Document Type



Author's Final Manuscript

Publication Title

Biological Psychiatry



Publication Date



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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