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The frequent occurrence of fatigue and disturbed sleep in cancer survivors and the negative effect of these symptoms on quality of life and clinical outcome underscore the need to identify mechanisms that cause cancer-related fatigue, with a view toward developing more effective treatments for this problem. Human studies of fatigue and disturbed sleep are limited by high interindividual genetic and environmental variability, difficulties with behavioral or reporting compliance, and the subjective nature of the problems. Although animal models also must overcome the barrier of assessing fatigue and sleep disturbance in the absence of obvious objective clinical markers, animal studies are easier to control and standardize than are studies of people. Moreover, animal models are crucial to the identification and understanding of underlying disease mechanisms. This review describes the need for, the feasibility of, and several possible approaches to measuring fatigue in animal models of cancer and to relating such measures to disturbed sleep, immune function, and other potential mechanisms. Developing and using animal models to better understand fatigue and disturbed sleep related to cancer and its treatment has an enormous potential to expand the knowledge base and foster hypotheses necessary for the future development and testing of interventions.

This review will examine how dopamine, a monoamine neurotransmitter, and adenosine, a neuromodulator, regulate behavioral activation, primarily as reflected by locomotor activity, in rodents. Complex interactions among 2 major types of adenosine receptors (A1AR and A2AAR) and 2 dopamine receptors (D1R and D2R) occur due to physical interactions that alter their ligand-binding properties and subsequent effects on common postreceptor signaling molecules. The output from these interactions in striatum modulates neurotransmission and subsequently influences spontaneous locomotor activity. Caffeine is a nonselective adenosine receptor antagonist that blocks 2 major types of adenosine receptors, A1AR and A2AAR, in the brain. Pharmacologic manipulation of these receptors with drugs such as caffeine offers potential therapeutic benefit for treatment of Parkinson disease.

A widely used in vivo technique in mice and other species is the surgical implantation of transmitters for telemetric monitoring of core body temperature, locomotor activity, and other variables. However, these devices are quite large relative to the size of the mouse abdomen. We report here on the results of several related studies that we conducted to evaluate refinement strategies relevant to implantation of abdominal devices in mice. First, we evaluated survival from surgery as a function of strain and body weight and found that both parameters influence the proportion of mice that survive. Second, we assessed the effect of several interventions on postsurgical recovery of food and water intakes, core temperature, and locomotor activity. Some of the interventions were associated with increased mortality (atipamezole) or were otherwise detrimental (the abdominal lubricant carboxymethylcellulose), whereas others had little or no effect on recovery (thermal support). These findings indicate that interventions presumed to promote recovery from surgery that are based on data from other species may not always have the anticipated positive effect in mice. This study therefore underscores the need to carefully assess the effect of modifications in experimental procedures to avoid causing unexpected complications in mice.

Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus (GHV) that causes acute infection and establishes life-long latency. EBV is associated with the development of B-cell lymphoproliferative disorders, several malignant cancers, the syndrome of infectious mononucleosis, and chronic interstitial lung disease. Although the molecular biology of EBV has been characterized extensively, the associated disease conditions and their pathogenesis are difficult to study in human populations because of variation in human environments and genetics, the well-documented effect of stressors on pathogenesis, and the chronic and latent properties of the virus. GHV are highly species-specific, and suitable animal models for EBV are not available. However, in 1980, a murine gammaherpesvirus (MuGHV, also known as MHV68 and gammaHV68) was identified as a natural pathogen of bank voles and wood mice. Experimental MuGHV infections in laboratory mice share many features of EBV infections in humans, including facets of the clinical human syndrome known as infectious mononucleosis. These features make MuGHV a valuable experimental model for studying the pathophysiology of a GHV in a natural host.

Fenbendazole is commonly used in laboratory animal medicine as an anthelmintic for elimination of pinworms. It is generally regarded as a safe drug with minimal side effects. In our facility, 2 breeding colonies of rats were treated with fenbendazole to eliminate pinworms. Analysis of the breeding records revealed that feeding Sprague-Dawley rats a diet containing fenbendazole on a continuous basis for 7 consecutive weeks was associated with a significant reduction in litter size. Although the mechanism underlying this effect is unknown, the finding prompts caution when using fenbendazole to treat valuable breeding colonies or strains that are poor breeders.

