Ananya Swaroop, Jodi R Paul, Laura J McMeekin, Ashley M Barnett, Alana M Colafrancesco, Drèson L Russell, Camille M Smith, Micah S Simmons, Laura A Volpicelli-Daley, Rita M Cowell, Karen L Gamble
{"title":"The molecular clock drives motivated locomotion and time-of-day-dependent firing patterns in mouse dopaminergic neurons.","authors":"Ananya Swaroop, Jodi R Paul, Laura J McMeekin, Ashley M Barnett, Alana M Colafrancesco, Drèson L Russell, Camille M Smith, Micah S Simmons, Laura A Volpicelli-Daley, Rita M Cowell, Karen L Gamble","doi":"10.1038/s44323-025-00044-2","DOIUrl":"10.1038/s44323-025-00044-2","url":null,"abstract":"<p><p>Though circadian locomotor rhythms are primarily driven by the suprachiasmatic nucleus, voluntary motor behavior also requires dopaminergic neuron (DAN) activity. However, it is unknown whether DAN molecular and electrophysiological properties and rhythmic motor behaviors are dependent on a molecular clock. Here, we show substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) DANs rhythmically express clock genes, and conditional deletion of <i>Bmal1</i> in DANs reduces motivated locomotion without robust cell loss or gross motor impairment. Further, DAN <i>Bmal1</i> conditional deletion disrupts 24-h rhythms in spike rate, revealing ultradian rhythms (~4-8 h). Lastly, SNc DAN bursting varies across time of day and increased early night bursting is dependent on the molecular clock and L-type calcium channel activation. Collectively, we provide evidence of a cell-intrinsic dopaminergic clock which regulates key behaviors and physiology. Future studies should consider the contribution of disrupted DAN molecular clocks in age-related motor diseases like Parkinson's Disease.</p>","PeriodicalId":501704,"journal":{"name":"npj Biological Timing and Sleep","volume":"2 1","pages":"28"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Varun Mandi, Haley Miller, Jeongkyung Lee, Young-Hwa Goo, Mousumi Moulik, Ke Ma, Antoni Paul, Vijay K Yechoor, Mariana G Figueiro
{"title":"Modulating light level patterns reduces rest/activity disruption associated with shiftwork.","authors":"Varun Mandi, Haley Miller, Jeongkyung Lee, Young-Hwa Goo, Mousumi Moulik, Ke Ma, Antoni Paul, Vijay K Yechoor, Mariana G Figueiro","doi":"10.1038/s44323-025-00043-3","DOIUrl":"10.1038/s44323-025-00043-3","url":null,"abstract":"<p><p>Long-term exposure to nonstandard work schedules can result in circadian misalignment, which has been linked to a series of maladies. To test whether modulating light patterns reduces shiftwork-induced rest/activity disruptions, 30 male C57BL/6 J mice individually housed in cages outfitted with running wheels were exposed to 6 simulated shiftwork light interventions. Mice experiencing high light levels during shiftwork exhibited a significant decrease in activity compared to low light levels during shiftwork and a conventional 12 L:12D condition, indicating circadian misalignment. In contrast, mice experiencing shiftwork in darkness combined with either modulated evening light pulses or circadian blind, vision-permissive light showed similar levels of rest/activity compared to a 12 L:12D condition, with phasor analysis indicating that their 24-h circadian rest/activity patterns were not misaligned. The results show that exposure to light that permits visibility but is below activation of the circadian system during shiftwork can prevent circadian misalignment.</p>","PeriodicalId":501704,"journal":{"name":"npj Biological Timing and Sleep","volume":"2 1","pages":"27"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Biological rhythms: Living your life, one half-day at a time.","authors":"Patrick Emery, Frédéric Gachon","doi":"10.1038/s44323-025-00037-1","DOIUrl":"10.1038/s44323-025-00037-1","url":null,"abstract":"<p><p>Circadian rhythms play a preeminent role in our life, organizing our physiology and behavior on a daily basis to resonate with our fluctuating environment. However, recent studies reveal that hundreds of mouse and human genes are expressed with a 12-h pattern. We take a close look at mammalian 12-h rhythms, their potential mechanisms and functions, and evidence linking them to circatidal rhythms, which enable marine animals to adapt to tides.