Sex differences in modulation of serotonergic circuits by the neuropeptide corticotropin releasing factor
Anxiety disorders disproportionately affect women: their chances of developing an anxiety disorder are twice as high than for men. Fundamental research studies the brain circuits involved in normal and/or pathological anxiety, yet only a minority of studies focus on sex-related differences. Recent research in our laboratory has identified a brain circuit that modulates anxiety only in female mice. Using light-driven activation of neurons, we have shown that activation of neurons using the neurotransmitter serotonin, and that send projections to the ventral hippocampus, increases anxiety levels only in females. We now want to understand what mechanisms could explain this sex-related difference.
Corticotropin-releasing factor or CRF is a neuropeptide that plays a critical role in anxiety disorders in humans and activates serotonergic neurons. We suspect that serotonergic neurones in the female brain will be more strongly activated by the stress neuropeptide CRF. To test this hypothesis, we propose to answer two questions:
1- What are the genetic differences between male and female serotonergic neurons that send projections to the ventral hippocampus? We will use recently developed techniques to study the entire pool of RNAs (an intermediate between DNA and proteins) in our subset of serotonergic neurons. We will analyse differences between male and female, with focus on genes related to CRF, such as the CRF receptor CRF-R2.
2- How does this sub-population of serotonergic neurons respond to CRF in vitro and in vivo? We will record from our serotonergic neurons of interest in vitro and in vivo, apply CRF or molecules that activate the CRF-R2, and measure the response of serotonergic neurons in females and males.
Taken together, this research will clarify some of the sex-related differences in response to stress and open new avenues to treat anxiety disorders in men and women.
Bénédicte Amilhon , Hôpital Sainte-Justine
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