Disruption of circadian clocks has ramifications for metabolism, brain, and behavior

Circadian (daily) rhythms are present in almost all plants and animals. In mammals, a brain clock located in the hypothalamic suprachiasmatic nucleus maintains synchrony between environmental light/dark cycles and physiology and behavior. Over the past 100 y, especially with the advent of electric lighting, modern society has resulted in a round-the-clock lifestyle, in which natural connections between rest/activity cycles and environmental light/dark cycles have been degraded or even broken. Instances in which rapid changes to sleep patterns are necessary, such as transmeridian air travel, demonstrate negative effects of acute circadian disruption on physiology and behavior. However, the ramifications of chronic disruption of the circadian clock for mental and physical health are not yet fully understood. By housing mice in 20-h light/dark cycles, incongruous with their endogenous ∼24-h circadian period, we were able to model the effects of chronic circadian disruption noninvasively. Housing in these conditions results in accelerated weight gain and obesity, as well as changes in metabolic hormones. In the brain, circadian-disrupted mice exhibit a loss of dendritic length and decreased complexity of neurons in the prelimbic prefrontal cortex, a brain region important in executive function and emotional control. Disrupted animals show decreases in cognitive flexibility and changes in emotionality consistent with the changes seen in neural architecture. How our findings translate to humans living and working in chronic circadian disruption is unknown, but we believe that this model can provide a foundation to understand how environmental disruption of circadian rhythms impacts the brain, behavior, and physiology.

[1]  Yoshiyuki Sakaki,et al.  Circadian Rhythms in Isolated Brain Regions , 2002, The Journal of Neuroscience.

[2]  I. Weiner,et al.  The effects of excitotoxic lesion of the medial prefrontal cortex on latent inhibition, prepulse inhibition, food hoarding, elevated plus maze, active avoidance and locomotor activity in the rat , 1998, Neuroscience.

[3]  Y Sakaki,et al.  Resetting central and peripheral circadian oscillators in transgenic rats. , 2000, Science.

[4]  D. Bechtold,et al.  Circadian dysfunction in disease. , 2010, Trends in pharmacological sciences.

[5]  Rachel Leproult,et al.  Effects of poor and short sleep on glucose metabolism and obesity risk , 2009, Nature Reviews Endocrinology.

[6]  A. B. Reddy,et al.  A clockwork web: circadian timing in brain and periphery, in health and disease , 2003, Nature Reviews Neuroscience.

[7]  N. Sousa,et al.  Morphological Correlates of Corticosteroid-Induced Changes in Prefrontal Cortex-Dependent Behaviors , 2005, The Journal of Neuroscience.

[8]  Steven A. Brown,et al.  Resetting of circadian time in peripheral tissues by glucocorticoid signaling. , 2000, Science.

[9]  B. Kolb,et al.  Do rats have a prefrontal cortex? , 2003, Behavioural Brain Research.

[10]  F. Turek From circadian rhythms to clock genes in depression , 2007 .

[11]  Till Roenneberg,et al.  Circadian clocks — the fall and rise of physiology , 2005, Nature Reviews Molecular Cell Biology.

[12]  A. Convit Links between cognitive impairment in insulin resistance: An explanatory model , 2005, Neurobiology of Aging.

[13]  F. Scheer,et al.  SCN Outputs and the Hypothalamic Balance of Life , 2006, Journal of biological rhythms.

[14]  F. Scheer,et al.  Adverse metabolic and cardiovascular consequences of circadian misalignment , 2009, Proceedings of the National Academy of Sciences.

[15]  V. Brown,et al.  Rodent models of prefrontal cortical function , 2002, Trends in Neurosciences.

[16]  F. Lert,et al.  Prevalence of overweight and weight gain in relation to night work in a nurses' cohort. , 1996, International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity.

[17]  M. Straume,et al.  Disturbed Diurnal Rhythm Alters Gene Expression and Exacerbates Cardiovascular Disease With Rescue by Resynchronization , 2007, Hypertension.

[18]  A. Kalsbeek,et al.  The biological clock tunes the organs of the body: timing by hormones and the autonomic nervous system. , 2003, The Journal of endocrinology.

[19]  J. Harvey Leptin regulation of neuronal excitability and cognitive function , 2007, Current opinion in pharmacology.

[20]  P. Moult,et al.  Hormonal regulation of hippocampal dendritic morphology and synaptic plasticity , 2008, Cell adhesion & migration.

[21]  Steven L. Cohen,et al.  Weight-reducing effects of the plasma protein encoded by the obese gene. , 1995, Science.

[22]  Douglas B. Ehlenberger,et al.  Rayburst sampling, an algorithm for automated three-dimensional shape analysis from laser scanning microscopy images , 2006, Nature Protocols.

[23]  M. Ralph,et al.  The Significance of Circadian Organization for Longevity in the Golden Hamster , 1998, Journal of biological rhythms.

[24]  A. Convit,et al.  Diabetes, sugar-coated but harmful to the brain. , 2007, Current opinion in pharmacology.

[25]  E. van Cauter,et al.  Metabolic consequences of sleep and sleep loss. , 2008, Sleep medicine.

[26]  M. Menaker,et al.  Chronic jet-lag increases mortality in aged mice , 2006, Current Biology.

[27]  Douglas B. Ehlenberger,et al.  Automated Three-Dimensional Detection and Shape Classification of Dendritic Spines from Fluorescence Microscopy Images , 2008, PloS one.

[28]  B. McEwen Protective and damaging effects of stress mediators: central role of the brain , 2006, Dialogues in clinical neuroscience.

[29]  J. D. Bruin,et al.  A behavioural analysis of rats with damage to the medial prefrontal cortex using the morris water maze: evidence for behavioural flexibility, but not for impaired spatial navigation , 1994, Brain Research.

[30]  E. Miller,et al.  An integrative theory of prefrontal cortex function. , 2001, Annual review of neuroscience.

[31]  C. Strader,et al.  Diet-induced obese mice develop peripheral, but not central, resistance to leptin. , 1997, The Journal of clinical investigation.

[32]  T. Kido,et al.  A Longitudinal Study on the Effect of Shift Work on Weight Gain in Male Japanese Workers , 2008, Obesity.

[33]  Kwangwook Cho,et al.  Chronic 'jet lag' produces temporal lobe atrophy and spatial cognitive deficits , 2001, Nature Neuroscience.

[34]  E. van Cauter,et al.  Depression: A Disorder of Timekeeping? , 2015, Perspectives in biology and medicine.

[35]  J. Feldon,et al.  Effect of excitotoxic lesions of rat medial prefrontal cortex on spatial memory , 2002, Behavioural Brain Research.

[36]  R. Silver,et al.  Minireview: The neuroendocrinology of the suprachiasmatic nucleus as a conductor of body time in mammals. , 2007, Endocrinology.

[37]  J. Morrison,et al.  Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress , 2005, Experimental Neurology.

[38]  Fred W. Turek,et al.  Obesity and Metabolic Syndrome in Circadian Clock Mutant Mice , 2005, Science.

[39]  A. Holmes,et al.  Stress-induced prefrontal reorganization and executive dysfunction in rodents , 2009, Neuroscience & Biobehavioral Reviews.

[40]  F. Scheer,et al.  Environmental light and suprachiasmatic nucleus interact in the regulation of body temperature , 2005, Neuroscience.

[41]  A. Irving,et al.  Leptin promotes rapid dynamic changes in hippocampal dendritic morphology , 2007, Molecular and Cellular Neuroscience.