Project Grant R15HD110925

THE IMPACT OF EARLY LIFE STRESS ON AMYGDALA CIRCUITRY AND CHRONIC EXCESSIVE AGGRESSION - EARLY LIFE STRESS IS A RELIABLE PREDICTOR OF AGGRESSION IN THE ADULT. FOR EXAMPLE, 38% OF VIOLENT CRIMINALS ARE PHYSICALLY ABUSED DURING CHILDHOOD, AND 28% WILL BE REARRESTED FOR A VIOLENT CRIME LATER IN LIFE, COSTING THE AMERICAN TAXPAYERS BILLIONS OF DOLLARS ANNUALLY. FEW TREATMENT OPTIONS EXIST, AND THOSE THAT DO ARE LARGELY INEFFECTIVE AND FAR FROM PREVENTATIVE. GIVEN THE IMMENSE DANGER OF UNCHECKED VIOLENCE AND AGGRESSION TO SOCIETY AND ITS RELATIONSHIP TO STRESS EXPERIENCED DURING CHILDHOOD, A MORE THOROUGH EXAMINATION OF THE UNDERLYING NEURAL MECHANISMS WILL BE ESSENTIAL IN DEVELOPING NEW AND BETTER THERAPIES. PREVIOUSLY WE SHOWED THAT SOCIAL ISOLATION EARLY IN ADOLESCENCE FOLLOWED BY ACUTE TRAUMATIC STRESS LATE IN ADOLESCENCE, WHICH WE REFER TO AS EARLY LIFE STRESS, PROMOTES LONG-LASTING AGGRESSION BY INDUCING PLASTICITY CHANGES WITHIN MEDIAL AMYGDALA (MEA) PATHWAYS. WEAKENING THESE PATHWAYS SUPPRESSES THE AGGRESSION INCREASE, WHILE STRENGTHENING THESE PATHWAYS CAN SIMULATE THE EFFECTS OF EARLY LIFE STRESS ON AGGRESSION. IMPORTANTLY, NEITHER SOCIAL ISOLATION NOR ACUTE TRAUMATIC STRESS ALONE IS SUFFICIENT TO PROMOTE THE LONG-LASTING INCREASE IN EXCESSIVE AGGRESSION, SUGGESTING THAT THESE STRESSORS DRIVE THE AGGRESSION INCREASE THROUGH DISTINCT BUT REINFORCING PLASTICITY MECHANISMS. THE OBJECTIVE OF THIS PROPOSAL WILL BE TO DETERMINE HOW SOCIAL ISOLATION AND ACUTE TRAUMATIC STRESS ALTER AMYGDALA CIRCUITS TO PRODUCE LONG-LASTING ATTACK BEHAVIOR. THE CENTRAL HYPOTHESIS IS THAT SOCIAL ISOLATION AND ACUTE TRAUMATIC STRESS DURING ADOLESCENCE INDUCE COMPLEMENTARY INTRINSIC, SYNAPTIC, AND STRUCTURAL PLASTICITY CHANGES IN MEA CIRCUITS TO DRIVE EXCESSIVE AGGRESSION IN THE ADULT. THIS WILL BE TESTED IN TWO SPECIFIC AIMS: 1) ASSESS THE ROLE OF SOCIAL ISOLATION DURING ADOLESCENCE ON MEA CIRCUIT PLASTICITY AND LONG-LASTING AGGRESSION AFTER ACUTE TRAUMATIC STRESS; 2) DETERMINE IF EARLY LIFE STRESS PROMOTES LONG-LASTING INCREASES IN AGGRESSION THROUGH STRUCTURAL PLASTICITY IN MEA PATHWAYS. THE PROPOSED STUDIES ARE CONCEPTUALLY AND TECHNICALLY INNOVATIVE BECAUSE THEY USE CUTTING-EDGE IN VIVO VIRAL TRACING, IMAGING, CHEMOGENETIC, AND OPTOGENETIC TECHNIQUES TO ADDRESS HOW SOCIAL ISOLATION AND ACUTE TRAUMATIC STRESS WORK IN TANDEM TO INDUCE INTRINSIC, SYNAPTIC, AND STRUCTURAL PLASTICITY CHANGES IN AMYGDALA CIRCUITS, LEADING TO EXCESSIVE AGGRESSION LASTING INTO ADULTHOOD. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE IT WILL IDENTIFY KEY NEURAL MECHANISMS GOVERNING HOW EARLY LIFE STRESS SHAPES BRAIN CIRCUITS TO DRIVE LONG-LASTING EXCESSIVE AGGRESSION. THE LONG-TERM GOAL OF THE PROPOSED STUDIES IS TO 1) ADVANCE OUR UNDERSTANDING OF HOW EARLY LIFE STRESS INDUCES PLASTICITY CHANGES IN AGGRESSION CIRCUITRY UNDERLYING LONG-LASTING AGGRESSIVE BEHAVIOR, 2) IMPROVE METHODS FOR DETECTING CHANGES IN PLASTICITY IN MOUSE MODELS OF AGGRESSION, AND 3) AID IN THE DEVELOPMENT OF NEW DRUG TARGETS FOR IMPROVED THERAPEUTICS FOR EXCESSIVE AND RECURRING AGGRESSION. THE RESULTS WILL HAVE AN IMPORTANT POSITIVE IMPACT BECAUSE THEY WILL PROVIDE FUNDAMENTAL KNOWLEDGE REGARDING THE IMPACT OF CHILDHOOD TRAUMA ON BRAIN FUNCTION, EVENTUALLY LEADING TO NEW DIAGNOSTIC AND THERAPEUTIC STRATEGIES FOR THE MANAGEMENT OF PATHOLOGICAL ANGER AND AGGRESSION.