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The Journal of Neuroscience : the... Aug 2022The ability to perform skilled arm movements is central to everyday life, as limb impairments in common neurologic disorders such as stroke demonstrate. Skilled arm...
The ability to perform skilled arm movements is central to everyday life, as limb impairments in common neurologic disorders such as stroke demonstrate. Skilled arm movements require adaptation of motor commands based on discrepancies between desired and actual movements, called sensory errors. Studies in humans show that this involves predictive and reactive movement adaptations to the errors, and also requires a general motivation to move. How these distinct aspects map onto defined neural signals remains unclear, because of a shortage of equivalent studies in experimental animal models that permit neural-level insights. Therefore, we adapted robotic technology used in human studies to mice, enabling insights into the neural underpinnings of motivational, reactive, and predictive aspects of motor adaptation. Here, we show that forelimb motor adaptation is regulated by neurons previously implicated in motivation and arousal, but not in forelimb motor control: the hypothalamic orexin/hypocretin neurons (HONs). By studying goal-oriented mouse-robot interactions in male mice, we found distinct HON signals occur during forelimb movements and motor adaptation. Temporally-delimited optosilencing of these movement-associated HON signals impaired sensory error-based motor adaptation. Unexpectedly, optosilencing affected neither task reward or execution rates, nor motor performance in tasks that did not require adaptation, indicating that the temporally-defined HON signals studied here were distinct from signals governing general task engagement or sensorimotor control. Collectively, these results reveal a hypothalamic neural substrate regulating forelimb motor adaptation. The ability to perform skilled, adaptable movements is a fundamental part of daily life, and is impaired in common neurologic diseases such as stroke. Maintaining motor adaptation is thus of great interest, but the necessary brain components remain incompletely identified. We found that impaired motor adaptation results from disruption of cells not previously implicated in this pathology: hypothalamic orexin/hypocretin neurons (HONs). We show that temporally confined HON signals are associated with skilled movements. Without these newly-identified signals, a resistance to movement that is normally rapidly overcome leads to prolonged movement impairment. These results identify natural brain signals that enable rapid and effective motor adaptation.
Topics: Animals; Forelimb; Humans; Male; Mice; Movement; Orexins; Stroke; Upper Extremity
PubMed: 35790405
DOI: 10.1523/JNEUROSCI.0705-22.2022 -
Autonomic Neuroscience : Basic &... Nov 2020Orexin (OX), which regulates sleep and wakefulness and feeding behaviors has 2 isoforms, orexin-A and -B (OXA and OXB). In this study, the distribution of OXA and OXB...
Orexin (OX), which regulates sleep and wakefulness and feeding behaviors has 2 isoforms, orexin-A and -B (OXA and OXB). In this study, the distribution of OXA and OXB was examined in the rat superior salivatory nucleus (SSN) using retrograde tracing and immunohistochemical and methods. OXA- and OXB-immunoreactive (-ir) nerve fibers were seen throughout the SSN. These nerve fibers surrounded SSN neurons retrogradely labeled with Fast blue (FB) from the corda-lingual nerve. FB-positive neurons had pericellular OXA- (47.5%) and OXB-ir (49.0%) nerve fibers. Immunohistochemistry for OX receptors also demonstrated the presence of OX1R and OX2R in FB-positive SSN neurons. The majority of FB-positive SSN neurons contained OX1R- (69.7%) or OX2R-immunoreactivity (57.8%). These neurons had small and medium-sized cell bodies. In addition, half of FB-positive SSN neurons which were immunoreactive for OX1R (47.0%) and OX2R (52.2%) had pericellular OXA- and OXB-ir nerve fibers, respectively. Co-expression of OX1R- and OX2R was common in FB-positive SSN neurons. The present study suggests a possibility that OXs regulate the activity of SSN neurons through OX receptors.
