His and Hers: Orexins’ Role in Sex Bias in Psychiatric Disease


Stress is interwoven with today’s nonstop society, and it can leave many of us feeling frayed at the edges. Women, especially, seem to experience higher rates of psychiatric disorders that are stress related, such as depression, anxiety, and post-traumatic stress disorder (PTSD), than men. Scientists at The Children’s Hospital of Philadelphia, with the support of a new grant from the National Institute of Mental Health (NIMH), are exploring the idea that these sex differences could be related to our brain’s orexin system, which is a key interface for arousal, sleep, vigilance, and feeding.

Orexins are neuropeptides that are made in the hypothalamus. Neurons use neuropeptides to communicate with each other, and orexins are particularly chatty — they project to multiple brain areas. One of the places that receives dense inputs from orexins is the thalamus, which is the brain region that Seema Bhatnagar, PhD, an associate professor in the CHOP Research Institute’s Division of Stress Neurobiology, enjoys studying the most. The thalamus is a busy central hub that relays sensory information to limbic and cortical brain regions that are important in regulating emotion and memory.

Previous research by Dr. Bhatnagar using rodent models suggested that orexins play a role in the ability to be alert and respond to a stress stimulus. Intrigued by this connection, she worked with Laura Grafe, PhD, a postdoctoral fellow in her lab who was interested in sex differences in responses to stress, to find out if orexins function differently in female and male rats. This is of much relevance to humans because of the pronounced sex differences in psychiatric diseases that are related to stressful life experiences.

“Typically, women have depression and some anxiety-type disorders at twice the rate as men,” said Dr. Bhatnagar, who also is an associate professor of Anesthesiology and Critical Care at the Perelman School of Medicine at the University of Pennsylvania. “We’ve been interested in identifying the mechanisms by which these sex differences occur in the impact of stress.”

In a series of experiments comparing adult female and male rats, Dr. Grafe demonstrated that under baseline conditions, female rats have higher levels of orexins that are more activated in the brain and also greater orexin concentrations in cerebrospinal fluid. She also showed that when the rats were exposed to repeated mild cognitive stress, female rats showed a baseline increase in stress hormones (glucocorticoids), their cognitive performance was impaired, and they did not habituate to the stressor as much as males.

Habituation is an adaptive process by which animals and humans learn that they do not need to fully respond to mild stressors that are not life-threatening. In people with PTSD, habituation is disrupted; they continue to be responsive to things that they know are not harmful but that they associate with previous trauma.

The study team’s next step was to demonstrate if the higher orexins in females were responsible for some of the changes that they observed when the animals were under stress. They tested this using a technique called designer receptors exclusively activated or inhibited by designer drugs (DREADDs), which are viral injections that allowed them to block the activity of orexin cells in the rats’ brains.

“If you block orexins in female rats, we found that you can prevent the baseline increase in glucocorticoids,” Dr. Bhatnagar said. “You also prevent the cognitive impairments. You don’t make them habituate any better, but some aspects are improved. This suggests that the orexins are involved in the sex differences in behaviors that are changed by stress. Of course we are interested in determining whether these effects can translate to humans, and that is something we are working on.”

The investigators’ future work will take a closer look at orexins’ electrophysiological and morphological properties to see if they are related in any way to sex differences and also at how orexins’ target regions and receptors in the brain may change under stress. And since orexins are integral to sleep and wakefulness, they are curious to see if higher orexins could influence females’ sleep parameters.

“Not a lot is known about sex differences and the amount and types of sleep that men get compared to women,” Dr. Bhatnagar said. “For example, females seem to be more easily aroused from sleep. We’re going to start looking at electroencephalogram recordings in female rats compared to males to get a basic idea of what sleep is like for the different sexes, how that may change under stress and how orexins may influence sex differences in sleep parameters.”

Another big unknown: When do these sex differences start in life? The study team will conduct experiments to see if orexins are promoted by ovarian hormones that start increasing in circulation during puberty.

As the investigators start to piece together the answers, they aim to gain a better understanding of the neurobiology underlying sex differences in stress response, which could one day lead to sex-specific approaches to treating stress-related psychiatric illnesses.

Dr. Grafe’s work also is supported by a postdoctoral fellowship from NIMH.

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