Search Results (51)

Background/Objectives: Schizophrenia is a severe psychiatric disorder frequently characterised by sleep and circadian disturbances, which are closely linked to cognitive dysfunction, symptom exacerbation, and poor functional outcomes. A growing body of evidence implicates the orexin (hypocretin) system—an essential regulator of arousal, sleep–wake stability, metabolic processes, and motivated behaviour—in the pathophysiology and treatment response of psychotic disorders. We aimed to investigate the relationships between the orexinergic system and psychoses. Methods: On 3 March 2026, we searched the PubMed, Scopus, PsycInfo/Articles and Cinahl databases for studies dealing with the orexin system and psychotic disorders and treatment response. Results: We found 20 eligible studies reporting variable and inconsistent alterations in orexin signalling in patients with schizophrenia. Studies were mostly cross-sectional and heterogeneous in design. Antipsychotic medications interfere with orexin-dependent pathways, potentially contributing to both therapeutic effects and adverse outcomes such as sleep disruption and metabolic dysregulation. Conclusions: While evidence from preclinical studies could point to an influence of dopaminergic activity through orexinergic mechanisms, with possible attenuation of antipsychotic-induced motor side effects and improvement of attentional deficits associated with NMDA receptor hypofunction, the utility of dual orexin receptor antagonists (DORAs) in psychoses is unclear. Despite the high prevalence of insomnia in schizophrenia, its pharmacological management remains suboptimal, with current treatments often limited by reduced efficacy or tolerability concerns. DORAs, which are currently approved medications for the treatment of insomnia, represent a novel and mechanistically distinct therapeutic option that may improve sleep while modulating arousal- and cognition-related circuits relevant to psychosis. Full article

Acute injuries to the central nervous system (CNS) share a rapid disruption of arousal, autonomic stability, and neuroimmune balance. Among the neuromodulatory systems affected, the orexin (hypocretin) network is uniquely positioned at the intersection of wakefulness, autonomic control, and motivated behavior. Experimental evidence across ischemic, hemorrhagic, traumatic, and systemic models shows that orexin signaling is sharply suppressed during the early post-injury collapse and gradually recovers as arousal circuits and homeostatic functions stabilize. Controlled enhancement of orexinergic tone has been found to improve arousal state, modulate inflammatory responses, and support behavioral engagement, although these effects are highly dependent on timing, receptor subtype, and physiological context. This review synthesizes evidence from ischemia, hemorrhagic stroke, traumatic brain and spinal cord injury, and systemic inflammatory states, and examines the conceptual and translational rationale for targeting orexin pathways. We summarize available pharmacological, peptide-based, neuromodulatory, and physiological strategies to boost orexinergic tone, highlighting the growing development of selective OX₂ agonists and experimental approaches to enhance endogenous orexin activity. By integrating findings across etiologies within a timing-aware framework, this review addresses a gap in the current literature, which has largely treated these injuries in isolation. While clinical testing in acute CNS injury has not yet been performed, the mechanistic convergence across etiologies suggests that orexinergic modulation may offer a phase-sensitive means to stabilize arousal and support recovery. Taken together, orexin emerges as a state-dependent integrator whose modulation could complement existing therapies by linking early arousal stabilization with longer-term motivational and functional recovery. Full article

Narcolepsy Type 1 (NT1) is a rare chronic neurological disorder characterized by core clinical manifestations such as excessive daytime sleepiness (EDS), cataplexy, sleep paralysis (SP), hypnagogic and hypnopompic hallucinations (HHs), and disrupted nocturnal sleep (DNS). Patients often experience comorbidities, including cognitive impairment, psychiatric disorders, and metabolic syndrome, necessitating lifelong management. Current therapeutic approaches primarily involve pharmacologic treatments for symptomatic relief, supplemented by non-pharmacologic interventions aimed at alleviating EDS and cataplexy. However, existing therapies are limited in efficacy and do not offer a cure. In recent years, a deeper understanding of the central role played by the orexin (hypocretin) system in the pathogenesis of NT1 has led to breakthrough advances in mechanism-based therapies targeting this pathway. Notably, selective orexin-2 receptor (OX2R) agonists such as TAK-861 have shown remarkable efficacy in Phase II/III clinical trials, holding the potential to fundamentally reshape the NT1 treatment landscape. This review systematically outlines current treatment options for NT1, with a focus on management strategies for atypical symptoms and special populations. It also highlights emerging therapeutic directions—including orexin-targeted agents, immunotherapies, and orexin cell/gene treatments—along with their future development. Full article

