Developmental regulation of mood states by 5-HT1A heteroreceptors

New York State Psychiatric Institute Dba Research Foundation For Mental Hygiene, Inc, New York NY

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Abstract

? DESCRIPTION (provided by applicant): The aim of the current proposal is to characterize a sensitive period during which lifelong setpoints for mood are established. Evidence to date suggests that disruption of the serotonin system during post-natal development in animal models results in altered anxiety and mood related behaviors in the full-grown adult animal. One receptor that is particularly relevant in this regard is the 5-HT1A receptor. If exists in two form in the nervous system; as an autoreceptor on the serotonin producing neurons in the raphe nucleus where it regulates the overall tone of the serotonin system, and as a heteroreceptor on non-serotonergic neurons, where it mediates responses to released serotonin. Recent data suggest that dysregulation of autoreceptor function in development leads to lifelong anxiety. This proposal examines the role of 5-HT1A heteroreceptors in mediated lifelong mood setpoints. Evidence to date from mouse models suggests that selective loss of heteroreceptor function leads to a depression-like phenotype, and that this phenotype is due to disruption of the receptors before the mice reach full maturity. The current proposal tests the hypothesis that serotonin signaling through heteroreceptors specifically in adolescence is important for setting lifelong response to stress and adversity. The hypothesis will be tested using transgenic as well as viral approaches that rely on reversible knockouts of the 5-HT1A heteroreceptor to localize their function both to a particular time and a particular structure. In addition to a loss of functon approach, a gain of function approach using a 5-HT1A heteroreceptor selective agonist will be used to test the possibility of using a brief treatment during a sensitive period to increase resilience throughout life. If successful, such an approach could translate into a valuable treatment strategy for youth at high risk for depression or other stress related disorders.