Topics: Animals; Autonomic Fibers, Preganglionic; Facial Nerve; Immunohistochemistry; Male; Orexin Receptors; Orexins; Rats; Rats, Wistar; Sublingual Gland; Submandibular Gland
PubMed: 32721850
DOI: 10.1016/j.autneu.2020.102712 -
Physiology & Behavior May 2021The intranasal (IN) administration of neuropeptides, such as insulin and orexins, has been suggested as a treatment strategy for age-related cognitive decline (ARCD).... (Review)
Review
The intranasal (IN) administration of neuropeptides, such as insulin and orexins, has been suggested as a treatment strategy for age-related cognitive decline (ARCD). Because dysfunctional neuropeptide signaling is an observed characteristic of ARCD, it has been suggested that IN delivery of insulin and/or orexins may restore endogenous peptide signaling and thereby preserve cognition. IN administration is particularly alluring as it is a relatively non-invasive method that directly targets peptides to the brain. Several laboratories have examined the behavioral effects of IN insulin in young, aged, and cognitively impaired rodents and humans. These studies demonstrated improved performance on various cognitive tasks following IN insulin administration. Fewer laboratories have assessed the effects of IN orexins; however, this peptide also holds promise as an effective treatment for ARCD through the activation of the cholinergic system and/or the reduction of neuroinflammation. Here, we provide a brief overview of the advantages of IN administration and the delivery pathway, then summarize the current literature on IN insulin and orexins. Additional preclinical studies will be useful to ultimately uncover the mechanisms underlying the pro-cognitive effects of IN insulin and orexins, whereas future clinical studies will aid in the determination of the most efficacious dose and dosing paradigm. Eventually, IN insulin and/or orexin administration may be a widely used treatment strategy in the clinic for ARCD.
Topics: Administration, Intranasal; Aged; Cognitive Dysfunction; Humans; Insulin; Neuropeptides; Orexin Receptors; Orexins
PubMed: 33621561
DOI: 10.1016/j.physbeh.2021.113370 -
Neuropsychopharmacology : Official... Feb 2022Drug-associated sensory cues increase motivation for drug and the orexin system is importantly involved in this stimulus-enhanced motivation. Ventral tegmental area...
Drug-associated sensory cues increase motivation for drug and the orexin system is importantly involved in this stimulus-enhanced motivation. Ventral tegmental area (VTA) is a major target by which orexin signaling modulates reward behaviors, but it is unknown whether this circuit is necessary for cue-driven motivation for cocaine. Here, we investigated the role of VTA orexin signaling in cue-driven motivation for cocaine using a behavioral economics (BE) paradigm. We found that infusion of the orexin-1 receptor (Ox1R) antagonist SB-334867 (SB) into VTA prior to BE testing reduced motivation when animals were trained to self-administer cocaine with discrete cues and tested on BE with those cues. SB had no effect when animals were trained to self-administer cocaine without cues or tested on BE without cues, indicating that learning to associate cues with drug delivery during self-administration training was necessary for cues to recruit orexin signaling in VTA. These effects were specific to VTA, as injections of SB immediately dorsal had no effect. Moreover, intra-VTA SB did not have an impact on locomotor activity, or low- or high-effort consumption of sucrose. Finally, we microinjected a novel retrograde adeno-associated virus (AAVretro) containing an orexin-specific short hairpin RNA (OxshRNA) into VTA to knock down orexin in the hypothalamus-VTA circuit. These injections significantly reduced orexin expression in lateral hypothalamus (LH) and decreased cue-driven motivation. These studies demonstrate a role for orexin signaling in VTA, specifically when cues predict drug reward.
Topics: Animals; Cocaine; Cues; Hypothalamic Area, Lateral; Orexin Receptors; Orexins; Ventral Tegmental Area
PubMed: 34635803
DOI: 10.1038/s41386-021-01173-5 -
Current Biology : CB Oct 2020The lateral hypothalamic area (LH) is a vital controller of arousal, feeding, and metabolism [1, 2], which integrates external and internal sensory information. Whereas...
The lateral hypothalamic area (LH) is a vital controller of arousal, feeding, and metabolism [1, 2], which integrates external and internal sensory information. Whereas sensory and whole-body output properties of LH cell populations have received much interest, their intrinsic synaptic organization has remained largely unstudied. Local inhibitory and excitatory connections could help integrate and filter sensory information and mutually inhibitory connections [3] could allow coordinating activity between LH cell types, some of which have mutually exclusive behavioral effects, such as LH VGLUT2 and VGAT neurons [4-7] and orexin- (ORX) and melanin-concentrating hormone (MCH) neurons [8-10]. However, classical Golgi staining studies did not find interneurons with locally ramifying axons in the LH [11, 12], and nearby subthalamic and thalamic areas lack local synaptic connectivity [13, 14]. Studies with optogenetic circuit mapping within the LH have demonstrated only a minority of connections when a large pool of presynaptic neurons was activated [15-19]. Because multiple patch clamp has not been used to study LH connectivity, aside from a limited dataset of MCH neurons where no connections were discovered [15], we used quadruple whole-cell recordings to screen connectivity within the LH with standard methodology we previously used in the neocortex [20-22]. Finding a lack of local connectivity, we used optogenetic circuit mapping to study the strength of LH optogenetic responses and network oscillations, which were consistent with ultra-sparse intrinsic connectivity within the LH. These results suggest that input from other brain structures is decisive for selecting active populations in the LH.