Surgical implantation of devices into the abdomen of PL/J mice was associated with fatal hemorrhage at 9 to 11 d after surgery. Coagulation profiles were evaluated to determine the underlying cause of this effect. The mean activated partial thromboplastin time (aPTT) of untreated PL/J mice was significantly higher than that of BALB/cByJ and C57BL/6J strains. The addition of human plasmas deficient in factors VIII, XI, or XII, prekallikrein, or high molecular-weight kininogen corrected the elevated aPTT of PL/J mice, but correction did not occur when factor IX-deficient human plasma was added. When compared to an assigned factor IX activity of 100% for pooled plasma from BALB/cByJ mice, C57BL/6J and PL/J mice revealed percent activities of 67% and 16%, respectively. PL/J mice could represent a new model for the study of pathogenesis and therapy of mild factor IX deficiency that is expressed and becomes clinically apparent secondary to major surgery.

Sleep-wake disturbances are common in epilepsy, yet the potential adverse effect of seizures on sleep is not well characterized. Genetically epilepsy-prone rats (GEPRs) are a well-studied model of genetic susceptibility to audiogenic seizures. To assess their suitability for investigating relationships between seizures and disordered sleep, we characterized the sleep, activity, and tempera ture patterns of 2 GEPR strains (designated 3 and 9) and Sprague-Dawley (SD) rats in the basal state, after forced wakefulness, and after exposure to sound-induced seizures at light onset and dark onset. Because of observed differences in rapid-eye-movement sleep (REMS), we also assessed serum levels of prolactin, which is implicated in REMS regulation. The data reveal that under basal conditions, the GEPR3 strain shows less SWS and REMS, higher core temperatures, and higher serum prolactin concentrations than do GEPR9 and SD strains. All 3 strains respond similarly to enforced sleep loss. Seizures induced at light onset delay the onset of SWS in both GEPR strains. Seizures induced at dark onset do not significantly alter sleep. Genotype assessment indicates that although both GEPR strains are inbred (that is, homozygous at 107 genetic markers), they differ from each other at 74 of 107 loci. Differences in basal sleep, temperature, and prolactin between GEPR3 and GEPR9 strains suggest different homeostatic regulation of these functions. Our detection of concurrent alterations in sleep, temperature, and prolactin in these 2 GEPR strains implicates the hypothalamus as a likely site for anatomic or physiologic variation in the control of these homeostatic processes.

Human patients with renal disease frequently develop disturbed sleep and severe fatigue. To develop a model for studying factors that contribute to these symptoms, we characterized the sleep patterns of various strains of mice after acute challenge with the fungal organism Candida albicans. After intravenous administration to mice, C. albicans typically colonizes the kidney, producing acute pyelonephritis. Various strains of inbred mice demonstrate marked variation in the temperature and sleep responses that develop after challenge, with individual strains generally showing increased or reduced somnolence in association with fever or hypothermia, respectively. C. albicans-infected mice may be a useful model for identifying the genes and mechanisms that link sleep, temperature, fatigue, and the immune response.

Persistent patent ductus arteriosus (PDA) and clinically silent PDAs are relatively common congenital cardiac defects in humans. We report here the occurrence of symptomatic PDA in adults from a colony of genetically epilepsy-prone rats (GEPRs). Affected rats displayed severe ventral edema. Echocardiography revealed PDA in several animals. Necropsy findings included cardiomegaly, hepatic hyperemia and centrilobular necrosis indicative of passive congestion, and vascular changes consistent with pulmonary hypertension. All affected rats were descendants of one of two brother-sister breeding pairs established from a single litter in April 2000. Clinically silent PDAs were also detected in the colony. Histological examination of the ligamentum arteriosus showed normal vascular tissue in asymptomatic GEPR and Sprague-Dawley rats. PDAs are likely to have a genetic component in the GEPR colony and may provide a novel model for the study of pathogenesis and therapy of this condition.

