Mechanisms linking sleep loss, circadian disruption and metabolism in older mice

Brigham And Women'S Hospital, Boston MA

Investigators

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Abstract

Chronic sleep loss and circadian disruption can impair metabolic functions in humans, and both sleep and circadian rhythmicity are disrupted with aging. Furthermore, sleep loss itself often leads to disruptions of circadian rhythmicity, and disrupted circadian rhythmicity can induce sleep loss. In Project 3, we will use mouse models to dissociate these two influences so as to better understand their independent impacts on metabolism and to study the physiological and molecular mechanisms mediating those metabolic effects. Aim 1 will study the changes in feeding, body weight, plasma levels of various metabolic markers and glucose tolerance and insulin sensitivity (whole body and fat tissue) in young and older mice experiencing chronic sleep loss following genetic lesions of galaninergic (GAL) neurons in the ventrolateral preoptic area (VLPO). We will also assess corticosteroid secretion and sympathovagal balance in these mice in order to study the physiological mechanisms contributing to the changes in insulin sensitivity. Finally, in Aim 1, we will trace the specific projections of GAL and non-GAL neurons in the VLPO to determine which of these neurons have connections with sites involved in energy metabolism, corticosteroid section and sympathovagal balance. In Aim 2, we will study the same metabolic outcomes as in Aim 1 of recurrent circadian disruption (RCD) achieved by exposing C57 mice (young and older) to a 10:10 LD cycle for 12 weeks and investigating the effects of feeding periods synchronized with either body temperature (Tb) or locomotor activity (LMA) rhythms) in attenuating the adverse metabolic effects. To understand the molecular mechanisms underlying these changes, in Aim 3, we will study changes in the phase and amplitude of central and peripheral clocks and the downstream changes in gene expression (by histone deacetylase 3 ChlP-seq) they drive in the peripheral tissues when the transgenic PER2::LUC mice (both young and older) are maintained on a 10:10 LD cycle and on each of the 3 different feeding regimens as in Aim 2 (unrestricted access to food or feeding synchronized with their LD or Tb cycle).