Thomas S. Kilduff’s research while affiliated with SRI International and other places

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Publications (22)


Orexin receptors in GtoPdb v.2023.1
  • Article
  • Full-text available

April 2023

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82 Reads

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2 Citations

IUPHAR/BPS Guide to Pharmacology CITE

Gary Aston-Jones

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Masashi Yanagisawa

Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [43]) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [117]. Orexin signaling has been associated with regulation of sleep and wakefulness, reward and addiction, appetite and feeding, pain gating, stress response, anxiety and depression. Currently the orexin receptor ligands in clinical use are the dual orexin receptor antagonists suvorexant and lemborexant and daridorexant, which are used as hypnotics, and several dual and OX2-selective antagonists are under development. Multiple orexin agonists are in development for the treatment of narcolepsy and other sleep disorders. Orexin receptor 3D structures have been solved [146, 144, 55, 126, 47, 109, 7, 145].

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The Development of Sleep/Wake Disruption and Cataplexy as Hypocretin/Orexin Neurons Degenerate in Male vs. Female Orexin/tTA; TetO-DTA Mice

October 2021

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28 Reads

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1 Citation

Narcolepsy Type 1 (NT1), a sleep disorder with similar prevalence in both sexes, is thought to be due to loss of the hypocretin/orexin (Hcrt) neurons. Several transgenic strains have been created to model this disorder and are increasingly being used for preclinical drug development and basic science studies, yet most studies have solely used male mice. We compared the development of narcoleptic symptomatology in male vs. female orexin-tTA; TetO-DTA mice, a model in which Hcrt neuron degeneration can be initiated by removal of doxycycline (DOX) from the diet. EEG, EMG, body temperature, gross motor activity and video recordings were conducted for 24-h at baseline and 1, 2, 4 and 6 weeks after DOX removal. Female DTA mice exhibited cataplexy, the pathognomonic symptom of NT1, by Week 1 in the DOX(-) condition but cataplexy was not consistently present in males until Week 2. By Week 2, both sexes showed an impaired ability to sustain long wake bouts during the active period, the murine equivalent of excessive daytime sleepiness in NT1. Body temperature appeared to be regulated at lower levels in both sexes as the Hcrt neurons degenerated. During degeneration, both sexes also exhibited the “Delta State”, characterized by sudden cessation of activity, high delta activity in the EEG, maintenance of muscle tone and posture, and the absence of phasic EMG activity. Since the phenotypes of the two sexes were indistinguishable by Week 6, we conclude that both sexes can be safely combined in future studies to reduce cost and animal use. Statement of Significance Although narcolepsy is a disorder that affects both men and women with similar frequency, most basic research and preclinical development studies of sleep have utilized male experimental subjects. The identification of the hypocretin/orexin (Hcrt) neuron loss as the likely cause of human narcolepsy has led to the development of transgenic mouse strains that model this disorder. Here, we compare the emergence of narcoleptic symptoms in male vs. female bigenic orexin-tTA; TetO DTA mice, a state-of-the-art narcolepsy model in which degeneration of the Hcrt neurons can be triggered by dietary manipulation. We find that female mice develop the narcoleptic phenotype more rapidly than males but that both sexes are equally symptomatic by the end of the degeneration period.


Orexin receptors in GtoPdb v.2021.3

September 2021

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47 Reads

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5 Citations

IUPHAR/BPS Guide to Pharmacology CITE

Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [42]) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [109]. Currently the only orexin receptor ligands in clinical use are suvorexant and lemborexant, which are used as hypnotics. Orexin receptor crystal structures have been solved [134, 133, 54, 117, 46].


