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Substance use disorder is a major global health concern, with a high prevalence among adolescents and young adults. The most common substances of abuse include alcohol, marijuana, cocaine, nicotine, and opiates. Evidence suggests that a mismatch between contemporary lifestyle and environmental demands leads to disrupted circadian rhythms that impair optimal physiological and behavioral function, which can increase the vulnerability to develop substance use disorder and related problems. The circadian system plays an important role in regulating the sleep–wake cycle and reward processing, both of which directly affect substance abuse. Distorted substance use can have a reciprocal effect on the circadian system by influencing circadian clock gene expression. Considering the detrimental health consequences and profound societal impact of substance use disorder, it is crucial to comprehend its complex association with circadian rhythms, which can pave the way for the generation of novel chronotherapeutic treatment approaches. In this narrative review, we have explored the potential contributions of disrupted circadian rhythms and sleep on use and relapse of different substances of abuse. The involvement of circadian clock genes with drug reward pathways is discussed, along with the potential research areas that can be explored to minimize disordered substance use by improving circadian hygiene.

Abstract Disrupted or atypical light–dark cycles disrupts synchronization of endogenous circadian clocks to the external environment; extensive circadian rhythm desynchrony promotes adverse health outcomes. Previous studies suggest that disrupted circadian rhythms promote neuroinflammation and neuronal damage post-ischemia in otherwise healthy mice, however, few studies to date have evaluated these health risks with aging. Because most strokes occur in aged individuals, we sought to identify whether, in addition to being a risk factor for poor ischemic outcome, circadian rhythm disruption can increase risk for vascular cognitive impairment and dementia (VCID). We hypothesized that repeated 6 h phase advances (chronic jet lag; CJL) for 8 weeks alters cerebrovascular architecture leading to increased cognitive impairments in aged mice. Female CJL mice displayed impaired spatial processing during a spontaneous alternation task and reduced acquisition during auditory-cued associative learning. Male CJL mice displayed impaired retention of the auditory-cued associative learning task 24 h following acquisition. CJL increased vascular tortuosity in the isocortex, associated with increased risk for vascular disease. These results demonstrate that CJL increased sex-specific cognitive impairments coinciding with structural changes to vasculature in the brain. We highlight that CJL may accelerate aged-related functional decline and could be a crucial target against disease progression.

Abstract Despite its demonstrated biological significance, time of day is a broadly overlooked biological variable in preclinical and clinical studies. How time of day affects the influence of peripheral tumors on central (brain) function remains unspecified. Thus, we tested the hypothesis that peripheral mammary cancer tumors alter the transcriptome of immune responses in the brain and that these responses vary based on time of day; we predicted that time of day sampling bias would alter the interpretation of the results. Brain tissues collected at mid dark and mid light from mammary tumor-bearing and vehicle injected mice were analyzed using the Nanostring nCounter immune panel. Peripheral mammary tumors significantly affected expression within the brain of over 100 unique genes of the 770 represented in the panel, and fewer than 25% of these genes were affected similarly across the day. Indeed, between 65 and 75% of GO biological processes represented by the differentially expressed genes were dependent upon time of day of sampling. The implications of time-of-day sampling bias in interpretation of research studies cannot be understated. We encourage considering time of day as a significant biological variable in studies and to appropriately control for it and clearly report time of day in findings.

Artificial light at night (ALAN) is a pervasive circadian rhythm disruptor. Exposure to ALAN is associated with detrimental effects on physiology and behavior, including disrupted metabolism, immune function, endocrine function, and pain behavior. Given the detrimental effects of ALAN and other circadian rhythm disruptors on pain, we sought to understand how ALAN may alter the progression and severity of diabetic neuropathy. To do this, we used a previously reported high-fat diet and streptozotocin injection protocol to induce a type II diabetic phenotype in ∼8 week old female and male mice and then exposed the mice to either control or ALAN lighting conditions in 14:10 h light-dark cycles for 4 weeks. Male mice housed in control conditions exhibited reduced responsiveness to cold pain; in contrast, ALAN blunted this effect in male mice. ALAN exposure also elevated blood glucose and altered body mass loss in male mice. These effects were not present in female mice. The results of this study highlight the need to consider and study ALAN exposure and sex as a biological variable as risk factors in the treatment and mitigation of pain.

