Aggression is essential to the survival of organisms as it allows individuals to obtain and defend resources and protect mates or offspring. Yet, aggression can become maladaptive when escalated and unrestrained, sometimes leading to violence in humans. Further, escalated aggression can occur in neuropsychiatric disorders such as intermittent explosive disorder, schizophrenia, and autism. Therefore, advances in understanding the cellular, molecular, and circuit pathways underlying aggression will be significant to human health. Both the serotonergic and dopaminergic neuromodulatory systems are implicated in aggression, yet the specific cell types and circuitry involved are unknown. The proposed research uses cutting-edge genetic and viral tools to understand the role of a specialized dopamine-responsive serotonergic (5-HT) neuron subtype critical to the modulation of aggression, using a mouse model system. This 5-HT neuron subtype is distinguished by the expression of type-II dopamine receptor (Drd2) and the pan serotonergic transcription factor Pet1, and are referred to as Drd2-Pet1 neurons. Largely unknown, is the circuitry involving Drd2-Pet1 neurons and the requirement for the Drd2 receptor in their modulation of behavior. Towards identifying brain regions with inputs onto Drd2-Pet1 neurons, novel viral vectors for intersectional (Cre- and Flp-dependent) trans-synaptic tracing were developed (Aim 1). Additionally, to probe the functional importance of Drd2 in this subset of 5-HT neurons, mice with 5-HT neuron specific deletion of Drd2 were generated and their behavioral phenotype was analyzed in a behavioral screening panel. This work has found that 5-HT neuron expression of Drd2 is critical for the modulation of male aggression and acoustic startle reactivity in females, suggesting a potential sexually dimorphic role (Aim 1). Proposed experiments will further examine the potential sexually dimorphic role of Drd2 expression in 5-HT neurons through the analysis of Drd2-Pet1 neuron modulation of female aggression (Aim 2.1) and characterization of the underlying circuit structure using mouse molecular genetic tools and viral neuronal circuit tracing techniques (Aim 2.2). This PhD dissertation project will inform upon the molecular, cellular, and circuit pathways underlying aggression and startle reactivity while testing novel viral-genetic tools that will be broadly applicable to the study of neuronal subtype connectivity.
The serotonergic (5-HT) and dopaminergic neuromodulatory systems have both been implicated in aggression, yet the specific cell types and circuitry involved remain unknown. This project will study a dopamine (DA)- responsive serotonergic neuron subtype involved in the modulation of aggression and acoustic startle reactivity in mice and will inform on the functional interplay between 5-HT and DA in the modulation of behavior. Understanding the circuit structure of this 5-HT neuron subtype may inform better therapeutics for the treatment of escalated aggression and/or altered startle reactivity, which can occur in neuropsychiatric disorders such as intermittent explosive disorder, schizophrenia, autism, and post-traumatic stress disorder.
