Metabolism and Physiology
Circadian rhythmicity has a profound effect on the physiological organization of multicellular organisms and, therefore, CCB places a significant emphasis upon an exploration of the biological clock to metabolism and physiology. This aspect of chronobiological research continues to be a growth area for biology and medicine as it is increasingly broadly recognized that important etiological and therapeutic connections exist between clock-based features of an organism and both its function in terms of sleep, mood, metabolism and aging as well as its pathologies such as cancer, cardiovascular disease, obesity, mental illness, and addiction.
At least 10% of the transcriptome, the total RNA in a cell, is expressed in a circadian fashion. As a consequence of the importance of biological rhythms to such a broad array of expressed genes, accurate phenotyping of a genetically altered organism requires consideration of circadian effects. Since the generation and phenotyping of mutants is an important element of many research programs concerned with metabolism, physiology, and disease models, the CCB is increasingly supporting the evaluation of potential circadian effects in genetically modified animals under study. CCB provides both logistical and intellectual leadership in broadening the study of circadian aspects to phenotyping. Currently, few researchers at UCSD have the capacity to gain access to animals around the clock, a minimal requirement to assess circadian organization of elements of the phenotype, or to alter lighting conditions, an often useful tool in assessment of possible circadian effects. Historically, the fundaments of circadian rhythmicity have not been a part of biological training and, thus, are not widely understood beyond specialists in chronobiology. Thus, one mission of the CCB is to assist the non-chronobiologist in incorporating a circadian dimension of phenotyping, where relevant. Accordingly, we are developing a core facility that would offer assistance with a) around the cycle sampling of tissues and other dependent measures; b) assessment of pacemaker function, if relevant; c) expertise in circadian analysis. Over time we expect to see ever-broadening collaborations with diverse faculty in biological and disease research as they seek to incorporate chronobiological tools into their investigations.
An early success story in the integration of chronobiological tools and concepts into broader physiological research lies in the study of reproduction at multiple levels of physiological organization. The Gonadotrophin releasing hormone (GnRH) neurons of the hypothalamus form a critical node in the regulation of the reproductive axis. These cells integrate seasonal information encoded by the circadian-driven melatonin rhythm, the metabolic state as reflected in peripheral fat depots, and the time of day as driven by circadian inputs received from the SCN, the principal mammalian pacemaker which is located just a few synapses away the GnRH neurons. In turn, GnRH cells sit atop the hypothalamic-pituitary-gonadal axis, which is involved in timing of puberty, estrous/menstrual rhythms, steroid secretion and behavior. GnRH cells additionally express a circahoral/ultradian pulsatile rhythm that is part and parcel of the regulatory mechanism. Despite its conceptual organization as a hierarchical axis, the reproductive mechanism is bidirectional such that feedback occurs at many levels. Gonadal steroids and proteins, for example, can exhibit strong negative and positive feedback on GnRH secretion.
Work at CCB is unraveling the chronobiological components of reproduction at multiple levels of physiological organization and abstraction. Clock genes play a critical role in regulating the secretory behavior of GnRH neuronal cells (Mellon). Therefore, the circadian rhythmicity intrinsic to these cells may very well be critical for fertility of the intact organism. At a somewhat higher level of physiologic organization, the hypothalamic neurocircuitry, circadian signals from the SCN and Kisspeptin1 cells regulate GnRH function, particularly as they relate to seasonality and development (Kauffman). Additionally, seasonal regulation by melatonin of reproductive physiology is being examined from an ontogenetic/life history (Gorman). This work assesses how pineal melatonin interacts with endogenous circannual processes to drive reproductive cycles in hamsters. At the organismal level, Parry is investigating the interrelation between reproductive hormones, mood, and circadian rhythmicity in women. With active research at so many levels, and growing recognition of the interplay between these different levels of physiological organization of rhythmicity in reproduction, this axis is ripe for further collaboration across levels of analysis. CCB looks forward to further elucidation of questions such as (1) how can the organization of the reproductive axis be better understood by bottom-up manipulations of clock function? (2) how do reproductive hormones feedback on circadian function? and (3) what roles do light and melatonin play in psychiatric conditions and in normal mood?
Metabolism, Cancer, Pain, and Other Systems
Building upon the demonstrated success of a multi-tiered exploration of circadian physiological regulation of reproduction, CCB is working to foster similar research schemes for the circadian regulation of metabolism and other areas. Working on nuclear receptors, which mediate effects of fat-soluble hormones and dietary lipids, Evans has demonstrated that at least half are rhythmic, a finding that affirms the centrality of circadian control but complicates the notion of a “basal metabolism.” Indeed, the nuclear receptor superfamily may be a critical component in the temporal coupling of brain and the periphery and interaction of reproduction and metabolism. CCB anticipates that extension of the logic of examining temporal expression patterns of genes and gene families, so profitably pioneered by Evans, Panda and Kay, will in time offer enhanced understanding of other systems of great physiological significance in support of cancer and pain research.