Background - Multiple Domain Screen - CCMS
CCMS as a preliminary screen for obesity: Neural origins of obesity - In the past, obesity was predominantly perceived as a metabolic disease. This view changed radically with the identification of the genes for the "big" five spontaneous single-gene mutations in mouse: ob, db (encoding leptin and receptor), Ay (agouti - antagonist of melanocortin stimulating receptors, MSH), fat (carboxypeptidase E), and tub (novel neuronal protein). A striking feature of these mutations is that they all act in the hypothalamus [43]. This suggests, at the least, that a significant subgroup of obesities arises from defects in the central regulation of energy homeostasis, and not simply from defects in metabolic pathways. In retrospect, this is hardly surprising considering the large number of neural systems involved in the control of feeding behavior and energy expenditure. Food intake is a behavior controlled primarily by inhibitory neural and humoral signals (e.g. msh, leptin, insulin) that lead to a cessation of ongoing ingestion, and a new meal is initiated when these signals diminish in the post-absorptive state. However, this behavior is modulated by a multitude of internal and external stimuli whose modes of action are not well understood. Control over feeding behavior rests within the CNS; the spinal cord and brainstem affect caloric homeostasis via the autonomic nervous system. The hypothalamus and the limbic system receive signals about the metabolic state of the body (e.g. quality of ingested food, gastric extension) and integrate this information with cortical information about such factors as taste, memory, and competing desires [44, 45].
CCMS as a tool for comprehensive characterization of mutants detected in other phenotypic domains - The CCMS also provides an efficient means of extending characterization of mutants detected in other phenotypic domains. This process will assist in classification of phenodeviants either by revealing potentially confounding deviations or by demonstrating that CCMS-monitored measures are normal. In addition, follow-up characterization using the CCMS may provide additional and/or more robust measures for use in subsequent heritability testing and/or mapping. The extensive quantitative profile provided by the CCMS will greatly enhance the value of identified mutants and increase the likelihood that mice will undergo further study.
Potential of CCMS as the initial core screen - Previous work and our preliminary data make us confident that CCMS will be an effective preliminary screen for deviations related to energy homeostasis and ingestive behavior. Additional evidence suggests that the CCMS may be an effective preliminary screen for other phenotypes, as will become evident with time and experience. However, one or more of the measures provided by the CCMS has been employed in CNS-related studies of addiction [70], multiple sclerosis [71], Down syndrome [40], and amyotrophic lateral sclerosis [72]. In addition, it seems likely that data collected by the CCMS will detect important non-neurological deviants (e.g. cardiac disease, [73] that will be directed to other mutagenesis centers.