Aging is a risk factor for the development of breast cancer. Foundational science studies have supported associations among neuroinflammation, breast cancer, and chemotherapy, but to date, these associations are based on studies using young adult rodents. The current study examined the neuroinflammatory effects of chemotherapy in aged, tumor-naïve and tumor-bearing mice with or without social enrichment. Mice received two intravenous injections of doxorubicin (A) and cyclophosphamide (C) at a two-week interval. Brain immune cells were enriched/assessed via flow cytometry, seven days following the second chemotherapy injection. Social enrichment enhanced peripheral immune cell trafficking in aged tumor-naive mice treated with AC. Group housed aged tumor bearing mice receiving AC had reduced percentage of IL-6+ monocytes and granulocytes relative to their singly housed counterparts. Notably, group housing aged experimental mice with young cage partners significantly reduced TNF + monocytes, tumor volume, and tumor mass. These data illustrate the importance of social enrichment in attenuating neuroinflammation and are the first to demonstrate that social support with young housing partners reduces tumor growth in aged mice.

Neuroscience and biological evidence emphasizes the profound influence of natural light on human health, offering benefits such as reducing fatigue, heightened alertness in healthcare providers, and improving patient outcomes. The objective of this review is to identify scientific studies and research to evaluate and report evidence of indoor lighting conditions’ influence on health outcomes, which can be used to develop lighting designs that align circadian rhythms in healthcare settings. A comprehensive search was conducted to identify rigorous empirical studies focused on the link between interior lighting conditions with health outcomes in the healthcare environment. For a comprehensive review of the existing literature, a four-phased methodology was employed including literature search, screening, and selection. Literature appraisals were conducted to determine the relevance and quality of evidence for each study identified. In addition, using a thematic analysis, patterns were identified, analyzed, and interpreted within the literature review. Accordingly, the results were organized into two main groups interventional human subjects and simulation-based studies. Despite evidence that natural light influences human health and happiness, a synthesis of reviewed studies suggests that the evidence for the benefits of artificial lighting in healthcare settings is less conclusive, with potential factors including variations in lighting design, inconsistent implementation of lighting interventions, and differing sample populations across studies. We conclude with an executive summary suggesting that future research should use standardized metrics and methods to focus on bridging the gap between theoretical understanding and practical application in lighting design for healthcare environments. Collaboration among architects, designers, lighting experts, and healthcare professionals can address these factors contributing to building a stronger evidence-based design for the benefits of artificial lighting in healthcare settings.

For over a hundred years, the lighting industry has primarily been driven by illumination aesthetics, energy efficiency and product cost with little consideration of the effects of light on health. The recent widespread replacement of traditional light sources by blue-enriched LED lights has heightened concerns about the disruption of the blue-sensitive human circadian system by these LED lights and their impact on the multiple health disorders linked to circadian disruption. Despite these health concerns, less than 0.5% of the lighting sold today modifies spectral content and intensity between day and night. We report that 248 scientists, with a total of 2,697 peer-reviewed publications on light and circadian clocks since 2008, reached consensus on 25 statements about the impact of light on circadian rhythms and health based on accumulated scientific evidence, including support for the widespread introduction of circadian lighting and warning labels on blue-enriched LED lights indicating they “maybe harmful if used at night”.