Fig. 1. Hypocretin/orexin-containing neurons and their projections, receptor distributions, and downstream behavioral outcomes. Hypocretin/orexin-producing neurons are located in the hypothalamus (Hy) and project to diverse brain regions differentially expressing hypocretin/orexin receptors 1 and 2 (OX 1 R and OX 2 R; receptor expression is indicated by the background color of each brain region), including the cerebral cortex, cingulate cortex, bed nucleus of the stria terminalis (BNST), nucleus accumbens (NAc), tuberomammillary nucleus (TMN), dorsal raphe (DR), locus coeruleus (LC), paraventricular thalamus (PVT), ventrolateral periaqueductal gray (vlPAG), the dorsal deep mesencephalic nucleus (dDPMe), pedunculopontine and laterodorsal tegmental nuclei (PPT and LDT), substantia nigra (SN), ventral tegmental area (VTA), central area of the amygdala (CeA), and the paraventricular nucleus (PVN). Through these projections, hypocretin/orexin-containing neurons are able to elicit diverse behavioral outputs.
Effects of hypocretin/orexin receptor agonists and antagonists on sleep/wake in preclinical studies
Effects of hypocretin/orexin receptor antagonists on sleep/wake parameters in clinical studies
Hypocretin/Orexin Receptor Pharmacology and Sleep Phases

May 2021

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742 Reads

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47 Citations

Monographs in Neural Sciences

The hypocretins/orexins are two excitatory neuropeptides, alternately called HCRT1 or orexin-A and HCRT2 or orexin-B, that are the endogenous ligands for two G-protein-coupled receptors, HCRTR1/OX1R and HCRTR2/OX2R. Shortly after the discovery of this system, degeneration of hypocretin/orexin-producing neurons was implicated in the etiology of the sleep disorder narcolepsy. The involvement of this system in a disorder characterized by the loss of control over arousal state boundaries also suggested its role as a critical component of endogenous sleep-wake regulatory circuitry. The broad projections of the hypocretin/orexin-producing neurons, along with differential expression of the two receptors in the projection fields of these neurons, suggest distinct roles for these receptors. While HCRTR1/OX1R is associated with regulation of motivation, reward, and autonomic functions, HCRTR2/OX2R is strongly linked to sleep-wake control. The association of hypocretin/orexin with these physiological processes has led to intense interest in the therapeutic potential of compounds targeting these receptors. Agonists and antagonists for the hypocretin/orexin receptors have shown potential for the treatment of disorders of excessive daytime somnolence and nocturnal hyperarousal, respectively, with the first antagonists approved by the US Food and Drug Administration (FDA) in 2014 and 2019 for the treatment of insomnia. These and related compounds have also been useful tools to advance hypocretin/orexin neurobiology.


Cerebrospinal fluid monoamine levels in central hypersomnolence disorders

January 2021

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31 Reads

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20 Citations

Sleep

Study objectives Whether the cause of daytime sleepiness in narcolepsy type 1 (NT1) is a direct consequence of the loss of orexin neurons or whether low orexin reduces the efficacy of the monoaminergic systems to promote wakefulness is unclear. The neurobiology underlying sleepiness in other central hypersomnolence disorders, narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH), is currently unknown. Methods Eleven biogenic amines including the monoaminergic neurotransmitters and their metabolites and five trace amines were measured in the cerebrospinal fluid (CSF) of 94 drug-free subjects evaluated at the French National Reference Center for Narcolepsy: 39 NT1(orexin-deficient) patients, 31 patients with objective sleepiness non-orexin deficient (NT2 and IH), and 24 patients without objective sleepiness. Results Three trace amines were undetectable in the sample: Tryptamine, Octopamine, and 3-iodothyronamine. No significant differences were found among the three groups for quantified monoamines and their metabolites in crude and adjusted models; however, CSF 5-HIAA levels tended to increase in NT1 compared to other patients after adjustment. Most of biomarkers were not associated with ORX-A levels, clinical or neurophysiological parameters, but a few biomarkers (e.g., MHPG and norepinephrine) correlated with daytime sleepiness and high REM sleep propensity. Conclusion We found no striking differences among CSF monoamines, their metabolites and trace amine levels, and few associations between them and key clinical or neurophysiological parameters in NT1,NT2/IH and patients without objective sleepiness. Although mostly negative, these findings are a significant contribution to our understanding of the neurobiology of hypersomnolence in these disorders that remain mysterious and deserve further exploration.