Animal models have been pivotal in uncovering the orexin (hypocretin) system as the fulcrum of sleep–wake regulation and in shaping therapeutic discovery for narcolepsy. Early canine and murine models established that orexin loss underlies narcolepsy type 1, while conditional and receptor-specific manipulations refined mechanistic insight. However, current paradigms capture only fragments of the human phenotype, often exaggerating cataplexy and under-representing narcolepsy type 2. Here, we follow the evolution of narcolepsy modelling from classical knockout and receptor-deficient systems to immune-driven and cell-replacement models, identifying critical translational gaps and proposing strategies to bridge them. We highlight how immune-competent mouse lines, astrocyte-to-neuron reprogramming, and patient-derived hypothalamic organoids bridge pathogenic insight with therapeutic innovation. Integrating these advances with small-molecule OX2R agonists, gene therapy, and multi-omics-based patient stratification defines a roadmap for moving beyond symptomatic control. This review seeks to unify immune, cellular, and computational perspectives to guide the next generation of animal models toward the prevention, repair, and long-term cure of narcolepsy. Full article

The orexin (hypocretin) system plays a central role in regulating the sleep–wake cycle through two neuropeptides, orexin-A and orexin-B, which act on OX1R and OX2R receptors. Emerging evidence links heightened orexin signaling with the pathophysiology of chronic insomnia. This review outlines the neurobiology of the orexinergic system, compares the pharmacological profile of dual orexin receptor antagonists (DORAs) to traditional GABAergic hypnotics, and evaluates the clinical efficacy and safety of Suvorexant, Lemborexant, and Daridorexant. DORAs function by selectively dampening orexin-driven arousal, thereby facilitating sleep onset and maintenance without disrupting natural sleep architecture. Clinical trials have shown that these agents significantly reduce sleep latency and enhance sleep continuity, with a favorable side effect profile. Overall, DORAs represent a distinct and clinically advantageous option for insomnia treatment, with growing interest in their potential utility across mood, anxiety, and neurodegenerative disorders. Full article

The relationship between sleep and epilepsy involves complex interactions between thalamocortical circuits, circadian mechanisms, and sleep architecture that fundamentally influence seizure susceptibility and cognitive outcomes. Epileptic activity disrupts essential sleep oscillations, particularly sleep spindles generated by thalamic circuits. Thalamic epileptic spikes actively compete with physiological sleep spindles, impairing memory consolidation and contributing to cognitive dysfunction in epileptic encephalopathy. This disruption explains why patients with epilepsy often experience learning difficulties despite adequate seizure control. Sleep stages show differential seizure susceptibility. REM sleep provides robust protection through enhanced GABAergic inhibition and motor neuron suppression, while non-REM sleep, particularly slow-wave sleep, increases seizure risk. These observations reveal fundamental mechanisms of seizure control within normal brain physiology. Circadian clock genes (BMAL1, CLOCK, PER, CRY) play crucial roles in seizure modulation. Dysregulation of these molecular timekeepers creates permissive conditions for seizure generation while being simultaneously disrupted by epileptic activity, establishing a bidirectional relationship. These mechanistic insights are driving chronobiological therapeutic approaches, including precisely timed antiseizure medications, sleep optimization strategies, and orexin/hypocretin system interventions. This understanding enables a paradigm shift from simple seizure suppression toward targeted restoration of physiological brain rhythms, promising transformative epilepsy management through sleep-informed precision medicine. Full article