Summary: The structure and function of the cardiovascular system are modulated across the day by circadian rhythms, making this system susceptible to circadian rhythm disruption. Recent evidence demonstrated that short-term exposure to a pervasive circadian rhythm disruptor, artificial light at night (ALAN), increased inflammation and altered angiogenic transcripts in the hippocampi of mice. Here, we examined the effects of four nights of ALAN exposure on mouse hippocampal vascular networks. To do this, we analyzed 2D and 3D images of hippocampal vasculature and hippocampal transcriptomic profiles of mice exposed to ALAN. ALAN reduced vascular density in the CA1 and CA2/3 of female mice and the dentate gyrus of male mice. Network structure and connectivity were also impaired in the CA2/3 of female mice. These results demonstrate the rapid and potent effects of ALAN on cerebrovascular networks, highlighting the importance of ALAN mitigation in the context of health and cerebrovascular disease.

Abstract Background Circadian rhythms are important for all aspects of biology; virtually every aspect of biological function varies according to time of day. Although this is well known, variation across the day is also often ignored in the design and reporting of research. For this review, we analyzed the top 50 cited papers across 10 major domains of the biological sciences in the calendar year 2015. We repeated this analysis for the year 2019, hypothesizing that the awarding of a Nobel Prize in 2017 for achievements in the field of circadian biology would highlight the importance of circadian rhythms for scientists across many disciplines, and improve time-of-day reporting. Results Our analyses of these 1000 empirical papers, however, revealed that most failed to include sufficient temporal details when describing experimental methods and that few systematic differences in time-of-day reporting existed between 2015 and 2019. Overall, only 6.1% of reports included time-of-day information about experimental measures and manipulations sufficient to permit replication. Conclusions Circadian rhythms are a defining feature of biological systems, and knowing when in the circadian day these systems are evaluated is fundamentally important information. Failing to account for time of day hampers reproducibility across laboratories, complicates interpretation of results, and reduces the value of data based predominantly on nocturnal animals when extrapolating to diurnal humans.

Pain behavior and the systems that mediate opioid analgesia and opioid reward processing display circadian rhythms. Moreover, the pain system and opioid processing systems, including the mesolimbic reward circuitry, reciprocally interact with the circadian system. Recent work has demonstrated the disruptive relationship among these three systems. Disruption of circadian rhythms can exacerbate pain behavior and modulate opioid processing, and pain and opioids can influence circadian rhythms. This review highlights evidence demonstrating the relationship among the circadian, pain, and opioid systems. Evidence of how disruption of one of these systems can lead to reciprocal disruptions of the other is then reviewed. Finally, we discuss the interconnected nature of these systems to emphasize the importance of their interactions in therapeutic contexts.

The automation of behavioral tracking and analysis in preclinical research can serve to advance the rate of research outcomes, increase experimental scalability, and challenge the scientific reproducibility crisis. Recent advances in the efficiency, accuracy, and accessibility of deep learning (DL) and machine learning (ML) frameworks are enabling this automation. As the ongoing opioid epidemic continues to worsen alongside increasing rates of chronic pain, there are ever-growing needs to understand opioid use disorders (OUDs) and identify non-opioid therapeutic options for pain. In this review, we examine how these related needs can be advanced by the development and validation of DL and ML resources for automated pain and withdrawal behavioral tracking. We aim to emphasize the utility of these tools for automated behavioral analysis, and we argue that currently developed models should be deployed to address novel questions in the fields of pain and OUD research.

Circadian rhythms are internal manifestations of the 24-h solar day that allow for synchronization of biological and behavioral processes to the external solar day. This precise regulation of physiology and behavior improves adaptive function and survival. Chronotherapy takes advantage of circadian rhythms in physiological processes to optimize the timing of drug administration to achieve maximal therapeutic efficacy and minimize negative side effects. Chronotherapy for cancer treatment was first demonstrated to be beneficial more than five decades ago and has favorable effects across diverse cancer types. However, implementation of chronotherapy in clinic remains limited. The present review examines the evidence for chronotherapeutic treatment for solid tumors. Specifically, studies examining chrono-chemotherapy, chrono-radiotherapy, and alternative chronotherapeutics (e.g., hormone therapy, TKIs, antiangiogenic therapy, immunotherapy) are discussed. In addition, we propose areas of needed research and identify challenges in the field that remain to be addressed.

