Stress, particularly during early life, is a major risk factor for several psychiatric disorders including depression. The prevalence of depression is twice as high in women compared with men. Thus in addition to stress, biological sex is an important contributor of depression susceptibility. The divergence in prevalence emerges during puberty, suggesting that this is a key period during which sex-dependent vulnerability to this stress-related disorder is established. Yet, how stress during puberty affects the brain in both males and females is not fully undersood. Current antidepressant drugs are suboptimal and the development of novel more effective antidepressants has been hampered. 80% of preclinical drug development studies neglect to include females and analyse biological sex as a variable. This inattention to biological sex may at least partly explain the poor translation of discoveries made in animal models to successful new treatments in the clinic whereby most individuals receiving antidepressants are female. The overall aim of this project is identify novel sex-dependent and sex-independent druggable targets for the treatment of depression. This will be achieved by identifying the neurobiological mechanisms that underlie sex-dependent and sex-independent vulnerability of the pubertal brain to stress-induced depression. Studies will focus on the hippocampus area of the brain since it is one of the main structures affected in depression and by sex hormones. In this way, we will identify new targets for antidepressant drug development which may be effective in both sexes or that might be more effective in one sex but not the other. These findings will drive novel antidepressant target selection in this era of personalised medicine.