Clinical and animal studies suggest that multiple brain systems are involved in mediating reward-motivated and related emotional behavior including the consumption of commonly used drugs and palatable food, and there is evidence that the repeated ingestion of or exposure to these rewarding substances may in turn stimulate these brain systems to produce an overconsumption of these substances along with co-occurring emotional disturbances. To understand this positive feedback loop, this review focuses on a specific population of hypothalamic peptide neurons expressing melanin-concentrating hormone (MCH), which are positively related to dopamine reward and project to forebrain areas that mediate this behavior. It also examines neurons expressing the peptide hypocretin/orexin (HCRT) that are anatomically and functionally linked to MCH neurons and the molecular systems within these peptide neurons that stimulate their development and ultimately affect behavior. This report first describes evidence in animals that exposure in adults and during adolescence to rewarding substances, such as the drugs alcohol, nicotine and cocaine and palatable fat-rich food, stimulates the expression of MCH as well as HCRT and their intracellular molecular systems. It also increases reward-seeking and emotional behavior, leading to excess consumption and abuse of these substances and neurological conditions, completing this positive feedback loop. Next, this review focuses on the model involving embryonic exposure to these rewarding substances. In addition to revealing a similar positive feedback circuit, this model greatly advances our understanding of the diverse changes that occur in these neuropeptide/molecular systems in the embryo and how they relate, perhaps causally, to the disturbances in behavior early in life that predict a later increased risk of developing substance use disorders. Studies using this model demonstrate in animals that embryonic exposure to these rewarding substances, in addition to stimulating the expression of peptide neurons, increases the intracellular molecular systems in neuroprogenitor cells that promote their development. It also alters the morphology, migration, location and neurochemical profile of the peptide neurons and causes them to develop aberrant neuronal projections to forebrain structures. Moreover, it produces disturbances in behavior at a young age, which are sex-dependent and occur in females more than in males, that can be directly linked to the neuropeptide/molecular changes in the embryo and predict the development of behavioral disorders later in life. These results supporting the close relationship between the brain and behavior are consistent with clinical studies, showing females to be more vulnerable than males to developing substance use disorders with co-occurring emotional conditions and female offspring to respond more adversely than male offspring to prenatal exposure to rewarding substances. It is concluded that the continued consumption of or exposure to rewarding substances at any stage of life can, through such peptide brain systems, significantly increase an individual’s vulnerability to developing neurological disorders such as substance use disorders, anxiety, depression, or cognitive impairments. Full article

The increasing incidence of autism spectrum disorder (ASD) increases the urgency of establishing the mechanism of its development for effective prevention and treatment. ASD’s etiology includes genetic predisposition and environmental triggers, both of which can play a role in the changed microbiota. Recent research has proved the impact of maternal microbiota on the neurodevelopment of the child. To investigate the co-play of genetic and microbiota factors in ASD development, we performed fecal microbiota transplantation (FMT) from children with ASD to female Shank3b^+/− mice and studied the autism-like symptoms in the male Shank3b^−/− and wild-type (WT) offspring. WT animals with prenatal exposure to ASD microbiota had delayed neurodevelopment and impaired food intake behavior, but also elevated plasma leptin concentration and body weight. Shank3b^−/− mice after FMT ASD exhibited impaired learning and exacerbated anxiety-like behavior in adulthood. Interestingly, FMT ASD improved learning in adolescent Shank3b^−/− mice. Prenatal exposure to ASD microbiota decreased the activity of hypocretin neurons of the lateral hypothalamic area in both genotypes. The combination of genetic predisposition and FMT ASD led to an increased colon permeability, evaluated by zonula occludens (ZO1, ZO3) and claudin factors. These results suggest the effect of parental FMT exposure on shaping offspring behavior in Shank3b^−/− mice and the potential of microbiota in the modulation of ASD. Full article

Background: Narcolepsy type 1 (NT1) is a rare neurological sleep disorder characterized by excessive daytime sleepiness and cataplexy. NT1 is thought to be caused by the loss of hypocretin-producing neurons in the hypothalamus due to autoimmunity. Since cerebrospinal fluid hypocretin testing is invasive and not always feasible in clinical practice, there is a critical need for less invasive biomarkers to improve diagnostic accuracy and accessibility. Very few studies have explored serum-based biomolecules that could serve as biomarkers for NT1. Methods: This study examines the differential abundance of serum metabolites in patients with NT1 using an LC-MS/MS-based comprehensive metabolomics approach. Results: An untargeted analysis identified a total of 1491 metabolites, 453 of which were differentially abundant compared to the control cohort. Ingenuity pathway analysis revealed that key pathways, such as the inflammatory response (p-value of 0.01, activation z-score of 0.5), generation and synthesis of reactive oxygen species (p-value of 0.0008, z-score of 1.3), and neuronal cell death (p-value of 0.04, z-score of 0.4), are predicted to be activated in NT1. A targeted analysis using parallel reaction monitoring validated 49 metabolites, including important downregulated metabolites such as uridine (fold change (FC) of 0.004), epinephrine (FC of 0.05), colchicine (FC of 0.2), corticosterone (FC of 0.3), and arginine (FC of 0.6), as well as upregulated metabolites such as p-cresol sulfate (FC of 2601.7), taurine (FC of 1315.4), inosine (FC of 429.7), and malic acid (FC of 7.9). Conclusions: Understanding the pathways identified in this study and further investigating the differentially abundant metabolites associated with them may pave the way for gaining insight into disease pathogenesis and developing novel therapeutic interventions. Full article

