The adolescent window of vulnerability for migraine: investigating the role of serotonin to #stopthepain in young rodents and (wo)men

Adolescence and early adulthood are times of extensive neuroanatomical, functional, and chemical reorganization of the human brain, reflecting substantial maturational changes in behavior and cognition. However, this crucial neurodevelopmental transitional period is characterized by the first onset of disorders, such as migraine and depression, which have clinical and pathophysiological overlap, are highly prevalent, and no genuinely efficacious treatments exist. #Stopthepain is the acronym of a project based on data-driven transversal, translational multidisciplinary preclinical, and clinical research that uses an innovative, dynamic approach to study new diagnostic and therapeutic targets for the treatment of migraine in adolescence and young adulthood. Adolescents and young adults (AYA) with severe and or recurrent migraines often suffer from high unmet medical needs. The search for new and better therapeutic strategies is more urgent than ever. Interestingly, AYAs often display very different or even opposite outcomes, with some individuals more susceptible to developing severe and recurrent migraine or responding adequately to treatment. Also, a significant difference exists in the onset and progression between males and females. Currently, knowledge is lacking regarding the reason for the inter-subject variability and timing of clinical outcomes. Still, we know from adult literature that a state of generalized (micro)inflammation and altered serotonergic tone (starting before birth) render the developing brain more susceptible to the development of this pathology. Thus, we will begin by studying inflammatory and metabolic mechanisms in male and female migraineurs and specific animal models using both peripheral as well as central markers to identify a standard set of risk processes, which may help to specify when in development and for whom a specific therapeutic intervention could be most effective. Our collaborative group provides an integrated basic and clinical approach to the proposed research with specific expertise in developing animal models related to pain and depressive-like behavior. We will adopt a network approach using the convergence of specific biological, genetic, cognitive, behavioral, and contextual factors by defining distinct phenotypes and informing what discrete diagnostic and therapeutic targets may be helpful in the development of new treatments emphasizing a cross-species approach that cuts across current categories to predict who will most at risk. The ultimate goal then is to study an overarching dimensional principle that involves the role of serotonin as well inflammatory processes in AYAs diagnosed with migraine and severe and recurrent headaches in (wo)men and rodents, which may serve as a basis for understanding what is familiar and yet unique about the role of serotonin in this debilitating developmental pathology during the last phase of neurodevelopment.