The Hypocretin/Orexin System: An Increasingly Important Role in Neuropsychiatry

Chen, Quanhui; Lecea, Luı́s de; Hu, Zhian; Guo, Dong

doi:10.1002/med.21326

Cited by 74 publications

(56 citation statements)

References 378 publications

(440 reference statements)

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“…Stressful life events can also impair cognitive function, including cognitive flexibility (6), which precipitates or exacerbates many psychiatric disorders (7). Patients with disorders such as panic disorder and PTSD exhibit altered concentrations of the hypothalamic peptides orexins in cerebrospinal fluid (5; 8; 9). Orexins regulate neuroendocrine and behavioral responses that are affected in stress-related illness including disruptions in the HPA axis, cognitive flexibility, arousal, food intake, and emotional memory (5; 10; 11).…”

Section: Introductionmentioning

confidence: 99%

Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility

Grafe

Cornfeld

Luz

et al. 2017

Biological Psychiatry

115

112

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BACKGROUND Women are twice as likely as men to suffer from stress-related psychiatric disorders. However, the biological basis of these sex differences is poorly understood. Orexins are altered in anxious and depressed patients. Using a rat model of repeated stress, we asked whether orexins contribute to sex differences in outcomes relevant to stress-related psychiatric diseases. METHODS Behavioral, neural, and endocrinal habituation to repeated restraint stress and subsequent cognitive flexibility was examined in adult male and female rats. In parallel, orexin expression and activation was determined in both sexes, and chromatin immunoprecipitation was used to determine transcription factors acting at the orexin promoter. DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) were used to inhibit orexin activation throughout repeated restraint to determine if the stress related impairments in females could be reduced. RESULTS Female rats exhibited impaired habituation to repeated restraint with subsequent deficits in cognitive flexibility compared to male rats. Increased orexin expression and activation was observed in females compared to males. The higher expression of orexin mRNA in females was due to actions of glucocorticoid receptors on the orexin promoter, as determined by chromatin immunoprecipitation. Finally, inhibition of orexins using DREADDs in females throughout repeated restraint abolished their heightened HPA responsivity and reduced stress-induced cognitive impairments. CONCLUSIONS The results demonstrate that orexins mediate the impairments in adaptations to repeated stress and in subsequent cognitive flexibility exhibited by female rats and provide evidence for a broader role for orexins in mediating functions relevant to stress related psychiatric diseases.

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Section: Introductionmentioning

confidence: 99%

Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility

Grafe

Cornfeld

Luz

et al. 2017

Biological Psychiatry

115

112

View full text Add to dashboard Cite

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“…The effects on the brain of HFD exposure during gestation include changes in various neuropeptides in the hypothalamus, which themselves are known to stimulate the ingestion of a HFD (Robert et al, 1989; Gomori et al, 2003; Naleid et al, 2007; Chang et al, 2008), project to brain areas involved in mediating emotional behaviors (Thompson et al, 1996; Kirouac et al, 2006), and have a role in controlling arousal and anxiety-like behaviors (Herman et al, 2003; Chen et al, 2015). In adult rats, a HFD is found to increase the levels and expression of enkephalin (ENK) in the paraventricular nucleus (PVN) and also of orexin (OX) and melanin-concentrating hormone (MCH) in the perifornical lateral hypothalamus (PFLH), while having little effect on or suppressing neuropeptide Y (NPY) in the arcuate nucleus (ARC) (Ikenasio-Thorpe et al, 2007; Chang et al, 2008; Barson et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Involvement of the CXCL12 System in the Stimulatory Effects of Prenatal Exposure to High-Fat Diet on Hypothalamic Orexigenic Peptides and Behavior in Offspring

Poon

Barson

Shi

et al. 2017

Front. Behav. Neurosci.

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Exposure to a high fat diet (HFD) during gestation stimulates neurogenesis and expression of hypothalamic orexigenic neuropeptides that affect consummatory and emotional behaviors. With recent studies showing a HFD to increase inflammation, this report investigated the neuroinflammatory chemokine, CXCL12, and compared the effects of prenatal CXCL12 injection to those of prenatal HFD exposure, first, by testing whether the HFD affects circulating CXCL12 in the dam and the CXCL12 system in the offspring brain, and then by examining whether prenatal exposure to CXCL12 itself mimics the effects of a HFD on hypothalamic neuropeptides and emotional behaviors. Our results showed that prenatal exposure to a HFD significantly increased circulating levels of CXCL12 in the dam, and that daily injections of CXCL12 induced a similar increase in CXCL12 levels as the HFD. In addition, prenatal HFD exposure significantly increased the expression of CXCL12 and its receptors, CXCR4 and CXCR7, in the hypothalamic paraventricular nucleus (PVN) of the offspring. Finally, the results revealed strong similarities in the effects of prenatal HFD and CXCL12 administration, which both stimulated neurogenesis and enkephalin (ENK) expression in the PVN, while having inconsistent or no effect in other regions of the hypothalamus, and also increased anxiety as measured by several behavioral tests. These results focus attention specifically on the CXCL12 chemokine system in the PVN of the offspring as being possibly involved in the stimulatory effects of prenatal HFD exposure on ENK-expressing neurons in the PVN and their associated changes in emotional behavior.

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“…The widespread projections of the orexin system reflect the variety of physiological functions of orexin peptides, which include: the modulation of arousal and sleep-wake cycles, energy homeostasis, reward processing, and stress (reviewed in [6][7][8]) (Box 1). Moreover, a role for orexins in emotional behavior regulation has been recently proposed, consistent with the existence of orexin neuronal projections to several limbic areas [9] (Figure 1) (see Glossary).…”

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confidence: 99%

Orexins and fear: implications for the treatment of anxiety disorders

Flores

Saravia

Maldonado

et al. 2015

Trends in Neurosciences

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An understanding of the neurobiological mechanisms involved in the regulation of fear is essential for the development of new treatments for anxiety disorders, such as phobias, panic, and post-traumatic stress disorders (PTSD). Orexins, also known as hypocretins, are neuropeptides located exclusively in hypothalamic neurons that have extensive projections throughout the central nervous system. Although this system was initially believed to be primarily involved in the regulation of feeding behavior, recent studies have shown that orexins also modulate neural circuits implicated in the expression and extinction of fear memories. Here, we discuss recent findings involving orexins in anxiety disorders and current clinical trials using orexin ligands that could be applied to identify new therapies for diseases characterized by pathological fear.

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The Hypocretin/Orexin System: An Increasingly Important Role in Neuropsychiatry

Cited by 74 publications

References 378 publications

Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility

Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility

Involvement of the CXCL12 System in the Stimulatory Effects of Prenatal Exposure to High-Fat Diet on Hypothalamic Orexigenic Peptides and Behavior in Offspring

Orexins and fear: implications for the treatment of anxiety disorders

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