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The sensation of pain is associated with increased mortality, but it is unknown whether pain perception can directly affect aging. We find that mice lacking TRPV1 pain receptors are long-lived, displaying a youthful metabolic profile at old age. Loss of TRPV1 inactivates a calcium-signaling cascade that ends in the nuclear exclusion of the CREB-regulated transcriptional coactivator CRTC1 within pain sensory neurons originating from the spinal cord. In long-lived TRPV1 knockout mice, CRTC1 nuclear exclusion decreases production of the neuropeptide CGRP from sensory endings innervating the pancreatic islets, subsequently promoting insulin secretion and metabolic health. In contrast, CGRP homeostasis is disrupted with age in wild-type mice, resulting in metabolic decline. We show that pharmacologic inactivation of CGRP receptors in old wild-type animals can restore metabolic health. These data suggest that ablation of select pain sensory receptors or the inhibition of CGRP are associated with increased metabolic health and control longevity.

Yersinia pestis was introduced to North America around 1900 and leads to nearly 100% mortality in prairie dog ( Cynomys spp.) colonies during epizootic events, which suggests this pathogen may exert a strong selective force. We characterized genetic diversity at an MHC class II locus ( DRB1) in Gunnison's prairie dog ( C. gunnisoni) and quantified population genetic structure at the DRB1 versus 12 microsatellite loci in three large Arizona colonies. Two colonies, Seligman ( SE) and Espee Ranch ( ES), have experienced multiple plague-related die-offs in recent years, whereas plague has never been documented at Aubrey Valley ( AV). We found fairly low allelic diversity at the DRB1 locus, with one allele ( DRB1*01) at high frequency (0.67-0.87) in all colonies. Two other DRB1 alleles appear to be trans-species polymorphisms shared with the black-tailed prairie dog ( C. ludovicianus), indicating that these alleles have been maintained across evolutionary time frames. Estimates of genetic differentiation were generally lower at the MHC locus ( FST = 0.033) than at microsatellite markers ( FST = 0.098). The reduced differentiation at DRB1 may indicate that selection has been important for shaping variation at MHC loci, regardless of the presence or absence of plague in recent decades. However, genetic drift has probably also influenced the DRB1 locus because its level of differentiation was not different from that of microsatellites in an FST outlier analysis. We then compared specific MHC alleles to plague survivorship in 60 C. gunnisoni that had been experimentally infected with Y. pestis. We found that survival was greater in individuals that carried at least one copy of the most common allele ( DRB1*01) compared to those that did not (60% vs. 20%). Although the sample sizes of these two groups were unbalanced, this result suggests the possibility that this MHC class II locus, or a nearby linked gene, could play a role in plague survival. [ABSTRACT FROM AUTHOR]

The relationship among ammonia levels, cage-changing frequency, and bedding types is an important and potentially controversial topic in the laboratory animal science community. Some bedding options may not provide sufficient urine absorption and bacterial regulation to minimize ammonia production during the interval between cage changes. High intracage ammonia levels can cause subclinical degeneration and inflammation of nasal passages, rhinitis and olfactory epithelial necrosis in exposed mice. Here we sought to compare the effects of 4 commonly used bedding substrates (1/4-in. irradiated corncob, reclaimed wood pulp, aspen wood chips, and recycled newspaper) on ammonia generation when housing female C57BL/6 mice in static and individually ventilated caging. Intracage ammonia levels were measured daily for 1 wk (static cage experiment) or 2 wk (IVC experiment). The results of this study suggest that the corncob, aspen wood chip, and recycled newspaper beddings that we tested are suitable for once-weekly cage changing for static cages and for changing every 2 wk for IVC. However, ammonia levels were not controlled appropriately in cages containing reclaimed wood pulp bedding, and pathologic changes occurred within 1 wk in the nares of mice housed on this bedding in static cages.

Since the anthrax attacks of 2001, the emphasis on developing animal models of aerosolized select agent pathogens has increased. Many scientists believe that nonhuman primate models are the most appropriate to evaluate pulmonary response to, vaccines for, and treatments for select agents such as Yersinia pestis (Y. pestis), the causative agent of plague. A recent symposium concluded that the cynomolgus macaque (Macaca fascicularis) plague model should be characterized more fully. To date, a well-characterized cynomolgus macaque model of pneumonic plague using reproducible bioaerosols of viable Y. pestis has not been published. In the current study, methods for creating reproducible bioaerosols of viable Y. pestis strain CO92 (YpCO92) and pneumonic plague models were evaluated in 22 Indonesian-origin cynomolgus macaques. Five macaques exposed to doses lower than 250 CFU remained free of any indication of plague infection. Fifteen macaques developed fever, lethargy, and anorexia indicative of clinical plague. The 2 remaining macaques died without overt clinical signs but were plague-positive on culture and demonstrated pathology consistent with plague. The lethal dose of plague in humans is reputedly less than 100 organisms; in this study, 66 CFU was the dose at which half of the macaques developed fever and clinical signs (ED(50)), The Indonesian cynomolgus macaque reproduces many aspects of human pneumonic plague and likely will provide an excellent model for studies that require a macaque model.

Clostridium piliforme is an obligate intracellular bacterium that causes enterohepatic disease in many animal species. C. piliforme infections are commonly subclinical in laboratory rats and mice, and little is known about host regulation of disease or of the effects of C. piliforme infections on investigations that use subclinically infected animals. To assess host regulation of subclinical C. piliforme infections and the effects of those infections on laboratory mice, the expression of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) was evaluated at 0, 1, 3, 7, 14 and 28 days after inoculation with C. piliforme. Subclinical infection was induced in weanling C. piliforme-susceptible DBA/2 or -resistant C57BL/6 mice with either a toxic or a non-toxic C. piliforme strain. Hepatic lesions and bacteria were demonstrated histologically in both mouse strains for 14 days after inoculation with the toxigenic bacterial strain, but were never demonstrated histologically following inoculation with the non-toxigenic strain. Hepatic TNF-alpha and IFN-gamma mRNA and serum protein levels were similarly elevated in both mouse strains 1 day after inoculation with both C. piliforme strains, as evaluated by reverse transcription PCR and enzyme-linked immunosorbent assays, respectively. Elevation of IFN-gamma persisted for 14 days after inoculation; TNF-alpha remained elevated at 28 days after inoculation.