Topics: Action Potentials; Animals; Brain Waves; Connectome; Hypothalamic Area, Lateral; Hypothalamic Hormones; Melanins; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neocortex; Neurons; Optogenetics; Orexins; Patch-Clamp Techniques; Pituitary Hormones
PubMed: 32822604
DOI: 10.1016/j.cub.2020.07.061 -
Physiology & Behavior Jul 2023Pavlovian conditioning can underly the maladaptive behaviors seen in psychiatric disorders such as anxiety and addiction. In both the lab and the clinic, these responses...
Pavlovian conditioning can underly the maladaptive behaviors seen in psychiatric disorders such as anxiety and addiction. In both the lab and the clinic, these responses can be attenuated through extinction learning, but often return with the passage of time, stress, or a change in context. Extinction to fear and reward cues are both subject to these return of behavior phenomena and have overlap in neurocircuitry, yet it is unknown whether they share any common predictors. The orexin system has been implicated in both fear and appetitive extinction and can be activated through a CO challenge. We previously found that behavioral CO reactivity predicts fear extinction and orexin activation. Here, we sought to extend our previous findings to determine whether CO reactivity might also predict extinction memory for appetitive light-food conditioning. We find that the same subcomponent of behavioral CO reactivity that predicted fear extinction also predicts appetitive extinction, but in the opposite direction. We show evidence that this subcomponent remains stable across two CO challenges, suggesting it may be a stable trait of both behavioral CO reactivity and appetitive extinction phenotype. Our findings further the possibility for CO reactivity to be used as a transdiagnostic screening tool to determine whether an individual would be a good candidate for exposure therapy.
Topics: Extinction, Psychological; Orexins; Carbon Dioxide; Individuality; Fear
PubMed: 37031791
DOI: 10.1016/j.physbeh.2023.114183 -
International Review of Neurobiology 2017The neuropeptide orexin/hypocretin (OX), while largely transcribed within the hypothalamus, is released throughout the brain to affect complex behaviors. Primarily... (Review)
Review
The neuropeptide orexin/hypocretin (OX), while largely transcribed within the hypothalamus, is released throughout the brain to affect complex behaviors. Primarily through the hypothalamus itself, OX homeostatically regulates adaptive behaviors needed for survival, including food intake, sleep-wake regulation, mating, and maternal behavior. However, through extrahypothalamic limbic brain regions, OX promotes seeking and intake of rewarding substances of abuse, like palatable food, alcohol, nicotine, and cocaine. This neuropeptide, in turn, is stimulated by the intake of or early life exposure to these substances, forming a nonhomeostatic, positive feedback loop. The specific OX receptor involved in these behaviors, whether adaptive behavior or substance seeking and intake, is dependent on the particular brain region that contributes to them. Thus, we propose that, while the primary function of OX is to maintain arousal for the performance of adaptive behaviors, this neuropeptide system is readily co-opted by rewarding substances that involve positive feedback, ultimately promoting their abuse.
Topics: Alcohol Drinking; Animals; Feeding and Eating Disorders; Homeostasis; Humans; Hypothalamus; Orexin Receptors; Orexins; Reward; Substance-Related Disorders
PubMed: 29056152
DOI: 10.1016/bs.irn.2017.06.006 -
Sheng Li Xue Bao : [Acta Physiologica... Aug 2019The neuropeptide orexin is widely distributed in the nervous system. Previous studies showed that orexin is involved in the feeding behavior regulation by binding to its... (Review)
Review
The neuropeptide orexin is widely distributed in the nervous system. Previous studies showed that orexin is involved in the feeding behavior regulation by binding to its receptor 1 (OX1R) and receptor 2 (OX2R) to activate the downstream signaling pathway. Recent studies have demonstrated that the system of orexin and its receptors are also involved in important physiological processes such as sleep-wake, learning and memory, and pathological processes of various neurological diseases. In this review, we summarized the research progress on the function of the orexin and its receptor system in physiological and pathological processes, and revealed the correlation between orexin and nervous system diseases, in order to provide the theoretical guidance for the diagnosis and treatment of the related diseases in the future.
