Acoustic Stimulation to Improve Slow-Wave Sleep in Alzheimer's Disease: A Multiple Night At-Home Intervention.

OBJECTIVES: To investigate the efficacy of closed-loop acoustic stimulation (CLAS) during slow-wave sleep (SWS) to enhance slow-wave activity (SWA) and SWS in patients with Alzheimer's disease (AD) across multiple nights and to explore associations between stimulation, participant characteristics, and individuals' SWS response. DESIGN: A 2-week, open-label at-home intervention study utilizing the DREEM2 headband to record sleep data and administer CLAS during SWS. SETTING AND PARTICIPANTS: Fifteen older patients with AD (6 women, mean age: 76.27 [SD = 6.06], mean MOCA-score: 16.07 [SD = 6.94]), living at home with their partner, completed the trial. INTERVENTION: Patients first wore the device for two baseline nights, followed by 14 nights during which the device was programmed to randomly either deliver acoustic stimulations of 50 ms pink noise (± 40 dB) targeted to the slow-wave up-phase during SWS or only mark the wave (sham). RESULTS: On a group level, stimulation significantly enhanced SWA and SWS with consistent SWS enhancement throughout the intervention. However, substantial variability existed in individual responses to stimulation. Individuals received more stimulations on nights with increased SWS compared to baseline than on nights with no change or a decrease. In individuals, having lower baseline SWS correlated with receiving fewer stimulations on average during the intervention. CONCLUSION: CLAS during SWS is a promising nonpharmacological method to enhance SWA and SWS in AD. However, patients with lower baseline SWS received fewer stimulations during the intervention, possibly resulting in less SWS enhancement. Individual variability in response to stimulation underscores the need to address personalized stimulation parameters in future research and therapy development.

Hypocretin-1 receptor antagonism improves inhibitory control during the Go/No-Go task in highly motivated, impulsive male mice.

RATIONALE: Motivation and inhibitory control are dominantly regulated by the dopaminergic (DA) and noradrenergic (NA) systems, respectively. Hypothalamic hypocretin (orexin) neurons provide afferent inputs to DA and NA nuclei and hypocretin-1 receptors (HcrtR1) are implicated in reward and addiction. However, the role of the HcrtR1 in inhibitory control is not well understood. OBJECTIVES: To determine the effects of HcrtR1 antagonism and motivational state in inhibitory control using the go/no-go task in mice. METHODS: n = 23 male C57Bl/6JArc mice were trained in a go/no-go task. Decision tree dendrogram analysis of training data identified more and less impulsive clusters of animals. A HcrtR1 antagonist (BI001, 12.5 mg/kg, per os) or vehicle were then administered 30 min before go/no-go testing, once daily for 5 days, under high (food-restricted) and low (free-feeding) motivational states in a latin-square crossover design. Compound exposure levels were assessed in a satellite group of animals. RESULTS: HcrtR1 antagonism increased go accuracy and decreased no-go accuracy in free-feeding animals overall, whereas it decreased go accuracy and increased no-go accuracy only in more impulsive, food restricted mice. HcrtR1 antagonism also showed differential effects in premature responding, which was increased in response to the antagonist in free-feeding, less impulsive animals, and decreased in food restricted, more impulsive animals. HcrtR1 receptor occupancy by BI001 was estimated at ~ 66% during the task. CONCLUSIONS: These data indicate that hypocretin signalling plays roles in goal-directed behaviour and inhibitory control in a motivational state-dependant manner. While likely not useful in all settings, HcrtR1 antagonism may be beneficial in improving inhibitory control in impulsive subpopulations.

International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology.

The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX1 and OX2 Orexin receptors are capable of coupling to all four families of heterotrimeric G proteins, and there are also other complex features of the orexin receptor signaling. The system was discovered 25 years ago and was immediately identified as a central regulator of sleep and wakefulness; this is exemplified by the symptomatology of the disorder narcolepsy with cataplexy, in which orexinergic neurons degenerate. Subsequent translation of these findings into drug discovery and development has resulted to date in three clinically used orexin receptor antagonists to treat insomnia. In addition to sleep and wakefulness, the orexin system appears to be a central player at least in addiction and reward, and has a role in depression, anxiety and pain gating. Additional antagonists and agonists are in development to treat, for instance, insomnia, narcolepsy with or without cataplexy and other disorders with excessive daytime sleepiness, depression with insomnia, anxiety, schizophrenia, as well as eating and substance use disorders. The orexin system has thus proved an important regulator of numerous neural functions and a valuable drug target. Orexin prepro-peptide and orexin receptors are also expressed outside the central nervous system, but their potential physiological role there remains unknown. Significance Statement The orexin system was discovered 25 years ago and immediately emerged as an essential sleep-wakefulness regulator. This discovery has tremendously increased the understanding of these processes and has thus far resulted in the market approval of three orexin receptor antagonists, which promote more physiological sleep than previous hypnotics. Further, orexin receptor agonists and antagonists with different pharmacodynamic properties are in development since research has revealed additional potential therapeutic indications. Orexin receptor signaling is complex and may represent novel features.