Animal Models of Narcolepsy and the Hypocretin/Orexin System: Past, Present, and Future

December 2020

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25 Reads

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22 Citations

Sleep

Animal models have advanced not only our understanding of the etiology and phenotype of the sleep disorder narcolepsy but have also informed sleep/wake regulation more generally. The identification of an inheritable narcolepsy phenotype in dogs in the 1970s allowed the establishment of a breeding colony at Stanford University, resulting in studies that provided the first insights into the genetics and neurotransmitter systems that underlie cataplexy and REM sleep atonia. Although the discovery of the hypocretin/orexin neuropeptides in 1998 initially seemed unrelated to sleep/wake control, the description of the phenotype of the prepro-orexin knockout (KO) mouse as strongly resembling cataplexy, the pathognomonic symptom of narcolepsy, along with identification of a mutation in hypocretin receptor-2 gene as the source of canine narcolepsy, unequivocally established the relationship between this system and narcolepsy. The subsequent discovery of hypocretin neuron degeneration in human narcolepsy demystified a disorder whose etiology had been unknown since its initial description 120 years earlier. These breakthroughs prompted the development of numerous other animal models that have allowed manipulation of the hypocretin/orexin system, thereby advancing our understanding of sleep/wake circuitry. While animal models have greatly informed understanding of this fascinating disorder and the role of the hypocretin/orexin system in sleep/wake control, the question of why these neurons degenerate in human narcolepsy is only beginning to be understood. The development of new immune-mediated narcolepsy models are likely to further inform the etiology of this sleep disorder and animal models will undoubtedly play a critical role in the development of novel narcolepsy therapeutics.



Dual orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy

April 2020

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141 Reads

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1 Citation

Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the hypothalamus and project throughout the brain to regulate sleep/wakefulness. Ablation of orexin neurons decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. Since it is unclear how orexin and MCH neurons interact to regulate sleep/wakefulness, we generated transgenic mice in which both orexin and MCH neurons could be ablated. Double-ablated mice exhibited increased wakefulness and decreased both rapid eye movement (REM) and non-REM (NREM) sleep. Double-ablated mice showed severe cataplexy compared with orexin neuron-ablated mice, suggesting that MCH neurons normally suppress cataplexy. Double-ablated mice also showed frequent sleep attacks with elevated spectral power in the delta and theta range, a unique state that we call ‘delta-theta sleep’. Together, these results indicate a functional interaction between orexin and MCH neurons in vivo that suggests the synergistic involvement of these neuronal populations in the sleep/wakefulness cycle.


Dual orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy

April 2020

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122 Reads

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3 Citations

Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the hypothalamus and project throughout the brain to regulate sleep/wakefulness. Ablation of orexin neurons decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. Since it is unclear how orexin and MCH neurons interact to regulate sleep/wakefulness, we generated transgenic mice in which both orexin and MCH neurons could be ablated. Double-ablated mice exhibited increased wakefulness and decreased both rapid eye movement (REM) and non-REM (NREM) sleep. Double-ablated mice showed severe cataplexy compared with orexin neuron-ablated mice, suggesting that MCH neurons normally suppress cataplexy. Double-ablated mice also showed frequent sleep attacks with elevated spectral power in the delta and theta range, a unique state that we call ‘delta-theta sleep’. Together, these results indicate a functional interaction between orexin and MCH neurons in vivo that suggests the synergistic involvement of these neuronal populations in the sleep/wakefulness cycle.


Figure 1. Consort diagram for the randomized controlled trial.
Figure 2. Effect of study medications on sleepiness, ability to maintain wake, psychomotor vigilance, sustained attention, and inhibitory control. PVT, Psychomotor Vigilance Task; A100, almorexant 100 mg; A200, almorexant 200 mg. Red vertical line indicates time of dosing at 15:00. Error bars represent 95% confidence intervals, uncorrected for multiple comparisons.
Figure 3. (A) Effect of study medications on verbal memory in the RAVLT. (B) Effect of study medications on verbal memory in the Verbal Paired Associates Test. A100, almorexant 100 mg; A200, almorexant 200 mg. Vertical line indicates time of dosing at 15:00. Error bars represent 95% confidence intervals, uncorrected for multiple comparisons.
Figure 4. Effect of study medications on processing speed, executive function, working memory, and visual-motor coordination. CI, 95% confidence interval. Stroop T-scores are based on population norms with mean = 50 and SD = 10. D-KEFS Tower and Digit Span scaled scores are based on a population norm with mean = 10 and SD = 3. Error bars represent 95% confidence intervals, uncorrected for multiple comparisons.
Characteristics of participants by treatment group
Acute Cognitive Effects of the Hypocretin Receptor Antagonist Almorexant Relative to Zolpidem and Placebo: A Randomized Clinical Trial

