Developmental Origins of Aggressive and Impulsive Behavior - Project Summary. Septal-hypothalamic neuronal activity centrally mediates aggressive behavior, while the monoamine neurotransmitters dopamine and serotonin play strong and mostly opposing modulatory roles. However, related circuit mechanisms and ontogeny are largely unknown. Making progress towards circuit mechanism, we found in mice that dopamine input from the ventral tegmental area to the lateral septum is sufficient for promoting aggression and necessary for establishing baseline aggression. Within the lateral septum, dopamine acts on D2 receptors to inhibit GABA neurons that project to the hypothalamus. These findings effectively link the clinically pertinent hyper-dopamine model of aggression with the classic septal- hypothalamic aggression axis. Making progress towards ontogeny, we identified a sensitive developmental window during adolescence where dopamine transporter blockade permanently increases adult aggression, impulsivity, and behavioral stimulant response, and in parallel leads to a hyperactive dopamine system. Conversely, periadolescent serotonin transporter blockade reduces aggression and behavioral stimulant response in adulthood, and in parallel leads to a hypoactive dopamine system. Here we will continue this line of research and study the overarching hypothesis that developmental DA and 5-HT signaling tunes DA input into the LS and NAc to impact aggression-related behaviors in adulthood. In Aim 1, we investigate the causal role of dopamine input into the nucleus accumbens in aggression-related behavior. Aggression is behaviorally classified into reactive aggression which occurs impulsively in response to perceived external threat and proactive aggression that is premeditated and directly motivated by a drive for appetitive reward. We hypothesize that nucleus accumbens input contributes to the appetitive value in proactive aggression. In Aim 2, we test the hypothesis that D2 receptors of the lateral septum contribute to sexual dimorphic differences in aggressive behavior. We already found D2 receptors mediate dopamine-promoted aggression in male mice as well as sexual dimorphism for D2 receptor expression. Furthermore, dopamine input into the lateral septum is not sufficient to trigger aggression in females. In Aim 3, we investigate the causal role of serotonin input into the lateral septum and nucleus accumbens in aggression-related behavior. Finally, in Aim 4, we investigate if permanently altered DAergic input into the LS and NAc drives the aggression phenotypes after dopamine and serotonin transporter blockade during development, by monitoring pathway-specific dopaminergic activity during behavior, paired with optogenetic rescue experiments. By mapping circuits to behavior in the context of sensitive developmental period interference, we will advance our understanding of normal as well as disrupted brain development and function. Such information will impact the understanding of human risk factors for maladaptive aggression and dopamine dysfunction. With the novel mechanistic and translational insight, we seek to inform clinical and epidemiological studies and improve diagnosis, prevention and treatment strategies for in psychiatry.