A contemporary training concept in critical care cardiology.

Critical care cardiology (CCC) in the modern era is shaped by a multitude of innovative treatment options and an increasingly complex, ageing patient population. Generating high-quality evidence for novel interventions and devices in an intensive care setting is exceptionally challenging. As a result, formulating the best possible therapeutic approach continues to rely predominantly on expert opinion and local standard operating procedures. Fostering the full potential of CCC and the maturation of the next generation of decision-makers in this field calls for an updated training concept, that encompasses the extensive knowledge and skills required to care for critically ill cardiac patients while remaining adaptable to the trainee's individual career planning and existing educational programs. In the present manuscript, we suggest a standardized training phase in preparation of the first ICU rotation, propose a modular CCC core curriculum, and outline how training components could be conceptualized within three sub-specialization tracks for aspiring cardiac intensivists.

The characteristic time scale of cultural evolution.

Numerous researchers from various disciplines have explored commonalities and divergences in the evolution of complex social formations. Here, we explore whether there is a "characteristic" time course for the evolution of social complexity in a handful of different geographic areas. Data from the Seshat: Global History Databank is shifted so that the overlapping time series can be fitted to a single logistic regression model for all 23 geographic areas under consideration. The resulting regression shows convincing out-of-sample predictions, and its period of extensive growth in social complexity can be identified via bootstrapping as a time interval of roughly 2,500 years. To analyze the endogenous growth of social complexity, each time series is restricted to a central time interval without major disruptions in cultural or institutional continuity, and both approaches result in a similar logistic regression curve. Our results suggest that these different areas have indeed experienced a similar course in the their evolution of social complexity, but that this is a lengthy process involving both internal developments and external influences.

Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease.

Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.

Orexin 2 receptor antagonism sex-dependently improves sleep/wakefulness and cognitive performance in tau transgenic mice.

BACKGROUND AND PURPOSE: Tau pathology contributes to a bidirectional relationship between sleep disruption and neurodegenerative disease. Tau transgenic rTg4510 mice model tauopathy symptoms, including sleep/wake disturbances, which manifest as marked hyperarousal. This phenotype can be prevented by early transgene suppression; however, whether hyperarousal can be rescued after onset is unknown. EXPERIMENTAL APPROACH: Three 8-week experiments were conducted with wild-type and rTg4510 mice after age of onset of hyperarousal (4.5 months): (1) Tau transgene suppression with doxycycline (200 ppm); (2) inactive phase rapid eye movement (REM) sleep enhancement with the dual orexin receptor antagonist suvorexant (50 mg·kg-1 ·day-1 ); or (3) Active phase non-NREM (NREM) and REM sleep enhancement using the selective orexin 2 (OX2 ) receptor antagonist MK-1064 (40 mg·kg-1 ·day-1 ). Sleep was assessed using polysomnography, cognition using the Barnes maze, and tau pathology using immunoblotting and/or immunohistochemistry. KEY RESULTS: Tau transgene suppression improved tauopathy and hippocampal-dependent spatial memory, but did not modify hyperarousal. Pharmacological rescue of REM sleep deficits did not improve spatial memory or tau pathology. In contrast, normalising hyperarousal by increasing both NREM and REM sleep via OX2 receptor antagonism restored spatial memory, independently of tauopathy, but only in male rTg4510 mice. OX2 receptor antagonism induced only short-lived hypnotic responses in female rTg4510 mice and did not improve spatial memory, indicating a tau- and sex-dependent disruption of OX2 receptor signalling. CONCLUSIONS AND IMPLICATIONS: Pharmacologically reducing hyperarousal corrects tau-induced sleep/wake and cognitive deficits. Tauopathy causes sex-dependent disruptions of OX2 receptor signalling/function, which may have implications for choice of hypnotic therapeutics in tauopathies.