April 2020

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202 Reads

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24 Citations

Sleep

Study Objectives Hypnotic medications can adversely affect behavior during unanticipated awakenings during the night. Animals treated with the hypocretin receptor antagonist almorexant (ALM) have less acute cognitive impairment compared to the GABAA receptor modulator zolpidem (ZOL). This study aimed to determine whether ALM produces less acute cognitive impairment than ZOL in human subjects. Methods Healthy, young adult, unmedicated male and female subjects participated in a controlled trial of a single dose of ALM 100mg (N = 48), ALM 200mg (N = 53), ZOL 10mg (N = 49), and placebo (PBO, N = 52). Results ZOL and both doses of ALM produced similar levels of subjective sleepiness and impaired the ability of subjects to remain awake in a dark, low stimulus setting relative to PBO. For most cognitive measures, performance under ZOL was significantly worse than ALM or PBO. For tasks involving verbal memory or visual-motor coordination, ZOL impaired performance, whereas the 2 doses of ALM were no different than PBO. For tasks involving higher order executive function, ZOL produced impairment in processing speed and inhibitory control, whereas the 2 doses of ALM were no different than PBO. Performance decrements for ALM were less than ZOL but greater than PBO for some reaction time measures. Conclusion The data provide support for the hypothesis that hypocretin receptor (Hcrt) antagonists produce less functional impairment than a benzodiazepine receptor agonist (BzRA). These observations are particularly relevant to patients treated with sedative-hypnotics who are at elevated risk for falls and other untoward events during the intended hours for sleep.


Citations (16)


... As well, through antagonism of alpha 2 auto receptors and consequent activation of alpha 1 post-synaptic adrenoreceptors, yohimbine has significant effects on brain dopamine turnover [97], it increases dopamine synthesis and utilization in the basal ganglia [98], elevates intracellular dopamine levels in the striatum [99], and extracellular dopamine levels in the prefrontal cortex [100] and nucleus accumbens [101] (but see [33]). Moreover, yohimbine interacts with the orexins; peptides that modulate the activity of the mesolimbic dopamine system [102] and a host of associated affective and motivational functions [103]. For example, orexin 1 receptor antagonists inhibit yohimbine-induced reinstatement of drug seeking [104,105] likely through the central amygdala [106] and inhibit the fMRI responses in fronto-hippocampal regions and components of the extended amygdala in rats treated with 0.75 mg/kg intravenous yohimbine [107]. ...

Reference:

The anxiogenic drug yohimbine is a reinforcer in male and female rats
Orexin receptors in GtoPdb v.2023.1

IUPHAR/BPS Guide to Pharmacology CITE

... We examined TH expression intensity as a function of SXB administration in locus coeruleus. Hcrt neurons project to virtually all brain regions, ending on Hcrt-receptors 1 and 2. The distribution of these receptors varies between brain regions (33)(34)(35). In data sets that were not normally distributed or with outlier data points (e.g. ...

Orexin receptors in GtoPdb v.2021.3

IUPHAR/BPS Guide to Pharmacology CITE

... Journal of Clinical and Basic Psychosomatics nucleus and brainstem arousal systems. [16][17][18][19][20][21][22] Disruptions in orexin signaling are linked to insomnia, where heightened arousal and vigilance hinder the ability to transition into and maintain sleep. [22][23][24][25][26] In addition to circadian rhythms, the homeostatic sleep drive, which builds up during wakefulness, plays a critical role in sleep regulation. ...