Circadian rhythms are ubiquitous endogenous rhythms with a period of approximately twenty-four hours [...]

Availability of artificial light and light-emitting devices have altered human temporal life, allowing 24-hour healthcare, commerce and production, and expanding social life around the clock. However, physiology and behavior that evolved in the context of 24 h solar days are frequently perturbed by exposure to artificial light at night. This is particularly salient in the context of circadian rhythms, the result of endogenous biological clocks with a rhythm of ~24 h. Circadian rhythms govern the temporal features of physiology and behavior, and are set to precisely 24 h primarily by exposure to light during the solar day, though other factors, such as the timing of meals, can also affect circadian rhythms. Circadian rhythms are significantly affected by night shift work because of exposure to nocturnal light, electronic devices, and shifts in the timing of meals. Night shift workers are at increased risk for metabolic disorder, as well as several types of cancer. Others who are exposed to artificial light at night or late mealtimes also show disrupted circadian rhythms and increased metabolic and cardiac disorders. It is imperative to understand how disrupted circadian rhythms alter metabolic function to develop strategies to mitigate their negative effects. In this review, we provide an introduction to circadian rhythms, physiological regulation of homeostasis by the suprachiasmatic nucleus (SCN), and SCN-mediated hormones that display circadian rhythms, including melatonin and glucocorticoids. Next, we discuss circadian-gated physiological processes including sleep and food intake, followed by types of disrupted circadian rhythms and how modern lighting disrupts molecular clock rhythms. Lastly, we identify how disruptions to hormones and metabolism can increase susceptibility to metabolic syndrome and risk for cardiovascular diseases, and discuss various strategies to mitigate the harmful consequences associated with disrupted circadian rhythms on human health.

Circadian rhythms convergently evolved to allow for optimal synchronization of individuals’ physiological and behavioral processes with the Earth’s 24-h periodic cycling of environmental light and temperature. Whereas the suprachiasmatic nucleus (SCN) is considered the primary pacemaker of the mammalian circadian system, many extra-SCN oscillatory brain regions have been identified to not only exhibit sustainable rhythms in circadian molecular clock function, but also rhythms in overall region activity/function and mediated behaviors. In this review, we present the most recent evidence for the ventral tegmental area (VTA) and nucleus accumbens (NAc) to serve as extra-SCN oscillators and highlight studies that illustrate the functional significance of the VTA’s and NAc’s inherent circadian properties as they relate to reward-processing, drug abuse, and vulnerability to develop substance use disorders (SUDs).

Chemotherapy is more effective in the treatment of peripheral tumors than brain metastases, likely reflecting the reduced ability of chemotherapy to cross the blood-brain barrier (BBB) and blood-tumor barrier at efficacious concentrations. Recent studies demonstrate circadian regulation of the BBB. Thus, we predicted that optimally timed chemotherapy would increase anti-tumor efficacy in a model of brain metastases of breast cancer (BMBC). First, we characterized novel daily alterations in BBB permeability to a commonly used chemotherapeutic, 14C-paclitaxel, within BMBC following injections given at four time points across the day. Peak and trough 14C-paclitaxel concentrations within BMBC occurred during the mid-dark phase and at the beginning of the light phase, respectively. Notably, chemotherapy injections during the dark phase increased cell death within BMBC and delayed onset of neurological symptoms relative to injections during the light phase. These data provide strong evidence for the beneficial effects of chrono-chemotherapy for the treatment of BMBC.