Navigating polycrisis: long-run socio-cultural factors shape response to changing climate.

Climate variability and natural hazards like floods and earthquakes can act as environmental shocks or socioecological stressors leading to instability and suffering throughout human history. Yet, societies experience a wide range of outcomes when facing such challenges: some suffer from social unrest, civil violence or complete collapse; others prove more resilient and maintain key social functions. We currently lack a clear, generally agreed-upon conceptual framework and evidentiary base to explore what causes these divergent outcomes. Here, we discuss efforts to develop such a framework through the Crisis Database (CrisisDB) programme. We illustrate that the impact of environmental stressors is mediated through extant cultural, political and economic structures that evolve over extended timescales (decades to centuries). These structures can generate high resilience to major shocks, facilitate positive adaptation, or, alternatively, undermine collective action and lead to unrest, violence and even societal collapse. By exposing the ways that different societies have reacted to crises over their lifetime, this framework can help identify the factors and complex social-ecological interactions that either bolster or undermine resilience to contemporary climate shocks. This article is part of the theme issue 'Climate change adaptation needs a science of culture'.

Effectiveness of conduction system pacing for cardiac resynchronization therapy: A systematic review and network meta-analysis.

INTRODUCTION: Cardiac resynchronization therapy (CRT) with biventricular pacing (BiV-CRT) is ineffective in approximately one-third of patients. CRT with Conduction system pacing (CSP-CRT) may achieve greater synchronization. We aimed to assess the effectiveness of CRT with His pacing (His-CRT) or left bundle branch pacing (LBB-CRT) in lieu of biventricular CRT. METHODS AND RESULTS: The PubMed, Embase, Web of Science, Scopus, and the Cochrane Library were systematically searched until August 19, 2023, for original studies including patients with reduced left ventricular ejection fraction (LVEF) who received His- or LBB-CRT, that reported either CSP-CRT success, LVEF, QRS duration (QRSd), or New York Heart Association (NYHA) classification. Effect measures were compared with frequentist network meta-analysis. Thirty-seven publications, including 20 comparative studies, were included. Success rates were 73.5% (95% CI: 61.2-83.0) for His-CRT and 91.5% (95% CI: 88.0-94.1) for LBB-CRT. Compared to BiV-CRT, greater improvements were observed for LVEF (mean difference [MD] for His-CRT +3.4%; 95% CI [1.0; 5.7], and LBB-CRT: +4.4%; [2.5; 6.2]), LV end-systolic volume (His-CRT:17.2mL [29.7; 4.8]; LBB-CRT:15.3mL [28.3; 2.2]), QRSd (His-CRT: -17.1ms [-25.0; -9.2]; LBB-CRT: -17.4ms [-23.2; -11.6]), and NYHA (Standardized MD [SMD]: His-CRT:0.4 [0.8; 0.1]; LBB-CRT:0.4 [-0.7; -0.2]). Pacing thresholds at baseline and follow-up were significantly lower with LBB-CRT versus both His-CRT and BiV-CRT. CSP-CRT was associated with reduced mortality (R = 0.75 [0.61-0.91]) and hospitalizations risk (RR = 0.63 [0.42-0.96]). CONCLUSION: This study found that CSP-CRT is associated with greater improvements in QRSd, echocardiographic, and clinical response. LBB-CRT was associated with lower pacing thresholds. Future randomized trials are needed to determine CSP-CRT efficacy.

Structural-demographic analysis of the Qing Dynasty (1644-1912) collapse in China.

This paper analyzes the collapse of the Qing dynasty (1644-1912) through the lens of the Structural Demographic Theory (SDT), a general framework for understanding the drivers of socio-political instability in state-level societies. Although a number of competing ideas for the collapse have been proposed, none provide a comprehensive explanation that incorporates the interaction of all the multiple drivers involved. We argue that the four-fold population explosion peaking in the 19th century, the growing competition for a stagnant number of elite positions, and increasing state fiscal stress combined to produce an increasingly disgruntled populace and elite, leading to significant internal rebellions. We find that while neither the ecological disasters nor the foreign incursions during the 19th century were sufficient on their own to bring down the Qing, when coupled with the rising internal socio-political stresses, they produced a rapid succession of triggering events that culminated in the Qing collapse.