Hypocretin/Orexin Receptor Pharmacology and Sleep Phases

Monographs in Neural Sciences

... Preclinical models support the implication of norepinephrine and dopamine in hypersomnolence (105), which is consistent with pharmacological studies that have demonstrated improvement of sleepiness with noradrenaline and dopamine reuptake inhibitors (106)(107)(108). Furthermore, low levels of norepinephrine in cerebrospinal fluid correlated with EDS in participants with central disorders of hypersomnolence (109). Conversely, sodium oxybate in IH is mainly hypothesized to improve nighttime sleep via its action on GABA B (gamma- ...

Cerebrospinal fluid monoamine levels in central hypersomnolence disorders
  • Citing Article
  • January 2021

Sleep

... Trên thế giới, những nghiên cứu liên quan đến biệt hóa hiPSCs thành tế bào thần kinh tiết Orexin còn tương đối hạn chế. Hầu hết các mô hình đánh giá bệnh in vitro và in vivo sử dụng tế bào thần kinh tiết Orexin đều được thực hiện trên động vật, phổ biến là chuột [6][7][8]. Những mô hình này tuy dễ tiếp cận nhưng hạn chế bởi nhiều khác biệt giữa người và động vật khác, do vậy, việc thiết lập và sử dụng tế bào có nguồn gốc từ người trở nên cần thiết hơn bao giờ hết. Về lĩnh vực này, ngoài nghiên cứu của F.T. Merkle và cs (2015) [9], K. Hayakawa và cs (2017) [10], cho tới nay vẫn chưa có công bố mới hơn. ...

Animal Models of Narcolepsy and the Hypocretin/Orexin System: Past, Present, and Future
  • Citing Article
  • December 2020

Sleep

... For this manual classification of sleep stages over large amounts of data, many approaches to automating this task have been proposed, such as clustering [16], k-nearest neighbours [25], support vector machines [3], or random forests [10]. ...

Automated Sleep Stage Scoring Using k-Nearest Neighbors Classifier

The Journal of Open Source Software

... However, another study using calcium imaging found contradictory results, showing that MCH neurons are indeed active in REM sleep but silent during cataplexy 15 . Moreover, MCH-Hcrt double ablated mice show a marked increase in cataplexy and decrease in REM sleep compared to selective Hcrt ablated animals 16 . These latter data would suggest that although the MCH system may play a role in REM sleep expression, its inactivity would favor cataplexy. ...

Dual orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy

... 36 According to studies, BZRA activates GABA A receptors, which are widely distributed throughout the central nervous system (CNS), mainly in the cerebral cortex, resulting in a widespread suppression of neuronal activity. [37][38][39][40] Therefore, it is possible that alterations in GABA receptors in the auditory system could be a potential mechanism for the increased risk of SSNHL in BZRA users. [18][19][20][21] Accordingly, BZRAs are known to enhance the inhibitory neurotransmitter in the central nervous system, 41 which can be beneficial for anxiety and sleep disorders. ...

Acute Cognitive Effects of the Hypocretin Receptor Antagonist Almorexant Relative to Zolpidem and Placebo: A Randomized Clinical Trial

Sleep

... A decreased number of orexin immunoreactive cells in 12-month-old Tg-SwDI mice Since increased NREM sleep, shortened wake bouts, and power spectra shifts are commonly observed in narcoleptic mice with neuropeptide orexin (hypocretin) deficiency or ablated orexin neurons (Chemelli et al., 1999, Chen et al., 2009, Liu et al., 2011, Hung et al., 2020, we questioned whether changes in orexin neurons could underlie these sleep alterations in these Tg-SwDI mice. Therefore, we examined the number of hypothalamic orexin immunoreactive (orexin-IR) and melanin-concentrating hormoneimmunoreactive (MCH) immunoreactive (MCH-IR) neurons, two cell groups regulating arousal and sleep in the same brain region Comparisons of state-dependent power spectra between Tg-SwDI and WT mice. ...

Dual orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy

eLife

... Hibernation employs a complex regulatory system to coordinate a homeostatic state of reduced metabolism, lower body temperature, and decreased activity in response to environmental challenges [90]. Hibernation, by significantly reducing energy consumption, minimizes the need to carry substantial amounts of food and fluids for life-support systems [91]. This conservation of payload capacity benefits spaceflight. ...

Shallow metabolic depression and human spaceflight: A feasible first step
  • Citing Article
  • January 2020

Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology