Production of hESCs for the study of human serotonergic neurons in health and disease

The neurotransmitter serotonin, one of the key modulatory neurotransmitters, is pivotally involved in myriad of neurological and behavioral disorders, including migraine, motor disorders, sleep disorders, eating disorders, and a spectrum of neuropsychiatr ic disorders including major depression, bipolar disorders, anxiety, schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD) and autism. The social and economic costs associated with disorders such as depression and migraine are enormous, both in t erms of quality of life, work productivity, morbidity and mortality. For example, depression is now the leading cause of medical disability among those aged 15-44 (WHO World Health Report), is a leading cause of suicidal death among teenagers and young ad ults, and alone is estimated to cost society tens of billions of dollars per year in the U.S. alone. Better treatment of serotonin-related neurological diorders is therefore of utmost priority. Despite their important role in so many disorders, very litt le is known about how human serotonergic neurons are regulated in health and disease. This project will provide the first human embryonic stem cell platform for generating human serotonergic neurons at high purity with a reporter gene for easy visualizati on, based on a similar platform already in existence based on mouse embryonic stem cells. This hESC platform will be used to elucidate the effects of mood-regulating drugs like serotonin agonists and reuptake inhibitors on human serotonergic neuron functi on, growth and synaptic plasticity, and thus how human serotonergic neurons react in disease treatment states. The information obtained will provide important information about the effects of widely used medical treatments and aid in developing better ph armacological therapies for debilitating human neurological disorders.