Safety and efficacy of renal sympathetic denervation: a 9-year long-term follow-up of 24-hour ambulatory blood pressure measurements.

Background: Renal sympathetic denervation (RDN) has been shown to lower arterial blood pressure both in the presence and in the absence of antihypertensive medication in an observation period of up to 3 years. However, long-term results beyond 3 years are scarcely reported. Methods: We performed a long-term follow-up on patients who were previously enrolled in a local renal denervation registry and who underwent radiofrequency RDN with the Symplicity Flex® renal denervation system between 2011 and 2014. The patients were assessed to evaluate their renal function by performing 24-hour ambulatory blood pressure measurement (ABPM), recording their medical history, and conducting laboratory tests. Results: Ambulatory blood pressure readings for 24 h were available for 72 patients at long-term follow-up (FU) [9.3 years (IQR: 8.5-10.1)]. We found a significant reduction of ABP from 150.1/86.1 ± 16.9/12.0 mmHg at baseline to 138.3/77.1 ± 16.5/11.1 mmHg at long-term FU (P < 0.001 for both systolic and diastolic ABP). The number of antihypertensive medications used by the patients significantly decreased from 5.4 ± 1.5 at baseline to 4.8 ± 1.6 at long-term FU (P < 0.01). Renal function showed a significant but expected age-associated decrease in the eGFR from 87.8 (IQR: 81.0-100.0) to 72.5 (IQR: 55.8-86.8) ml/min/1.73 m2 (P < 0.01) in patients with an initial eGFR > 60 ml/min/1.73 m2, while a non-significant decrease was observed in patients with an initial eGFR < 60 ml/min/1.73 m2 at long-term FU [56.0 (IQR: 40.9-58.4) vs. 39.0 (IQR: 13.5-56.3) ml/min/1.73 m2]. Conclusions: RDN was accompanied by a long-lasting reduction in blood pressure with a concomitant reduction in antihypertensive medication. No negative effects could be detected, especially with regard to renal function.

Explaining population booms and busts in Mid-Holocene Europe.

Archaeological evidence suggests that the population dynamics of Mid-Holocene (Late Mesolithic to Initial Bronze Age, ca. 7000-3000 BCE) Europe are characterized by recurrent booms and busts of regional settlement and occupation density. These boom-bust patterns are documented in the temporal distribution of 14C dates and in archaeological settlement data from regional studies. We test two competing hypotheses attempting to explain these dynamics: climate forcing and social dynamics leading to inter-group conflict. Using the framework of spatially-explicit agent-based models, we translated these hypotheses into a suite of explicit computational models, derived quantitative predictions for population fluctuations, and compared these predictions to data. We demonstrate that climate variation during the European Mid-Holocene is unable to explain the quantitative features (average periodicities and amplitudes) of observed boom-bust dynamics. In contrast, scenarios with social dynamics encompassing density-dependent conflict produce population patterns with time scales and amplitudes similar to those observed in the data. These results suggest that social processes, including violent conflict, played a crucial role in the shaping of population dynamics of European Mid-Holocene societies.

Altered EEG power spectrum, but not sleep-wake architecture, in HCN1 knockout mice.

Sleep is a complex biological state characterized by large populations of neurons firing in a rhythmic or synchronized manner. HCN channels play a critical role in generating and sustaining synchronized neuronal firing and are involved in the actions of anaesthetics. However, the role of these channels in sleep-wakefulness per se has yet to be studied. We conducted polysomnographic recordings of Hcn1 constitutive knockout (Hcn1 KO) and wild-type (WT) mice in order to investigate the potential role of HCN1 channels in sleep/wake regulation. EEG and EMG data were analysed using the Somnivore™ machine learning algorithm. Time spent in each vigilance state, bout number and duration, and EEG power spectral activity were compared between genotypes. There were no significant differences in the time spent in wake, rapid eye movement (REM) or non-REM (NREM) sleep between Hcn1 KO and WT mice. Wake bout duration during the inactive phase was significantly shorter in Hcn1 KO mice whilst no other bout parameters were affected by genotype. Hcn1 KO mice showed a reduction in overall EEG power which was particularly prominent in the theta (5-9 Hz) and alpha (9-15 Hz) frequency bands and most evident during NREM sleep. Together these data suggest that HCN1 channels do not play a major role in sleep architecture or modulation of vigilance states. However, loss of these channels significantly alters underlying neuronal activity within these states which may have functional consequences.

