Hypocretin /orexin contributes to the expression of some but not all forms of stress and arousal

Furlong, Teri M.; Vianna, Daniel Machado Luiz; Liu, Lu; Carrive, Pascal

doi:10.1111/j.1460-9568.2009.06952.x

Cited by 157 publications

(144 citation statements)

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“…In mammals, the HCRT neurons receive abundant projections from the amygdala (Winsky-Sommerer et al, 2004;Zhang et al, 2009;Sakurai and Mieda, 2011), a key component of the fear response pathway, and innervate the PVN , which regulates stress and anxiety via the hypothalamic-pituitaryadrenal axis. In agreement with this idea, in HCRT knock-out and HCRT neuron-ablated transgenic mice, emotional stresses generate attenuated responses of locomotor activity, as well as blood pressure, heart rate, and cardiorespiratory responses (Kayaba et al, 2003;Furlong et al, 2009;Zhang et al, 2009). In zebrafish, we found that deficiency in the response to external stimuli is not specific to light and was also observed in the larvae reaction to sound stimuli.…”

Section: Discussionsupporting

confidence: 48%

Genetic Ablation of Hypocretin Neurons Alters Behavioral State Transitions in Zebrafish

et al. 2012

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Sleep is an essential biological need of all animals studied to date. The sleep disorder narcolepsy is characterized by excessive daytime sleepiness, fragmentation of nighttime sleep, and cataplexy. Narcolepsy is caused by selective degeneration of hypothalamic hypocretin/ orexin (HCRT) neurons. In mammals, HCRT neurons primarily regulate the sleep/wake cycle, feeding, reward-seeking, and addiction. The role of HCRT neurons in zebrafish is implicated in both sleep and wake regulation. We established a transgenic zebrafish model enabling inducible ablation of HCRT neurons and used these animals to understand the function of HCRT neurons and narcolepsy. Loss of HCRT neurons increased the expression of the HCRT receptor (hcrtr). Behavioral assays revealed that HCRT neuron-ablated larvae had normal locomotor activity, but demonstrated an increase in sleep time during the day and an increased number of sleep/wake transitions during both day and night. Mild sleep disturbance reduced sleep and increased c-fos expression in HCRT neuron-ablated larvae. Furthermore, ablation of HCRT neurons altered the behavioral response to external stimuli. Exposure to light during the night decreased locomotor activity of wild-type siblings, but induced an opposite response in HCRT neuron-ablated larvae. Sound stimulus during the day reduced the locomotor activity of wild-type sibling larvae, while HCRT neuron-ablated larvae demonstrated a hyposensitive response. This study establishes zebrafish as a model for narcolepsy, and indicating a role of HCRT neurons in regulation of sleep/wake transitions during both day and night. Our results further suggest a key role of HCRT neurons in mediating behavioral state transitions in response to external stimuli.

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Section: Discussionsupporting

confidence: 48%

Genetic Ablation of Hypocretin Neurons Alters Behavioral State Transitions in Zebrafish

et al. 2012

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“…The descending pathways mediating the DMH-evoked increase in respiratory activity may involve chemosensitive orexin neurons. In support of this hypothesis, microdialysis of CO 2 -enriched fluid (25% CO 2 ) into the orexin neuron-rich DMH/ perifornical region of the hypothalamus increases resting activity (26), and activation of hypothalamic orexin neurons produces defense-like or panic-like cardiorespiratory responses (17,21,22). Descending orexin projections to the RTN-pFRG region, located in the ventral medulla and intimately related to the central command of respiration, have also been identified (25).…”

Section: Role Of the Dmh And Nts 5-ht 3 Receptors In The Respiratory mentioning

confidence: 86%

Long-lasting bradypnea induced by repeated social defeat

Brouillard

Carrive

Camus

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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peated social defeat in the rat induces long-lasting cardiovascular changes associated with anxiety. In this study, we investigated the effects of repeated social defeat on breathing. Respiratory rate was extracted from the respiratory sinus arrhythmia (RSA) peak frequency of the ECG in rats subjected to social defeat for 4 consecutive days. Respiratory rate was recorded under anesthesia 6 days (Dϩ10) or 26 days (Dϩ30) after social defeat. At Dϩ10, defeated (D) rats spent less time in the open arms of the elevated plus maze test, had heavier adrenal glands, and displayed bradypnea, unlike nondefeated animals. At Dϩ30, all signs of anxiety had disappeared. However, one-half of the rats still displayed bradypnea (D L rats, for low respiratory rate indicated by a lower RSA frequency), whereas those with higher respiratory rate (D H rats) had recovered. Acute blockade of the dorsomedial hypothalamus (DMH) or nucleus tractus solitarii (NTS) 5-HT 3 receptors reversed bradypnea in all D rats at Dϩ10 and in DL rats at Dϩ30. Respiratory rate was also recorded in conscious animals implanted with radiotelemetric ECG probes. DH rats recovered between Dϩ10 and Dϩ18, whereas DL rats remained bradypneic until Dϩ30. In conclusion, social stress induces sustained chronic bradypnea mediated by DMH neurons and NTS 5-HT3 receptors. These changes are associated with an anxiety-like state that persists until Dϩ10, followed by recovery. However, bradypnea may persist in one-half of the population up until Dϩ30, despite apparent recovery of the anxiety-like state.anxiety; breathing; serotonin; social defeat; telemetric recording BREATHING AND ANXIETY ARE intimately related (44). For example, respiratory distress and asphyxia are associated with dreadful feelings, and fear and anxiety can have profound effects on breathing. Clinical studies have shown that panic disorder, characterized by acute and unexpected anxiety attacks and substantial anxiety over the possibility of experiencing further attacks, is associated with symptoms including palpitations, shortness of breath, sweating, and hyperventilation (1). In addition, high levels of anxiety-related behavior in rats are associated with elevation of the resting respiratory rate (9). The respiratory rate also decreases during certain specific responses to stress, for instance during freezing behavior in the rat, when it is associated with ultrasonic vocalizations (19). However, much less is known about the long-term effects of emotional stress on breathing. In adult rats, intense neonatal emotional stress, such as maternal separation, can lead to a decrease in breathing rate during non-rapid-eye-movement sleep (24). A lower respiratory rate was also observed in anesthetized Flinder-Sensitive rats, a well-validated animal model of depression (33). However, respiratory rate does not appear to be altered in patients with major depression, although cardiovascular changes are observed (4). Clearly, more work needs to be done to understand the long-term effects of emotional stress on breathin...