Several endogenous and exogenous factors interact to influence stroke occurrence, in turn contributing to discernable daily distribution patterns in the frequency and severity of cerebrovascular events. Specifically, strokes that occur during the morning tend to be more severe and are associated with elevated diastolic blood pressure, increased hospital stay, and worse outcomes, including mortality, compared to strokes that occur later in the day. Furthermore, disrupted circadian rhythms are linked to higher risk for stroke and play a role in stroke outcome. In this review, we discuss the interrelation among core clock genes and several factors contributing to ischemic outcomes, sources of disrupted circadian rhythms, the implications of disrupted circadian rhythms in foundational stroke scientific literature, followed by a review of clinical implications. In addition to highlighting the distinct daily pattern of onset, several aspects of physiology including immune response, endothelial/vascular and blood brain barrier function, and fibrinolysis are under circadian clock regulation; disrupted core clock gene expression patterns can adversely affect these physiological processes, leading to a prothrombotic state. Lastly, we discuss how the timing of ischemic onset increases morning resistance to thrombolytic therapy and the risk of hemorrhagic transformation.

Abstract The Earth's surface temperature is rising, and precipitation patterns throughout the Earth are changing; the source of these shifts is likely anthropogenic in nature. Alterations in temperature and precipitation have obvious direct and indirect effects on both plants and animals. Notably, changes in temperature and precipitation alone can have both advantageous and detrimental consequences depending on the species. Typically, production of offspring is timed to coincide with optimal food availability; thus, individuals of many species display annual rhythms of reproductive function. Because it requires substantial time to establish or re‐establish reproductive function, individuals cannot depend on the arrival of seasonal food availability to begin breeding; thus, mechanisms have evolved in many plants and animals to monitor and respond to day length in order to anticipate seasonal changes in the environment. Over evolutionary time, there has been precise fine‐tuning of critical photoperiod and onset/offset of seasonal adaptations. Climate change has provoked changes in the availability of insects and plants which shifts the timing of optimal reproduction. However, adaptations to the stable photoperiod may be insufficiently plastic to allow a shift in the seasonal timing of bird and mammal breeding. Coupled with the effects of light pollution which prevents these species from determining day length, climate change presents extreme evolutionary pressure that can result in severe deleterious consequences for individual species reproduction and survival. This review describes the effects of climate change on plants and animals, defines photoperiod and the physiological events it regulates, and addresses the consequences of global climate change and a stable photoperiod.

Diabetes poses a high risk for debilitating complications in neural tissues, regulating glucose uptake through insulin-dependent and predominantly insulin-independent pathways. Supramolecular nanostructures provide a flexible strategy for combinatorial regulation of glycemia. Here, we compare the effects of free insulin to insulin bound to positively charged nanofibers comprised of self-assembling amino acid compounds (AACs) with an antioxidant-modified side chain moiety (AAC2) in both in vitro and in vivo models of type 1 diabetes. Free AAC2, free human insulin (hINS) and AAC2-bound-human insulin (AAC2-hINS) were tested in streptozotocin (STZ)-induced mouse model of type 1 diabetes. AAC2-hINS acted as a complex and exhibited different properties compared to free AAC2 or hINS. Mice treated with the AAC2-hINS complex were devoid of hypoglycemic episodes, had improved levels of insulin in circulation and in the brain, and increased expression of neurotransmitter taurine transporter, Slc6a6. Consequently, treatment with AAC2-hINS markedly advanced both physical and cognitive performance in mice with STZ-induced and genetic type 1 diabetes compared to treatments with free AAC2 or hINS. This study demonstrates that the flexible nanofiber AAC2 can serve as a therapeutic platform for the combinatorial treatment of diabetes and its complications.