Default Mode Network Modulation by Psychedelics: A Systematic Review.

Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents-lysergic acid diethylamide, psilocybin, and ayahuasca-modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics.

The labelled container: Conceptual development of social group representations.

Pietraszewski contends that group representations that rely on a "containment metaphor" fail to adequately capture phenomena of group dynamics such as shifts in allegiances. We argue, in contrast, that social categories allow for computationally efficient, richly structured, and flexible group representations that explain some of the most intriguing aspects of social group behaviour.

Disentangling the evolutionary drivers of social complexity: A comprehensive test of hypotheses.

During the Holocene, the scale and complexity of human societies increased markedly. Generations of scholars have proposed different theories explaining this expansion, which range from broadly functionalist explanations, focusing on the provision of public goods, to conflict theories, emphasizing the role of class struggle or warfare. To quantitatively test these theories, we develop a general dynamical model based on the theoretical framework of cultural macroevolution. Using this model and Seshat: Global History Databank, we test 17 potential predictor variables proxying mechanisms suggested by major theories of sociopolitical complexity (and >100,000 combinations of these predictors). The best-supported model indicates a strong causal role played by a combination of increasing agricultural productivity and invention/adoption of military technologies (most notably, iron weapons and cavalry in the first millennium BCE).

Orexin Signaling: A Complex, Multifaceted Process.

The orexin system comprises two G protein-coupled receptors, OX1 and OX2 receptors (OX1R and OX2R, respectively), along with two endogenous agonists cleaved from a common precursor (prepro-orexin), orexin-A (OX-A) and orexin-B (OX-B). For the receptors, a complex array of signaling behaviors has been reported. In particular, it becomes obvious that orexin receptor coupling is very diverse and can be tissue-, cell- and context-dependent. Here, the early signal transduction interactions of the orexin receptors will be discussed in depth, with particular emphasis on the direct G protein interactions of each receptor. In doing so, it is evident that ligands, additional receptor-protein interactions and cellular environment all play important roles in the G protein coupling profiles of the orexin receptors. This has potential implications for our understanding of the orexin system's function in vivo in both central and peripheral environments, as well as the development of novel agonists, antagonists and possibly allosteric modulators targeting the orexin system.

Losing sleep with age.

Hypocretin neuron hyperexcitability underlies disrupted sleep quality associated with age.

Differential sleep/wake response and sex differences following acute suvorexant, MK-1064 and zolpidem administration in the rTg4510 mouse model of tauopathy.

BACKGROUND AND PURPOSE: Transgenic mouse models of tauopathy display prominent sleep/wake disturbances which manifest primarily as a hyperarousal phenotype during the active phase, suggesting that tau pathology contributes to sleep/wake changes. However, no study has yet investigated the effect of sleep-promoting compounds in these models. Such information has implications for the use of hypnotics as potential therapeutic tools in tauopathy-related disorders. EXPERIMENTAL APPROACH: This study examined polysomnographic recordings in 6-6.5-month-old male and female rTg4510 mice following acute administration of suvorexant (50 mg·kg-1 ), MK-1064 (30 mg·kg-1 ) or zolpidem (10 mg·kg-1 ), administered at the commencement of the active phase. KEY RESULTS: Suvorexant, a dual OX receptor antagonist, promoted REM sleep in rTg4510 mice, without affecting wake or NREM sleep. MK-1064, a selective OX2 receptor antagonist, reduced wake and increased NREM and total sleep time. MK-1064 normalised the hyperarousal phenotype of male rTg4510 mice, whereas female rTg4510 mice exhibited a more transient response. Zolpidem, a GABAA receptor positive allosteric modulator, decreased wake and increased NREM sleep in both male and female rTg4510 mice. Of the three compounds, the OX2 receptor antagonist MK-1064 promoted and normalised physiologically normal sleep, especially in male rTg4510 mice. CONCLUSIONS AND IMPLICATIONS: Our findings indicate that hyperphosphorylated tau accumulation and associated hyperarousal does not significantly alter the responses of tauopathy mouse models to hypnotics. However, the sex differences observed in the sleep/wake response of rTg4510 mice to MK-1064, but not suvorexant or zolpidem, raise questions about therapeutic implications for the use of OX2 receptor antagonists in human neurodegenerative disorders.

Hypocretins (orexins): The ultimate translational neuropeptides.

The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin-induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance-use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit-related neuropsychiatric and neurodegenerative conditions.