Unsatisfactory sleep is a worldwide concern, as evidenced by the high prevalence of insomnia symptoms and diagnosis in the general population, and an issue that has also risen among adolescents. These circumstances are a cause of worry due to, among other factors, the observed bidirectional association of sleep disturbances and the risk of substance use disorder development. In this regard, across the globe, several reports indicate that substance consumption is at an all-time high, with alcohol, nicotine, and cannabis leading the charts. Additionally, the age of onset has dropped, with reports suggesting that first contact is usually during adolescence. Although the nature of the link between poor sleep and substance use disorder development is still not fully understood, it is possible that an overactive orexinergic system could play a role, as it has been observed that treatment with orexinergic antagonists improves insomnia symptoms and that postmortem studies show an increase in orexin immunoreactive neurons in sections obtained from habitual opioid consumers. We further argue that it is during adolescence that this maladaptive loop can be established, priming for the development of substance use disorders. Full article

The significant correlation between ancient medicinal practices and brain function marks a revolutionary frontier in the field of neuroscience. Acupuncture, a traditional oriental medicine, can affect brain regions, such as the hypothalamus, anterior cingulate, posterior cingulate, and hippocampus, and produces specific therapeutic effects, such as pain relief, suppression of hypertension, and alleviation of drug addiction. Among the brain regions, the hypothalamus, a small yet critical region in the brain, plays a pivotal role in maintaining homeostasis by regulating a wide array of physiological processes, including stress responses, energy balance, and pain modulation. Emerging evidence suggests that acupuncture may exert its therapeutic effects by modulating the activity of the hypothalamus and its associated neural circuits, particularly in relation to pain, stress, and metabolic regulation. Thus, we conducted a comprehensive review of past and current research on the role of the hypothalamus in mediating the therapeutic effects of acupuncture. Full article

Sleep is the most important physiological function of all animals studied to date. Sleep disorders include narcolepsy, which is characterized by excessive daytime sleepiness, disruption of night sleep, and muscle weakness—cataplexy. Narcolepsy is known to be caused by the degeneration of orexin-synthesizing neurons (hypocretin (HCRT) neurons or orexin neurons) in the hypothalamus. In mammals, HCRT neurons primarily regulate the sleep/wake cycle, nutrition, reward seeking, and addiction development. The hypocretin system of the brain is involved in a number of neurological disorders. The distinctive pathologies associated with the disruption of HCRT neurons are narcolepsy and cataplexy, which are caused by the loss of hypocretin neurons that produce HCRT. In Danio, the hypocretin system is also involved in the regulation of sleep and wakefulness. It is represented by a single hcrt gene that encodes the peptides HCRT1 and HCRT2, as well as one HCRT receptor (HCRTR), which is structurally closest to the mammalian HCRTR2. The overexpression of the hcrt gene in Danio rerio larvae causes wakefulness, whereas the physical destruction of HCRT cells or a pharmacological blockade of the type 2 hypocretin receptor leads to fragmentation of sleep in fish larvae, which is also observed in patients with narcolepsy. These data confirm the evolutionary conservatism of the hypocretin system. Thus, Danio rerio is an ideal model for studying the functions of HCRT neural networks and their functions. Full article