Hearing in laboratory animals is a topic that traditionally has been the domain of the auditory researcher. However, hearing loss and exposure to various environmental sounds can lead to changes in multiple organ systems, making what laboratory animals hear of consequence for researchers beyond those solely interested in hearing. For example, several inbred mouse strains commonly used in biomedical research (e.g., C57BL/6, DBA/2, and BALB/c) experience a genetically determined, progressive hearing loss that can lead to secondary changes in systems ranging from brain neurochemistry to social behavior. Both researchers and laboratory animal facility personnel should be aware of both strain and species differences in hearing in order to minimize potentially confounding variables in their research and to aid in the interpretation of data. Independent of genetic differences, acoustic noise levels in laboratory animal facilities can have considerable effects on the inhabitants. A large body of literature describes the nonauditory impact of noise on the biology and behavior of various strains and species of laboratory animals. The broad systemic effects of noise exposure include changes in endocrine and cardiovascular function, sleep-wake cycle disturbances, seizure susceptibility, and an array of behavioral changes. These changes are determined partly by species and strain; partly by noise intensity level, duration, predictability, and other characteristics of the sound; and partly by animal history and exposure context. This article reviews some of the basic strain and species differences in hearing and outlines how the acoustic environment affects different mammals.

The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.

This white paper by eighty members of the Complex Trait Consortium presents a community's view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?

Excess sleepiness, abnormal sleep patterns, non-restorative sleep, and fatigue are becoming increasingly pervasive in modern society. Identifying substances and mechanisms that modulate sleep and vigilance during health and disease is a critical prelude to eventual development of interventions to prevent or alleviate these disabling problems. A unified interdisciplinary approach that includes neurophysiology, neuroanatomy, neurochemistry, and molecular biology will promote elucidation of the complex biology of sleep. Integration of basic sleep physiology with modern genetic techniques will eventually lead to identification of specific genes and substances involved in regulation of various facets of sleep. The review presented here highlights recent progress in defining the anatomy and physiology of sleep-wake regulatory systems, delineating the role of homeostatic and circadian process in regulating sleep and wakefulness, and establishing the relationship of sleep and sleep disorders to other medical conditions. Particular emphasis is placed on reviewing the interactions between sleep, infectious challenge, and host defense response, and on identifying mechanisms that contribute to variation in sleep patterns among various strains of inbred mice.

Interactions between sleep and the immune system have been recognized for millennia. The lethargy and increased desire to sleep that accompany mild infections such as colds or "the flu" are common experiences. These experiences have fostered the belief that sleep promotes recovery from infectious challenge. Another common belief is that the lack of sleep increases susceptibility to infectious disease. However, despite these age-old and widespread beliefs, surprisingly little empirical evidence supports the hypotheses that increased sleep aids recovery from, and lack of sleep increases susceptibility to, infections. Although research conducted over the last 30 years has clearly demonstrated that sleep is altered during the course of infection, few experiments have directly tested the functional impact of sleep on responses to immune challenge. We will review relevant literature documenting that sleep patterns do indeed change during states of infectious disease, discuss potential mediators of these alterations in behavior, and finally address the issue of whether sleep or sleep loss impacts the ability of the host to mount an appropriate immune response.

Most neuroscience research is performed by using anesthetized animals or tissue samples obtained from animals that have been euthanatized. However, study of many important issues requires the use of animals that are alert and capable of engaging in behavior. Various methods have been used to humanely perform neuroscience experiments that involved unanesthetized animals. These techniques often involve surgical implantation of an apparatus that permits direct manipulation of brain tissue or measurement of neurochemicals or neuronal activity in conscious animals. We describe here common surgical techniques used to prepare animals for long-term neuroscience studies, discuss several issues related to short- and long-term postoperative care of animals with implants, and offer suggestions that veterinary and research personnel can use to prevent or mitigate some common problems that may develop when preparing and maintaining animals for these studies.