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.

Volatile anesthetics can cause neuronal and glial toxicity in the developing mammalian brain, as well as long-term defects in learning and memory. The goals of this study were to compare anesthetics using a clinically relevant exposure paradigm, and to assess the anesthetic effects on hippocampal development and behavior. Our hypothesis was that volatile anesthetics disrupt hippocampal development, causing neurobehavioral defects later in life. Bromodeoxyuridine (BrdU) was administered to rats on postnatal day (P)1, and the rats were exposed to volatile anesthetics (isoflurane, sevoflurane, or desflurane) for 2 h on P2. On days P7 and P14, the BrdU-labeled cells were quantified in the hippocampal dentate gyrus using immunohistochemical assays and fluorescent microscopy. Caspase-3 positive cells were quantified on P2 to evaluate apoptosis. The remaining animals underwent behavioral testing at ages 6 weeks and 6 months, using the Morris Water Maze. Significantly fewer BrdU-positive cells were detected in the hippocampal dentate gyrus in both isoflurane and desflurane-treated animals compared with controls at P7, but there were no changes in cell numbers after sevoflurane exposure. Cell counts for all three anesthetics compared with controls were equivalent at P14. Isoflurane or desflurane exposure yielded slight differences in the behavioral tests at 6 weeks, but no differences at 6 months post-exposure. We conclude that a single 2-h exposure at P2 to either isoflurane or desflurane causes a transient disruption of hippocampal neuronal development with no significant detectable long-term effects on learning and memory, whereas the same exposure to sevoflurane has no effects.

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