Wake Cycle Research Articles

Are the Sleep–Wake Cycle and Sleep Duration Ethnically Determined? A Comparison of Tibetan and Japanese Children’s Sleep

Background: Several environmental factors affect sleep. We investigated the sleep and sleep-related habits of preschool children living in Tibet and conducted an international comparison with those in Japan. Methods: We conducted a community-based cross-sectional study using the Chinese version of the Japanese Sleep Questionnaire for Preschoolers (JSQ-P-C) and compared the results with previous data on Japanese children. Results: The sleep status of 3113 children aged 3–6 years old in Qinghai province was evaluated. The average wake time and bedtime of the Tibetan children were 7:20 ± 0:31 and 21:16 ± 0:43, respectively. Their mean nocturnal sleep duration was 10.0 ± 0.7 h. In comparing 3-year-old children, the time for which they viewed TV in Tibet was shorter (65.5 ± 44.6 min) than that in Japan (149.7 ± 76.6 min), and the mother’s bedtime was earlier in Tibet (21:28 ± 2:14) than in Japan (23:20 ± 1:05). However, the bedtime and sleep duration of the Tibetan children (21:17 ± 0:37 and 10.0 ± 0.7 h) were fairly similar to those of the Japanese children (21:24 ± 1:57 and 9.8 ± 0.8 h). Conclusions: The late bedtime and short nocturnal sleep duration of Tibetan toddlers were the same as those of Japanese toddlers despite considerable differences in their lifestyle and environment.

Interleukin-12 modulates sleep–wake activity and improves performance in a memory task

Abstract Background Cytokines, known for their pro- and anti-inflammatory roles, are also key regulators of sleep–wake cycles. Classical pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), are associated with increased sleep, particularly slow-wave sleep (SWS), while anti-inflammatory cytokines, like interleukin-10 (IL-10), generally reduce sleep duration. Given the essential role of sleep in memory consolidation, this study aimed to investigate whether interleukin-12 (IL-12), a pro-inflammatory cytokine, could increase sleep duration following a memory acquisition task and subsequently improve memory performance. Male Swiss mice were surgically implanted with electrodes for electrocorticogram (ECoG) and electromyogram (EMG) recordings to track their sleep–wake cycles. After a recovery period, baseline sleep–wake activity was recorded. The mice were then randomly assigned to two groups and treated with either IL-12 (0.5 µg, i.p.) or a phosphate-buffered saline (PBS, i.p.) control, administered immediately before the multiple-trial inhibitory avoidance (MTIA) task, a behavioral test used to assess memory performance. Following the memory acquisition session, sleep–wake activity was immediately recorded for a continuous 24-h period. Results Mice treated with IL-12 exhibited longer latency to cross into the dark compartment during the MTIA test, indicating improved memory retention compared to the control group. Interestingly, this improved performance was associated with prolonged wakefulness, particularly in the first three hours after task acquisition. Conclusion The study shows that IL-12 can improve memory retention through prolonged wake episodes rather than increased sleep. This finding challenges the conventional understanding that sleep is the primary state for memory consolidation, suggesting that under specific conditions, wakefulness may also play a key role in supporting memory processes. Further research is needed to explore the underlying mechanisms of IL-12's cognitive effects.

Altered sleep and inflammation are related to outcomes in neonatal encephalopathy.

Immune dysregulation and delayed onset of sleep wake cycling (SWC) are associated with worse outcome in neonatal encephalopathy (NE), however the association between sleep and immune dysfunction in NE remains unclear. Aimed to evaluate association of sleep and systemic inflammation with outcomes in NE. Amplitude-integrated electroencephalography (aEEG) recordings were collected on infants undergoing therapeutic hypothermia (TH). Duration to onset of (SWC) and sleep quality (SQ) were examined. Blood samples collected during the first 2 days of life. Thirteen pro- and anti-inflammatory serum cytokines were quantified. Adverse outcome defined as death or abnormal MRI brain. Earlier onset of SWC and better SQ had less adverse outcomes. SQ provided better prognostic value and showed better interobserver agreement compared to duration to SWC. Better SQ associated with lower cytokines EPO and interleukin (IL)-1β. In infants with unfavourable outcome, shorter duration to SWC was associated with higher EPO and better SQ was associated with lower TNF-α. Earlier onset of SWC or better SQ showed less systemic inflammation and fewer adverse outcomes. SQ during TH provided better prognostic information than time of onset of SWC. Modulation of circadian rhythm in infants with NE may have an immunomodulatory role, leading to improved outcomes.