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“…In orexin knockout mice, the cardiovascular and respiratory responses evoked by disinhibition of the DMH/PeF are greatly reduced compared with responses in wild-type mice (87,164). Similarly, systemic administration of the dual orexin receptor antagonist Almorexant reduces the cardiovascular responses associated with arousal and psychological stress but not those associated with cold stress, a physical stressor (63). In addition, the increases in arterial pressure, heart rate, renal sympathetic nerve activity, and respiratory rate evoked by disinhibition of neurons in the PeF and DMH are reduced by about 50% after systemic administration of Almorexant (80).…”

Section: Role Of Dmh and Pef In Integrating Stress-evoked Responsesmentioning

confidence: 95%

“…Psychological stressors can be further subdivided into conditioned stressors (i.e., ones that are normally innocuous but which are perceived as threatening because of previous experiences) or unconditioned stressors (i.e., ones that are intrinsically threatening, such as the sight, sound, or odor of a predator). Physical and psychological stressors activate different populations of neurons in the brain (44,63,102). Similarly, there is evidence that the autonomic responses to conditioned and unconditioned psychological stressors are also mediated by different pathways in the brain (62).…”

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confidence: 99%

Central mechanisms regulating coordinated cardiovascular and respiratory function during stress and arousal

Dampney

2015

American Journal of Physiology-Regulatory, Integrative and Comp

127

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Actual or potentially threatening stimuli in the external environment (i.e., psychological stressors) trigger highly coordinated defensive behavioral responses that are accompanied by appropriate autonomic and respiratory changes. As discussed in this review, several brain regions and pathways have major roles in subserving the cardiovascular and respiratory responses to threatening stimuli, which may vary from relatively mild acute arousing stimuli to more prolonged life-threatening stimuli. One key region is the dorsomedial hypothalamus, which receives inputs from the cortex, amygdala, and other forebrain regions and which is critical for generating autonomic, respiratory, and neuroendocrine responses to psychological stressors. Recent studies suggest that the dorsomedial hypothalamus also receives an input from the dorsolateral column in the midbrain periaqueductal gray, which is another key region involved in the integration of stress-evoked cardiorespiratory responses. In addition, it has recently been shown that neurons in the midbrain colliculi can generate highly synchronized autonomic, respiratory, and somatomotor responses to visual, auditory, and somatosensory inputs. These collicular neurons may be part of a subcortical defense system that also includes the basal ganglia and which is well adapted to responding to threats that require an immediate stereotyped response that does not involve the cortex. The basal ganglia/colliculi system is phylogenetically ancient. In contrast, the defense system that includes the dorsomedial hypothalamus and cortex evolved at a later time, and appears to be better adapted to generating appropriate responses to more sustained threatening stimuli that involve cognitive appraisal. defensive behavior; sympathetic activity; respiratory activity; hypothalamus; midbrain; sympathetic premotor nuclei AN ANIMAL'S SURVIVAL is dependent on being able to respond appropriately to stressors, which can be categorized into two different groups: interoceptive (also-called physical) stressors and exteroceptive (also-called psychological) stressors (44,133). Physical stressors are those that directly threaten homeostasis, such as hypoxia, hemorrhage, or infection, whereas psychological stressors can be defined as actual or perceived threats in the external environment. Psychological stressors can be further subdivided into conditioned stressors (i.e., ones that are normally innocuous but which are perceived as threatening because of previous experiences) or unconditioned stressors (i.e., ones that are intrinsically threatening, such as the sight, sound, or odor of a predator). Physical and psychological stressors activate different populations of neurons in the brain (44,63,102). Similarly, there is evidence that the autonomic responses to conditioned and unconditioned psychological stressors are also mediated by different pathways in the brain (62). In this review, which is based on my 2013 Carl Ludwig Distinguished Lecture to the American Physiological Society, I consider the brain mec...

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Hypocretin /orexin contributes to the expression of some but not all forms of stress and arousal

Cited by 157 publications

References 40 publications

Genetic Ablation of Hypocretin Neurons Alters Behavioral State Transitions in Zebrafish

Genetic Ablation of Hypocretin Neurons Alters Behavioral State Transitions in Zebrafish

Long-lasting bradypnea induced by repeated social defeat

Central mechanisms regulating coordinated cardiovascular and respiratory function during stress and arousal

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