Cardiovascular diseases are the top cause of mortality in the United States, and ischemic heart disease accounts for 16% of all deaths around the world. Modifiable risk factors such as diet and exercise have often been primary targets in addressing these conditions. However, mounting evidence suggests that environmental factors that disrupt physiological rhythms might contribute to the development of these diseases, as well as contribute to increasing other risk factors that are typically associated with cardiovascular disease. Exposure to light at night, transmeridian travel, and social jetlag disrupt endogenous circadian rhythms, which, in turn, alter carefully orchestrated bodily functioning, and elevate the risk of disease and injury. Research into how disrupted circadian rhythms affect physiology and behavior has begun to reveal the intricacies of how seemingly innocuous environmental and social factors have dramatic consequences on mammalian physiology and behavior. Despite the new focus on the importance of circadian rhythms, and how disrupted circadian rhythms contribute to cardiovascular diseases, many questions in this field remain unanswered. Further, neither time-of-day nor sex as a biological variable have been consistently and thoroughly taken into account in previous studies of circadian rhythm disruption and cardiovascular disease. In this review, we will first discuss biological rhythms and the master temporal regulator that controls these rhythms, focusing on the cardiovascular system, its rhythms, and the pathology associated with its disruption, while emphasizing the importance of the time-of-day as a variable that directly affects outcomes in controlled studies, and how temporal data will inform clinical practice and influence personalized medicine. Finally, we will discuss evidence supporting the existence of sex differences in cardiovascular function and outcomes following an injury, and highlight the need for consistent inclusion of both sexes in studies that aim to understand cardiovascular function and improve cardiovascular health.

For many individuals in industrialized nations, the widespread adoption of electric lighting has dramatically affected the circadian organization of physiology and behavior. Although initially assumed to be innocuous, exposure to artificial light at night (ALAN) is associated with several disorders, including increased incidence of cancer, metabolic disorders, and mood disorders. Within this review, we present a brief overview of the molecular circadian clock system and the importance of maintaining fidelity to bright days and dark nights. We describe the interrelation between core clock genes and the cell cycle, as well as the contribution of clock genes to oncogenesis. Next, we review the clinical implications of disrupted circadian rhythms on cancer, followed by a section on the foundational science literature on the effects of light at night and cancer. Finally, we provide some strategies for mitigation of disrupted circadian rhythms to improve health.

Appropriately timed light is critical for circadian organization; exposure to dim light at night (dLAN) disrupts temporal organization of endogenous biological timing. Exposure to dLAN in adult mice is associated with elevated body mass and changes in metabolism putatively driven by voluntary changes in the time of food intake. We predicted that exposure of young mice to LAN could affect adult metabolic function. At 3 weeks (Experiment 1) or 5 weeks (Experiment 2) of age, mice were either maintained in standard light-dark (DARK) cycles or exposed to nightly dLAN (5 lux). In the first two experiments, food intake and locomotor activity were assessed after 4 weeks and a glucose tolerance test was administered after 6 weeks in experimental lighting conditions. In Experiment 3, tissues were collected around the clock at 6 h intervals to investigate rhythmic hepatic clock gene expression in mice exposed to dLAN from 3 or 5 weeks of age. Male and female mice exposed to dLAN beginning at 3 weeks of age displayed similar growth rates and body mass to DARK-reared offspring, despite increasing day-time food intake. Exposure to dLAN beginning at 5 weeks of age increased body mass and daytime food intake in male, but not female, mice. Consistent with the body mass phenotype, clock gene expression was unaltered in the liver. In contrast to adults, dLAN exposure during the development of the peripheral circadian system has sex- and development-dependent effects on body mass gain.

Ischemic events in humans are not evenly distributed across the day. To discriminate between temporal differences in the incidence of ischemia and susceptibility to ischemic events, we examined the outcome of global ischemia in a murine model at three time points during the day. Global cerebral ischemia in mice during the light phase impairs survival and exacerbates outcome compared to ischemia at other times of the day. Specifically, mice that underwent cardiac arrest during the light phase had greater numbers of degenerating neurons, greater microglial activation, and increased proinflammatory cytokine production in the ischemia-vulnerable hippocampus, as well as increased locomotor activity. Time-of-day differences were not altered by the melatonin receptor antagonist luzindole. Our results document that brain tissue displays endogenous fluctuations in susceptibility to ischemic damage and demonstrate that small differences in time of onset can significantly influence ischemic outcomes.