</p>","PeriodicalId":501704,"journal":{"name":"npj Biological Timing and Sleep","volume":"2 1","pages":"21"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The complexity and commonness of the two-process model of sleep regulation from a mathematical perspective.","authors":"Anne C Skeldon, Derk-Jan Dijk","doi":"10.1038/s44323-025-00039-z","DOIUrl":"10.1038/s44323-025-00039-z","url":null,"abstract":"<p><p>The two-process model (2pm) of sleep regulation is a conceptual framework and consists of mathematical equations. It shares similarities with models for cardiac, respiratory and neuronal rhythms and falls within the wider class of coupled oscillator models. The 2pm is related to neuronal mutual inhibition models of sleep-wake regulation. The mathematical structure of the 2pm, in which the sleep-wake cycle is entrained to the circadian pacemaker, explains sleep patterns in the absence of 24 h time cues, in different species and in early childhood. Extending the 2pm with a process describing the response of the circadian pacemaker to light creates a hierarchical entrainment system with feedback which permits quantitative modelling of the effect of self-selected light on sleep and circadian timing. The extended 2pm provides new interpretations of sleep phenotypes and provides quantitative predictions of effects of sleep and light interventions to support sleep and circadian alignment in individuals, including those with neurodegenerative disorders.</p>","PeriodicalId":501704,"journal":{"name":"npj Biological Timing and Sleep","volume":"2 1","pages":"24"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Revisiting brain gene expression changes and protein modifications tracking homeostatic sleep pressure.","authors":"Valérie Mongrain, Marcos G Frank, Tanya Leduc","doi":"10.1038/s44323-025-00045-1","DOIUrl":"10.1038/s44323-025-00045-1","url":null,"abstract":"<p><p>This review describes how transcriptomic/proteomic studies have contributed identifying molecular markers of sleep homeostasis and offers a perspective on the need to interrogate more comprehensively different dynamics, brain regions, and cell types. Modifications in molecular dynamics with development/aging are also emphasized. We suggest the concept of sleep homeostasis to be regarded as a variety of homeostats (not a single one) serving different functions for the brain across the lifespan.</p>","PeriodicalId":501704,"journal":{"name":"npj Biological Timing and Sleep","volume":"2 1","pages":"30"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144796533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chantal Sharples, Zoe Grace McFarlane, Maria Fernandes Pinheiro, Matthew Alan Jones
{"title":"Integrating temperature into the Arabidopsis circadian system.","authors":"Chantal Sharples, Zoe Grace McFarlane, Maria Fernandes Pinheiro, Matthew Alan Jones","doi":"10.1038/s44323-025-00055-z","DOIUrl":"10.1038/s44323-025-00055-z","url":null,"abstract":"<p><p>This review discusses how temperature signals are integrated into the Arabidopsis circadian clock and proposes Temperature-Dependent Alternative Splicing (TDAS) of core clock genes as an additional mechanism to adapt the circadian system to temperature changes. We present examples of TDAS in a range of organisms, pointing towards a conserved mechanism that enables temperature adaptation.</p>","PeriodicalId":501704,"journal":{"name":"npj Biological Timing and Sleep","volume":"2 1","pages":"35"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Harnessing the circadian nature of the choroid plexus and cerebrospinal fluid.","authors":"Ryann M Fame","doi":"10.1038/s44323-025-00033-5","DOIUrl":"10.1038/s44323-025-00033-5","url":null,"abstract":"<p><p>Cerebrospinal fluid (CSF) exchanges with the central nervous system's immediate environment and interfaces with systemic circulation at the blood-CSF barrier. CSF composition reflects brain states, contributes to brain health and disease, is modulated by circadian rhythms and behaviors, and turns over multiple times per day, enabling rapid signal relay. Mechanisms of how CSF elements change over circadian time and influence function can be harnessed for diagnostic biomarkers and therapeutic intervention.</p>","PeriodicalId":501704,"journal":{"name":"npj Biological Timing and Sleep","volume":"2 1","pages":"19"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Chronic circadian disruption alters cardiac function and glucose regulation in mice.","authors":"Jenna E J Gearey, Melinda Wang, Michael C Antle","doi":"10.1038/s44323-025-00032-6","DOIUrl":"https://doi.org/10.1038/s44323-025-00032-6","url":null,"abstract":"<p><p>Cardiometabolic disease is a leading cause of death worldwide. One factor that may contribute to the risk, onset, and severity of symptoms is disrupted circadian rhythms. Our study uses two strains of mice to further elucidate this relationship: healthy controls, and a mouse model