Material below is adapted from the SfN Short Course The Stress Response: Sex-Specific Neural Mechanisms, by Debra A. Bangasser and Kimberly R. Wiersielis. Short Courses are daylong scientific trainings on emerging neuroscience topics and research techniques held the day before SfN’s annual meeting.
There are well-established differences in the rates of psychiatric disorders, such as major depression and post-traumatic stress disorder, which disproportionately affect women, and attention deficit hyperactivity disorder and schizophrenia, which more often affect men. Stress can also increase the severity of these disorders. Researchers are investigating how sex differences in stress responses might influence the development and progression of psychiatric disorders. One possible driver of sex differences in responses is corticotropin-releasing factor (CRF), a hormone produced by the hypothalamus that activates the body’s stress response.
Previous studies have shown sex differences in CRF regulation and expression, as well as in the expression of a protein that binds CRF and makes it less available to activate the stress response in the brain. This decreased availability can have neurological and behavioral effects. For example, higher levels of CRF in female mice have been connected to increased anxiety.
There are also sex differences in expression, density, and distribution of the receptors to which CRF binds. For instance, binding to one CRF receptor is more abundant in the amygdala of female rats, while binding to another is more abundant in the amygdala of male rats. These differences become apparent after puberty. Expression levels of CRF receptors also differ between male and female rats.
Another way to control the stress response is by changing where CRF receptors are in the cell, a process that is also subject to sex differences. If too much CRF is released, which can over-arouse stress-related neural circuits, neurons may respond by bringing CRF receptors into the cell, away from the surface where they can interact with CRF and activate downstream stress responses. Male rats activate this type of receptor internalization in response to swimming-induced stress, but female rats do not. Researchers have also observed this lack of internalization in female mice.
CRF receptors also signal through different pathways in male and female animals. These signaling differences could have downstream effects on animal behavior. In females, the preferred CRF receptor signaling pathway could lead to greater arousal, while in males, the chosen pathways could lead to greater CRF receptor internalization. Different signaling pathways likely involve distinct outcomes at the cellular level and system-wide and could provide some explanation for sex differences in the development of psychiatric diseases, a possibility researchers are still exploring.
Sex differences in sensitivity to CRF’s effects vary by brain region. As discussed, female animals appear to be more susceptible to the ways in which CRF can affect anxiety and arousal, but CRF seems to exert a greater effect on cognition in males. This effect of CRF on cognition offers a possible explanation for the greater incidence of both attention deficit hyperactivity disorder and schizophrenia in males.
Scientists do not yet fully understand the basis for the sex differences in CRF function, though they have investigated a variety of possibilities. Circulating sex hormones appear to play a role in some cases but have no effect on sex differences in other cases. Sex differences are instead attributed to hormone surges during development or to the different genes expressed by sex chromosomes. More studies are needed to understand the mechanisms that set-up the distinct male and female responses to CRF.
While the sex differences discussed here are specific to CRF function, it is likely that other proteins that act in the brain also function differently in males and females. By investigating the neuroscience of these proteins in both male and female animals, scientists hope to uncover the underlying mechanisms that lead to sex differences in human psychiatric disease.
