult hippocampus relative to those observed in saline treated controls. Thus, in contrast with reports of deleterious effects of BrdU in embryonic and neonatal tissue and adult tissue studied in vitro, BrdU does not appear to have cytotoxic effects on proliferating hippocampal cells or immature neurons in vivo in rats.