Developmental Genetics of Serotonin Neuron Subtypes in Brain Reward Circuits

Harvard Medical School, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Recovery Act Funds through the NIH Basic Behavioral and Social Science Opportunity Network (NOT- OD-10-O32) would enable us to incorporate, for the first time, fundamental behavioral research into an existing program (parent R21 DA023643) centered on decoding the tremendous heterogeneity among brain serotonergic neurons. Serotonergic neurons are broadly defined by their production of the major neurotransmitter serotonin (5-hydroxytryptamine, 5HT) and are implicated in human disorders ranging from psychiatric conditions of mind, mood, aggression and drug-seeking behaviors to disorders of cardiorespiratory homeostasis. Here, through a Revision (supplemental) Aim, we propose to delineate from the many different types of 5HT neurons, those most contributory to aggression in mice. Delineation of this key subset of 5HT neurons would be transformative, not only to our understanding of the neural circuitry underlying aggression modulation, but also toward identifying potential behaviorally selective therapeutic targets and/or diagnostics. These goals are central to OBSSR and NOT-OD-10-032. Enabling this scope-expansion of R21 DA023643 to include behavioral 5HT circuitry mapping are recent advances from my lab: (1) generation of a molecular framework that classifies murine 5HT neuron subtypes based on gene expression differences;(2) generation of the recombinase-based transgenic tools that provide in vivo genetic access to each of these identified 5HT neuron subclasses (original aim of R21 DA023643);and (3) development of new 'chemico-genetic'and 'exocyto-genetic'neuronal silencing transgenics, that when partnered with our cell subtype selective recombinase tools allow us to separately silence in the mouse each of the 5HT neuron subclasses and assay the impact on, and thus their role in modulating, aggression. This work is innovative, using novel behavioral genetic approaches, yet feasible because we have all necessary tools and expertise in place;further, it is of clinical importance - pathological aggression and its sequelae (such as higher rates of depression, anxiety, post-traumatic stress disorder and worse overall health functioning such as lower cognition and increased somatization) impair our society at all levels, from our youth to our elderly, and is heightened by pervasive factors such as alcohol and other drugs of abuse. Notice NOT-OD-10-032 Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications (R01, R15, R21, R21/R33, R37) through the NIH Basic Behavioral and Social Science Opportunity Network (OppNet). PUBLIC HEALTH RELEVANCE: Pathological aggression is a pervasive health problem with identifiable genetic, biological, environmental and treatment correlates. Underlying brain circuitry involves neurons that produce the major neurotransmitter serotonin, and clinical management commonly involves serotonin-related therapeutics - yet management strategies are hindered by the many other behavioral and physiological processes also modulated by serotonergic neurons. Here we propose cutting-edge molecular genetic studies in mice aimed at identifying the specific subset of serotonergic neurons most critical for aggression modulation;delineation of this subset would be transformative toward identifying behaviorally selective therapeutic targets and/or diagnostics.