Narcolepsy type 1 (NT1) is an uncommon, persistent sleep disorder distinguished by significant daytime sleepiness, episodes of cataplexy, and irregularities in rapid eye movement sleep. The etiology of NT1 is linked to the destruction of hypothalamic neurons responsible for the synthesis of the wake-promoting neuropeptide known as hypothalamic orexin. The pathophysiological mechanisms underlying NT1 remain inadequately elucidated; however, a model that incorporates the interplay of genetic predisposition, environmental influences, immune system factors, and a deficiency in hypocretin (HCRT) provides a framework for elucidating the pathogenesis of NT1. The prevalence of NT1 has been observed to rise following influenza A (H1N1) pdm09 and the administration of the Pandemrix influenza vaccine. The strong association between narcolepsy and the HLA-DQB1*06:02 allele strongly indicates an autoimmune etiology for this condition. Increasing evidence suggests that T cells play a critical role in this autoimmune-mediated HCRT neuronal loss. Studies have identified specific T cell subsets, including CD4⁺ and CD8⁺ T cells, that target HCRT neurons, contributing to their destruction. Clarifying the pathogenesis of NT1 driven by autoimmune T cells is crucial for the development of effective therapeutic interventions for this disorder. This review examines the risk factors associated with the pathogenesis of NT1, explores the role of T cells within the immune system in the progression of NT1, and evaluates immune-mediated animal models alongside prospective immunotherapeutic strategies. Full article

Orexin-A is a neuropeptide product of the lateral hypothalamus that acts on two receptors, OX1R and OX2R. The orexinergic system is involved in feeding, sleep, and pressure regulation. Recently, orexin-A levels have been found to be negatively correlated with renal function. Here, we analyzed orexin-A levels as well as the incidence of SNPs in the hypocretin neuropeptide precursor (HCRT) and its receptors, HCRTR1 and HCRTR2, in 64 patients affected by autosomal dominant polycystic kidney disease (ADPKD) bearing truncating mutations in the PKD1 or PKD2 genes. Twenty-four healthy volunteers constituted the control group. Serum orexin-A was assessed by ELISA, while the SNPs were investigated through Sanger sequencing. Correlations with the main clinical features of PKD patients were assessed. PKD patients showed impaired renal function (mean eGFR 67.8 ± 34.53) and a statistically higher systolic blood pressure compared with the control group (p < 0.001). Additionally, orexin-A levels in PKD patients were statistically higher than those in healthy controls (477.07 ± 69.42 pg/mL vs. 321.49 ± 78.01 pg/mL; p < 0.001). Furthermore, orexin-A inversely correlated with blood pressure (p = 0.0085), while a direct correlation with eGFR in PKD patients was found. None of the analyzed SNPs showed any association with orexin-A levels in PKD. In conclusion, our data highlights the emerging role of orexin-A in renal physiology and its potential relevance to PKD. Further research is essential to elucidate the intricate mechanisms underlying orexin-A signaling in renal function and its therapeutic implications for PKD and associated cardiovascular complications. Full article

Orexin/hypocretin terminals innervate the dorsal raphe nucleus (DRN), which projects to motor control areas important for spontaneous physical activity (SPA) and energy expenditure (EE). Orexin receptors are expressed in the DRN, and obesity-resistant (OR) rats show higher expression of these receptors in the DRN and elevated SPA/EE. We hypothesized that orexin-A in the DRN enhances SPA/EE and that DRN-GABA modulates the effect of orexin-A on SPA/EE. We manipulated orexin tone in the DRN either through direct injection of orexin-A or through the chemogenetic activation of lateral-hypothalamic (LH) orexin neurons. In the orexin neuron activation experiment, fifteen minutes prior to the chemogenetic activation of orexin neurons, the mice received either the GABA-agonist muscimol or antagonist bicuculline injected into the DRN, and SPA/EE was monitored for 24 h. In a separate experiment, orexin-A was injected into the DRN to study the direct effect of DRN orexin on SPA/EE. We found that the activation of orexin neurons elevates SPA/EE, and manipulation of GABA in the DRN does not alter the SPA response to orexin neuron activation. Similarly, intra-DRN orexin-A enhanced SPA and EE in the mice. These results suggest that orexin-A in the DRN facilitates negative energy balance by increasing physical activity-induced EE, and that modulation of DRN orexin-A is a potential strategy to promote SPA and EE. Full article