of insulin resistance with short freerunning periods (~ 22.75 h) and enlarged hearts, raised in either a 24-h or 22.75-h LD cycle. Through glucose and insulin tolerance tests, routine electrocardiograms from one to four months old, and histology, we reveal worse cardiometabolic health outcomes for mice gestated and housed in a mismatched LD cycle compared to those in an LD cycle that matches their endogenous rhythm. This was characterized by heightened blood glucose levels following a glucose or insulin bolus, altered electrophysiological parameters of the cardiac waveform, and increased cardiomyocyte size. Circadian disruption due to work/social schedules or circadian-related disorders in people is often confounded with other unhealthy lifestyles. The present study demonstrates that circadian disruption on its own can lead to adverse health states.</p>","PeriodicalId":501704,"journal":{"name":"npj Biological Timing and Sleep","volume":"2 1","pages":"18"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12074981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matt Spick, Cheryl M Isherwood, Lee A Gethings, Christopher J Hughes, Matthew E Daly, Hana Hassanin, Daan R van der Veen, Debra J Skene, Jonathan D Johnston
{"title":"Challenges and opportunities for statistical power and biomarker identification arising from rhythmic variation in proteomics.","authors":"Matt Spick, Cheryl M Isherwood, Lee A Gethings, Christopher J Hughes, Matthew E Daly, Hana Hassanin, Daan R van der Veen, Debra J Skene, Jonathan D Johnston","doi":"10.1038/s44323-024-00020-2","DOIUrl":"10.1038/s44323-024-00020-2","url":null,"abstract":"<p><p>Time-of-day variation in the molecular profile of biofluids and tissues is a well-described phenomenon, but-especially for proteomics-is rarely considered in terms of the challenges this presents to reproducible biomarker identification. We provide a case study analysis of human circadian and ultradian rhythmicity in proteins, including in the complement and coagulation cascades and apolipoproteins, with PLG, CFAH, ZA2G and ITIH2 demonstrated as rhythmic for the first time. We also show that rhythmicity increases the risk of Type II errors due to the reduction in statistical power from increased variance, and that controlling for rhythmic time-of-day variation improves statistical power and reduces the chances of Type II errors. We recommend that best practice in proteomics study design should account for temporal variation and that time of sampling be reported as part of study metadata. These simple steps can mitigate against both false and missed discoveries, as well as improving reproducibility.</p>","PeriodicalId":501704,"journal":{"name":"npj Biological Timing and Sleep","volume":"2 1","pages":"3"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joshua B Benoit, Joy Bose, Oluwaseun M Ajayi, Ashley Webster, Karl Grieshop, David Lewis, Hailie Talbott, Michal Polak
{"title":"Shifted levels of sleep and activity during the night as mechanisms underlying ectoparasite resistance.","authors":"Joshua B Benoit, Joy Bose, Oluwaseun M Ajayi, Ashley Webster, Karl Grieshop, David Lewis, Hailie Talbott, Michal Polak","doi":"10.1038/s44323-025-00031-7","DOIUrl":"10.1038/s44323-025-00031-7","url":null,"abstract":"<p><p>Parasites harm host fitness and are pervasive agents of natural selection capable of driving the evolution of host resistance traits. Previously we demonstrated evolutionary responses to artificial selection for increasing behavioral immunity to <i>Gamasodes queenslandicus</i> mites for <i>Drosophila melanogaster</i>. Here, we report transcriptional shifts in metabolic processes due to selection for mite resistance. We also show decreased starvation resistance and increased use of nutrient reserves in flies from mite-resistant lines. Resistant lines exhibited increased activity, reduced sleep, and elevated oxygen consumption during the night. Using a panel of <i>D. melanogaster</i> lines exhibiting variable sleep durations, we found a positive correlation between mite resistance and reduced sleep. Restraining the activity of artificially selected mite-resistant flies during exposure to parasites reduced their resistance advantage relative to control flies. The results suggest that ectoparasite resistance in this system involves increased activity during the scotophase and metabolic gene expression at the expense of starvation resistance.</p>","PeriodicalId":501704,"journal":{"name":"npj Biological Timing and Sleep","volume":"2 1","pages":"15"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}