Sociability encompasses a range of complex behaviors that require coordinated activity of multiple neural circuits for successful expression. Effective social engagement is highly rewarding and relies upon mu opioid receptor signaling within the nucleus accumbens, an important reward center of the brain. Selective blockade of the mu opioid receptor within the nucleus accumbens suppresses social interactions whereas the stimulation of these receptors significantly increases social interactions. As mu opioid receptors are expressed on presynaptic axon terminals as well as a variety of postsynaptic cells in the nucleus accumbens, the mechanisms by which mu opioid receptors control social responding remains unclear. Therefore, the broad objective of this proposal is to understand how mu opioid receptors on nucleus accumbens microcircuitry mediate social behavior. The focus of this proposal will be on the medium spiny projection neurons, which constitute the primary cell type of the nucleus accumbens. Medium spiny neurons are distinguished by their expression of Drd1 or Drd2 dopamine receptor subtypes, and activation of these different cell types has distinct effects on reward-related behavioral output. In this proposal I will selectively manipulate the expression of mu opioid receptors on medium spiny neuron sub-types and characterize the resultant cellular and social phenotype (Aim 1). Additionally, I will use chemogenetics to restore inhibitory modulation of specific medium spiny neuron subtype following mu opioid receptor deletion, and determine the impact on social behavior (Aim 2). This project will clarify how mu opioid receptor activity changes medium spiny neuron activity dynamics in the nucleus accumbens in a manner necessary for social behavioral expression. Through my training I will acquire the background, conceptual and technical knowledge to complete this proposal. My sponsor, Dr. Patrick Rothwell, and co-sponsor, Dr. Kevin Wickman, provide outstanding mentorship, focused on my technical and professional development as a neuroscientist. In addition, the University of Minnesota Graduate Program in Neuroscience offers a supportive and collaborative scientific environment and has numerous Core Facilities that will be available to me for training and equipment use. The proposed project will help me become an independent research scientist as I develop the ability to identify and interrogate cellular, circuit and behavioral abnormalities that arise in neuropsychiatric diseases.
Social behavior is disrupted in several neuropsychiatric diseases and has a significant impact on the emotional well-being and thus quality of life for those individuals. This proposal will provide insight into the specific cellular and circuit mechanisms mediating sociability, with a focus on identifying specific targets for therapeutic intervention.
