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Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility
Open accessAbstract
Background Women are twice as likely as men to experience stress-related psychiatric disorders. 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 examined whether orexins contribute to sex differences in outcomes relevant to stress-related psychiatric diseases. Methods Behavioral, neural, and endocrine habituation to repeated restraint stress and subsequent cognitive flexibility was examined in adult male and female rats. In parallel, orexin expression and activation were determined in both sexes, and chromatin immunoprecipitation was used to determine transcription factors acting at the orexin promoter. Designer receptors exclusively activated by designer drugs were used to inhibit orexin activation throughout repeated restraint to determine if the stress-related impairments in female rats could be reduced. Results Female rats exhibited impaired habituation to repeated restraint with subsequent deficits in cognitive flexibility compared with male rats. Increased orexin expression and activation were observed in female rats compared with male rats. The higher expression of orexin messenger RNA in female rats was due to actions of glucocorticoid receptors on the orexin promoter, as determined by chromatin immunoprecipitation. Inhibition of orexins using designer receptors exclusively activated by designer drugs in female rats throughout repeated restraint abolished their heightened hypothalamic-pituitary-adrenal responsivity and reduced stress-induced cognitive impairments. Conclusions 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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“Previous research has shown that orexin neurons in males and females have differences in response to stress and disease.110–112”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [110]
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Metadata
- Authors
- Grafe, L. A., Cornfeld, A., Luz, S., Valentino, R., & Bhatnagar, S.
- Affiliations
- Children's Hospital of Philadelphia (US)
- University of Pennsylvania (US)
- Corresponding author
- Bhatnagar, Seema
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 81
- Issue
- 8
- Pages
- 683-692
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5359079
- OpenAlex
- W2537084688
- Cited by
- 135
- References
- 40
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 14 · 2023: 16 · 2022: 17 · 2021: 20 · 2020: 15 · 2019: 9 · 2018: 11 · 2017: 6
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Scholarship, Research, and Creative Work at Bryn Mawr College (Bryn Mawr College) (submittedVersion)
- Funders
- National Institute of Mental Health (R01MH109975, F32MH109269)
- National Institute of Neurological Disorders and Stroke (T32NS007413)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- orexin, sex differences, stress response, cognitive flexibility, repeated restraint stress, glucocorticoid receptor, hypothalamic-pituitary-adrenal axis, stress habituation, stress-related psychiatric disorders, DREADD
- MeSH terms
- Orexins, Animals, Cognition, Female, Habituation, Psychophysiologic, Hypothalamo-Hypophyseal System, Male, Pituitary-Adrenal System, Receptors, Glucocorticoid, Restraint, Physical, RNA, Messenger, Sex Characteristics, Stress, Psychological, Rats, Sprague-Dawley, Chromatin Immunoprecipitation, Rats
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