Topics: Humans; Nervous System Diseases; Orexin Receptors; Orexins; Signal Transduction
PubMed: 31440763
DOI: No ID Found -
Brain Research Mar 2020At its discovery, orexin/hypocretin (OX) was hypothesized to promote food intake. Subsequently, with the identification of the participation of OX in numerous other... (Review)
Review
At its discovery, orexin/hypocretin (OX) was hypothesized to promote food intake. Subsequently, with the identification of the participation of OX in numerous other phenomena, including arousal and drug seeking, this neuropeptide was proposed to be involved in highly motivated behaviors. The present review develops the hypothesis that the primary evolutionary function of OX is to promote foraging behavior, seeking for food under conditions of limited availability. Thus, it will first describe published literature on OX and homeostatic food intake, which shows that OX neurons are activated by conditions of food deprivation and in turn stimulate food intake. Next, it will present literature on excessive and binge-like food intake, which demonstrates that OX stimulates both intake and willingness to work for palatable food. Importantly, studies show that binge-like eating can be inhibited by OX antagonists at doses far lower than those required to suppress homeostatic intake (3 mg/kg vs. 30 mg/kg), suggesting that an OX-based pharmacotherapy, at the right dose, could specifically control dysregulated eating. Finally, the review will discuss the role of OX in foraging behavior, citing literature which shows that OX neurons, which are activated during the anticipation of food reward, can promote a number of phenomena involved in successful foraging, including food-anticipatory locomotor behavior, olfactory sensitivity, visual attention, spatial memory, and mastication. Thus, OX may promote homeostatic eating, as well as binge eating of palatable food, due to its ability to stimulate and coordinate the activities involved in foraging behavior.
Topics: Animals; Behavior, Animal; Brain; Eating; Feeding Behavior; Homeostasis; Hypothalamus; Neurons; Orexins
PubMed: 30125533
DOI: 10.1016/j.brainres.2018.08.018 -
Brain Pathology (Zurich, Switzerland) Mar 2022An increased number of histaminergic neurons, identified by labeling histidine-decarboxylase (HDC) its synthesis enzyme, was unexpectedly found in patients with...
An increased number of histaminergic neurons, identified by labeling histidine-decarboxylase (HDC) its synthesis enzyme, was unexpectedly found in patients with narcolepsy type 1 (NT1). In quest for enlightenment, we evaluate whether an increase in HDC cell number and expression level would be detected in mouse models of the disease, in order to provide proof of concepts reveling possible mechanisms of compensation for the loss of orexin neurons, and/or of induced expression as a consequence of local neuroinflammation, a state that likely accompanies NT1. To further explore the compensatory hypothesis, we also study the noradrenergic wake-promoting system. Immunohistochemistry for HDC, orexin, and melanin-concentrating hormone (MCH) was used to count neurons. Quantitative-PCR of HDC, orexin, MCH, and tyrosine-hydroxylase was performed to evaluate levels of mRNA expression in the hypothalamus or the dorsal pons. Both quantifications were achieved in genetic and neuroinflammatory models of narcolepsy with major orexin impairment, namely the orexin-deficient (Orex-KO) and orexin-hemagglutinin (Orex-HA) mice respectively. The number of HDC neurons and mRNA expression level were unchanged in Orex-KO mice compared to controls. Similarly, we found no change in tyrosine-hydroxylase mRNA expression in the dorsal pons between groups. Further, despite the presence of protracted local neuroinflammation as witnessed by the presence of reactive microglia, we found no change in the number of neurons nor the expression of HDC in Orex-HA mice compared to controls. Importantly, no correlation was found in all conditions between HDC and orexin. Our findings indicate that, in mice, the expression of histamine and noradrenalin, two wake-promoting systems, are not modulated by orexin level whether the lack of orexin is constitutive or induced at adult age, showing thus no compensation. They also show no recruitment of histamine by local neuroinflammation. Further studies will be needed to further define the role of histamine in the pathophysiology of NT1.
Topics: Animals; Histamine; Histidine Decarboxylase; Humans; Mice; Mixed Function Oxygenases; Narcolepsy; Orexins; RNA, Messenger
PubMed: 34672414
DOI: 10.1111/bpa.13027