The Effect of Sleep Quality on Stress Levels in Night Shift and Non-night Shift Workers: A Cross-Sectional Study

The sleep–wake cycle, which is regulated by the endogenous circadian rhythm, is disrupted by night-shift work. Altered sleep patterns owing to shift work have been associated with irritability, depressed mood, anxiety, and nervousness. The objective of the study was to evaluate the effect of sleep quality on stress in night shift workers and non-night shift workers. A cross – sectional study was conducted in 30night shift and 30 non-night shift workers of Railway Mail Service and Postal Department, Thrissur, Kerala. Sleep quality was assessed using Pittsburg Sleep Quality Index and stress was assessed using Perceived Stress Scale. The findings revealed that a majority of night shift workers reported poor sleep quality, with a significant correlation observed between sleep quality and shift work. Furthermore, stress levels were markedly higher among night workers with poor sleep quality. Regression analysis indicated a positive association between impaired sleep quality and elevated stress levels.

Circadian and sleep–wake homeostatic modulation of EEG activity during sleep and wakefulness

AbstractThe human sleep–wake cycle is regulated by two distinct processes: the circadian timing system (CTS) and the sleep–wake homeostatic (SWH) process. The CTS is driven by a small region in the anterior hypothalamus of the brain, which is known as the “circadian clock.” By contrast, the SWH can be conceptualized as an hourglass, whereby sleep pressure builds up during waking hours and is released during sleep. In contrast to the CTS, there is no specific brain region that controls this hourglass process. A complex modulation of these two processes affects electroencephalographic (EEG) activity throughout the 24‑h day, resulting in the emergence of specific EEG features. These features can be classified into three categories: those that show clear circadian patterns, those that are predominantly influenced by the homeostatic process, and those that show a combination of both. This review describes the EEG features quantified by spectral analysis during sleep and wakefulness derived from specific human study protocols, which enable the separation of the influence of the circadian clock and the sleep–wake hourglass process. Second, the potential for circadian and SWH modulation to influence interictal activity and seizure occurrence will be discussed, along with its implications for the diagnosis, treatment, and seizure prediction and prevention.

New Insights into Health Conditions Related to Malfunctions in Clock Genes

Chronotypes play a crucial role in regulating sleep–wake cycles and overall health. The aim of this study was to investigate chronotype, sleep quality, polymorphisms of clock genes and the level of leptin in serum. We used standardized questionnaires to assess chronotype and sleep quality. Genetic analysis was performed to determine the selected clock gene polymorphism. Serum leptin level was measured by the Elisa method. The results showed that serum leptin concentration was elevated in women, as well as in men who had a high waist-to-hip ratio (WHR) and body mass index (BMI). The evidence indicated that younger students (<22 years old) were most likely to experience poor sleep quality. Nevertheless, our multivariate analysis revealed that young age and a morning-oriented chronotype were associated with better sleep quality. We noted that clock gene polymorphisms were present in 28.6% of the participants. Moreover, polymorphisms of PER1 c.2247C>T (rs2735611) and PER2 c.-12C>G (rs2304672) genes were associated with serum leptin level and chronotype, respectively. These findings provide insights into the relationships between chronotype, sleep quality, clock gene polymorphisms and obesity risk in biomedical students. Understanding these factors can contribute to better sleep management and potential interventions to improve health outcomes in humans.

Serum melatonin levels and in a sample of Iranian patients with migraine

Migraine, a complex disorder, is characterized by recurrent headache episodes. The production of melatonin in the pineal gland, which is crucial for controlling circadian rhythms and sleep–wake cycles, is altered in various conditions, including neurological disorders such as migraine. Recent studies underscore the significance of serum melatonin levels in patients with chronic and episodic migraine, the focus of this study. This case‒control study, conducted from September 2017 to June 2020 in Tehran, Iran, selected potential participants aged 18–65 years from a headache clinic at Sina Hospital (affiliated with Tehran University of Medical Sciences). Both episodic migraine and chronic migraine were diagnosed following the diagnostic criteria in the International Classification of Headache Disorders’ third edition. Melatonin levels were measured according to the instructions of the ELISA kits. There were significant differences in the frequency of headache days and the duration of abortive medication usage between the two groups (P value < 0.001). Besides, analysis revealed significantly lower serum melatonin levels in patients with episodic ((80.45–45.06) 72.83) and chronic migraine ((154.34–63.34) 70.38, P value < 0.001) than in healthy controls (281.25–160.86) 280). Although no considerable differences were found between episodic and chronic migraine patients, the current study demonstrated that serum melatonin levels were substantially greater in healthy controls than in patients with migraine.

Microglial morphology aligns with vigilance stage‐specific neuronal oscillations in a brain region‐dependent manner

AbstractMicroglia, the resident immune cells in the brain, dynamically adapt their morphology based on their functional state. This study explored the relationship between microglial morphology and sleep–wake cycles in mice. Using Iba1 immunostaining to identify microglia, we quantified morphological changes in microglia at different timepoints in multiple brain regions (cortex, hippocampus, basal forebrain, hindbrain, and cerebellum) in B6 male mice using semi‐automated 3D structural analysis. Simultaneously, in a separate group, we monitored wake and sleep stage‐specific brain activity using EEG/EMG recordings. During natural sleep–wake cycles, we observed increased microglial complexity (enlarged volume, territorial coverage, and ramification) during wakefulness, characterized by high‐frequency theta (8–12 Hz) and gamma activity (30–80 Hz). Conversely, during NREM sleep, which is dominated by delta activity (0.5–4 Hz), microglia displayed reduced complexity. Notably, this pattern was absent in brain regions lacking direct functional connections to areas generating vigilance stage‐dependent thalamocortical oscillations. We then extended wakefulness to decouple circadian influence from sleep–wake‐specific neuronal activity. This procedure attenuated the decrease in microglial complexity observed during natural sleep, suggesting a crucial role for neuronal activity. Subsequent recovery sleep restored microglial features, independent of the time of day (zeitgeber time). These findings reveal a dynamic interplay between vigilance stage‐specific thalamocortical activity and microglial morphology across various brain regions. This suggests a potential role for microglia in sleep regulation and warrants further investigation to understand the underlying mechanisms.

P-tau217 and other blood biomarkers of dementia: variation with time of day

Plasma biomarkers of dementia, including phosphorylated tau (p-tau217), offer promise as tools for diagnosis, stratification for clinical trials, monitoring disease progression, and assessing the success of interventions in those living with Alzheimer’s disease. However, currently, it is unknown whether these dementia biomarker levels vary with the time of day, which could have implications for their clinical value. In two protocols, we studied 38 participants (70.8 ± 7.6 years; mean ± SD) in a 27-h laboratory protocol with either two samples taken 12 h apart or 3-hourly blood sampling for 24 h in the presence of a sleep–wake cycle. The study population comprised people living with mild Alzheimer’s disease (PLWA, n = 8), partners/caregivers of PLWA (n = 6) and cognitively intact older adults (n = 24). Single-molecule array technology was used to measure phosphorylated tau (p-tau217) (ALZpath), amyloid-beta 40 (Aβ40), amyloid-beta 42 (Aβ42), glial fibrillary acidic protein, and neurofilament light (NfL) (Neuro 4-Plex E). Analysis with a linear mixed model (SAS, PROC MIXED) revealed a significant effect of time of day for p-tau217, Aβ40, Aβ42, and NfL, and a significant effect of participant group for p-tau217. For p-tau217, the lowest levels were observed in the morning upon waking and the highest values in the afternoon/early evening. The magnitude of the diurnal variation for p-tau217 was similar to the reported increase in p-tau217 over one year in amyloid-β-positive mild cognitively impaired people. Currently, the factors driving this diurnal variation are unknown and could be related to sleep, circadian mechanisms, activity, posture, or meals. Overall, this work implies that the time of day of sample collection may be relevant in the implementation and interpretation of plasma biomarkers in dementia research and care.

A - 139 A Neuropsychological Case Study of an Individual Diagnosed with Langerhans Cell Histiocytosis

Abstract Objective Langerhans cell histiocytosis (LCH) is a rare, idiopathic, cancer-like condition resulting from an overproduction of Langerhans cells. Disseminated LCH can spread across various anatomical systems, and prognosis is mainly dependent on organ involvement. Due to the rarity of this condition, potential neuropsychological effects are not fully understood. However, current research suggests that individuals with LCH are prone to develop various comorbid neuropsychiatric problems such as depression, anxiety, and impaired intellectual functioning. Method The current case is an 18-year-old, right-handed, Hispanic female who was diagnosed with LCH (brain and bone) in 2020. Cognitive symptoms began in 2016 at age 11. She was initially diagnosed with a low-grade glioma after a biopsy of a supracellular mass in 2017 but has developed various comorbid conditions since then. These include panhypopituitarism, NMDA encephalitis with behavioral disturbance, encephalomalacia, and epilepsy. She has undergone two 9-month rounds of chemotherapy and has been followed for neuroimaging with MRI and CT since 2017. Results Neuropsychological test findings from January 2024 indicated global deficits in intellectual functioning. Severe disruptions in sleep–wake cycle were also evident during testing. Although language abilities were relatively well preserved, abstract reasoning and executive functioning were greatly impaired. Psychological screeners also suggested anxiety and depression. Conclusions This case provides evidence of neurocognitive and psychiatric symptoms that can occur as a result of LCH and frequent comorbid health conditions. Neuropsychological testing can help monitor these effects on individuals with LCH across the lifespan.

Metadata recommendations for light logging and dosimetry datasets

BackgroundLight exposure significantly impacts human health, regulating our circadian clock, sleep–wake cycle and other physiological processes. With the emergence of wearable light loggers and dosimeters, research on real-world light exposure effects is growing. There is a critical need to standardize data collection and documentation across studies.ResultsThis article proposes a new metadata descriptor designed to capture crucial information within personalized light exposure datasets collected with wearable light loggers and dosimeters. The descriptor, developed collaboratively by international experts, has a modular structure for future expansion and customization. It covers four key domains: study design, participant characteristics, dataset details, and device specifications. Each domain includes specific metadata fields for comprehensive documentation. The user-friendly descriptor is available in JSON format. A web interface simplifies generating compliant JSON files for broad accessibility. Version control allows for future improvements.ConclusionsOur metadata descriptor empowers researchers to enhance the quality and value of their light dosimetry datasets by making them FAIR (findable, accessible, interoperable and reusable). Ultimately, its adoption will advance our understanding of how light exposure affects human physiology and behaviour in real-world settings.

Narcolepsy and pediatric acute-onset neuropsychiatric syndrome: A case report that suggests a putative link between the two disorders

Narcolepsy with cataplexy (NT1) is a rare hypothalamic disorder that presents with a dysregulation of the sleep–wake cycle (i.e., excessive daytime sleepiness and sleep and cataplectic attacks) and other motor, cognitive, psychiatric, metabolic, and autonomic disturbances, with putative autoimmune pathogenesis. Pediatric acute-onset neuropsychiatric syndrome (PANS) is a clinically heterogeneous disorder that presents with acute-onset obsessive–compulsive symptoms and/or a severe eating restriction, with concomitant cognitive, behavioral, or affective symptoms caused by infections and other environmental triggers provoking an inflammatory brain response, which evolves into a chronic or progressive neuroimmune disorder. In this study, we present the case of a 13-year-old boy with vocal tics and syncopal-like episodes, eventually diagnosed as NT1 and PANS, and from this we discuss the hypothesis that both NT1 and PANS might belong to the same immunological spectrum, resulting in comparable imbalances in key neurotransmitter axes (i.e., orexinergic and dopaminergic), with conceptual and operational implications, especially with regards to the pharmacological tretament

Сontribution of circadian rhythms to the development of neurological disorders after prolonged anesthesia

Despite the improvement of pre-, intra- and postoperative care methods, the problem of the development of postoperative neurological complications following prolonged anesthesia remains. A mechanism of occurrence of these complications may be circadian rhythm disorders. This article presents a review of the literature data on the prevalence, pathophysiological mechanisms, and risk factors of postoperative autonomic and circadian disorders. Notably, circadian rhythm disorders in surgical patients are observed at several levels: disruption of the sleep and wakefulness cycle, decreased melatonin secretion, instability of cortisol levels and body temperature, and changes in the vegetative balance towards sympathetic regulation. These disorders contribute to the development of postoperative pain and cognitive and anxiety-depressive disorders, hinder effective rehabilitation, and may be associated with postoperative mortality.

Hypothesis on the potential of repetitive transcranial magnetic stimulation to modulate neurochemical pathways and circadian rhythm in ADHD

Disturbances in the circadian rhythms are generally present in adults subjects with Attention Deficit Hyperactivity Disorder. However, may present in children with the same clinical condition. Poor sleep quality interferes with neural inputs and outputs in areas that are fundamental in neurobiological aspects, such as the dorsolateral prefrontal cortex, which can affect circadian rhythm, cognition, emotional and social control. The dorsolateral prefrontal cortex is an area involved in executive functions and sleep–wake regulation and is underactivated in subjects Attention Deficit Hyperactivity Disorder, which may be one of the main causes of alterations in the circadian cycle. Currently, studies with non-invasive therapeutic methods for adult populations and children with these disorders remain scarce, revealing a significant gap in understanding and treatment. In this context, the aim is investigate the potential effectiveness of repetitive transcranial magnetic stimulation as alternative non-invasive treatment of these disorders. In the present study, it is suggested that use excitatory currents from 10 Hz to 20 Hz in the right dorsolateral prefrontal cortex leads to an improvement in the circadian rhythm mechanism. This is because the excitatory current will promote an increase in dopamine (a neurotransmitter that regulates the circadian cycle) and an increase in glutamate and glutamine concentrations to restore homeostasis in brain regions linked to the sleep–wake cycle.

Efficient Sleep–Wake Cycle Staging via Phase–Amplitude Coupling Pattern Classification

The objective and automatic detection of the sleep–wake cycle (SWC) stages is essential for the investigation of its physiology and dysfunction. Here, we propose a machine learning model for the classification of SWC stages based on the measurement of synchronization between neural oscillations of different frequencies. Publicly available electrophysiological recordings of mice were analyzed for the computation of phase–amplitude couplings, which were then supplied to a multilayer perceptron (MLP). Firstly, we assessed the performance of several architectures, varying among different input choices and numbers of neurons in the hidden layer. The top performing architecture was then tested using distinct extrapolation strategies that would simulate applications in a real lab setting. Although all the different choices of input data displayed high AUC values (&gt;0.85) for all the stages, the ones using larger input datasets performed significantly better. The top performing architecture displayed high AUC values (&gt;0.95) for all the extrapolation strategies, even in the worst-case scenario in which the training with a single day and single animal was used to classify the rest of the data. Overall, the results using multiple performance metrics indicate that the usage of a basic MLP fed with highly descriptive features such as neural synchronization is enough to efficiently classify SWC stages.

Multifaceted Roles of Melatonin in Sleep Disorders

Hormone protein melatonin helps regulate the sleep–wake cycle or circadian rhythm, making it a critical substance in sleep regulation. Melatonin synthesis mainly occurs in the epiphysis of the pineal gland, although extra-pineal melatonin has been observed in other sites of the body, such as salivary glands, the gastrointestinal tract, the placenta and breast milk. Over the years, research into melatonin has shown that it has multiple roles in sleep disorders, revealing its mechanisms of action, clinical implications and therapeutic performance. In this paper, we review recent findings on the role of melatonin in sleep disorders which include insomnia, delayed sleep phase disorder (DSPD), jet lag, and shift work sleep disorder (SWSD). In addition, we report results where melatonin agonists and novel therapeutic targets have been designed and utilized to manipulate the melatonin receptors. This paper helps delineate melatonin’s role in sleep disorders from the literature, and clarify new perspectives for prevention and treatment of human health.

More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα

AbstractCircadian rhythms, governed by the dominant central clock, in addition to various peripheral clocks, regulate almost all biological processes, including sleep–wake cycles, hormone secretion and metabolism. In certain contexts, the regulation and function of the peripheral oscillations can be decoupled from the central clock. However, the specific mechanisms underlying muscle‐intrinsic clock‐dependent modulation of muscle function and metabolism remain unclear. We investigated the outcome of perturbations of the primary and secondary feedback loops of the molecular clock in skeletal muscle by specific gene ablation of Period circadian regulator 2 (Per2) and RAR‐related orphan receptor alpha (Rorα), respectively. In both models, a dampening of core clock gene oscillation was observed, while the phase was preserved. Moreover, both loops seem to be involved in the homeostasis of amine groups. Highly divergent outcomes were seen for overall muscle gene expression, primarily affecting circadian rhythmicity in the PER2 knockouts and non‐oscillating genes in the RORα knockouts, leading to distinct outcomes in terms of metabolome and phenotype. These results highlight the entanglement of the molecular clock and muscle plasticity and allude to specific functions of different clock components, i.e. the primary and secondary feedback loops, in this context. The reciprocal interaction between muscle contractility and circadian clocks might therefore be instrumental to determining a finely tuned adaptation of muscle tissue to perturbations in health and disease. imageKey points Specific perturbations of the primary and secondary feedback loop of the molecular clock result in specific outcomes on muscle metabolism and function. Ablation of Per2 (primary loop) or Rorα (secondary loop) blunts the amplitude of core clock genes, in absence of a shift in phase. Perturbation of the primary feedback loop by deletion of PER2 primarily affects muscle gene oscillation. Knockout of RORα and the ensuing modulation of the secondary loop results in the aberrant expression of a large number of non‐clock genes and proteins. The deletion of PER2 and RORα affects muscle metabolism and contractile function in a circadian manner, highlighting the central role of the molecular clock in modulating muscle plasticity.

The Effects of Obstructive Sleep Apnea on the Cardiovascular System: A Comprehensive Review.

Obstructive sleep apnea (OSA) is an increasingly relevant cause of cardiovascular morbidity worldwide. Although the association between OSA and the cardiovascular system is well-known, the extent of its effects is still a topic of interest, including pathophysiologic mechanisms, cardiovascular sequelae, and OSA therapies and their effects. Commonly described mechanisms of cardiovascular etiologies revolve around sympathetic activation, inflammation, and intermittent hypoxia resulting from OSA. Ultimately, these effects lead to manifestations in the cardiovascular system, such as arrhythmias, hypertension, and heart failure, among others. The resulting sequelae of OSA may also have differential effects based on gender and age; several studies suggest female gender to have more susceptibility to cardiovascular mortality, as well as an increase in age. Furthermore, several therapies for OSA, both established and emerging, show a reduction in cardiovascular morbidity and may even reduce cardiovascular burden. Namely, the establishment of CPAP has led to improvement in hypertension and cardiac function in patients with heart failure and even reduced the progression of early stages of atherosclerosis. Effective management of OSA decreases abnormal neural sympathetic activity, which results in better rhythm control and blood pressure control, both in waking and sleep cycles. With newer therapies for OSA, its effects on the cardiovascular system may be significantly reduced or even reversed after long-term management. The vast extent of OSA on the cardiovascular system, as well as current and future therapeutic strategies, will be described in detail in this review.

Exercise derived myokine irisin as mediator of cardiorespiratory, metabolic and thermal adjustments during central and peripheral chemoreflex activation

Exercise elicits physiological adaptations, including hyperpnea. However, the mechanisms underlying exercise-induced hyperpnea remain unresolved. Skeletal muscle acts as a secretory organ, releasing irisin (IR) during exercise. Irisin can cross the blood–brain barrier, influencing muscle and tissue metabolism, as well as signaling in the central nervous system (CNS). We evaluated the effect of intracerebroventricular or intraperitoneal injection of IR in adult male rats on the cardiorespiratory and metabolic function during sleep–wake cycle under room air, hypercapnia and hypoxia. Central IR injection caused an inhibition on ventilation (VE) during wakefulness under normoxia, while peripheral IR reduced VE during sleep. Additionally, central IR exacerbates hypercapnic hyperventilation by increasing VE and reducing oxygen consumption. As to cardiovascular regulation, central IR caused an increase in heart rate (HR) across all conditions, while no change was observed following peripheral administration. Finally, central IR attenuated the hypoxia-induced regulated hypothermia and increase sleep episodes, while peripheral IR augmented CO2-induced hypothermia, during wakefulness. Overall, our results suggest that IR act mostly on CNS exerting an inhibitory effect on breathing under resting conditions, while stimulating the hypercapnic ventilatory response and increasing HR. Therefore, IR seems not to be responsible for the exercise-induced hyperpnea, but contributes to the increase in HR.

Cannabinoid and Orexigenic Systems Interplay as a New Focus of Research in Alzheimer’s Disease

Alzheimer’s disease (AD) remains a significant health challenge, with an increasing prevalence globally. Recent research has aimed to deepen the understanding of the disease pathophysiology and to find potential therapeutic interventions. In this regard, G protein-coupled receptors (GPCRs) have emerged as novel potential therapeutic targets to palliate the progression of neurodegenerative diseases such as AD. Orexin and cannabinoid receptors are GPCRs capable of forming heteromeric complexes with a relevant role in the development of this disease. On the one hand, the hyperactivation of the orexins system has been associated with sleep–wake cycle disruption and Aβ peptide accumulation. On the other hand, cannabinoid receptor overexpression takes place in a neuroinflammatory environment, favoring neuroprotective effects. Considering the high number of interactions between cannabinoid and orexin systems that have been described, regulation of this interplay emerges as a new focus of research. In fact, in microglial primary cultures of APPSw/Ind mice model of AD there is an important increase in CB2R–OX1R complex expression, while OX1R antagonism potentiates the neuroprotective effects of CB2R. Specifically, pretreatment with the OX1R antagonist has been shown to strongly potentiate CB2R signaling in the cAMP pathway. Furthermore, the blockade of OX1R can also abolish the detrimental effects of OX1R overactivation in AD. In this sense, CB2R–OX1R becomes a new potential therapeutic target to combat AD.