Humans possess a fundamental need for social contact, which is essential for survival and mental well- being. Therefore, situations of social isolation, exclusion, or disconnection are highly aversive, and can lead to negative feelings of loneliness. However, we have a poor understanding of the brain circuitry which underlies this emotional state, and how this generates a need to seek social contact. Additionally, in many neuropsychiatric disorders, including depression, anxiety, and autism spectrum disorders social withdrawal and impaired social interaction are defining features. As a first step, we must uncover the neural mechanisms which underlie our inherent drive to seek and engage in social contact, in order to understand how these might go awry in mood disorders. We have recently gathered exciting preliminary data implicating an understudied population of dopamine (DA) neurons in the dorsal raphe nucleus (DRN) in representing the subjective experience of social isolation. We find that these neurons are sensitive to acute periods of social isolation, and manipulations of their activity in vivo can induce or suppress a ?loneliness-like? state, in a manner predicted by social rank. We hypothesize that the DRN DA neurons mediate a ?loneliness-like? state, and provide the motivational drive to re-establish social contact. With this research proposal, we therefore seek to explore and unravel this largely uncharted territory within the dopaminergic circuit and explore its functional importance for social contact. To achieve this, we will first identify the input-output architecture of this type of neurons. This will generate a neuroanatomical roadmap and the foundation for detailed circuit- and projection-specific analyses. Furthermore, we will test which input and output regions are involved in conveying essential information about the social environment. For this we will examine the naturally-occurring activity within the DRN dopamine neurons, and establish how manipulating their activity affects social behavior. This will provide insight into how the neural dynamics of this population differ in grouped and socially-isolated animals. We will additionally explore the DRN DA system in relation to the establishment and maintenance of social hierarchy. These experiments will unravel the relationship between DRN DA function and social rank, and further our understanding of the neural mechanisms which contribute to individual differences in social behavior. Importantly, we will work with Ian Wickersham and Liqun Luo to be at the forefront of viral vector approaches needed to successfully execute this proposal. Given my lab?s track record, the unique preliminary data set generated by my team, the questions identified and the necessary steps already taken, we are particularly well-suited to execute this study, and are thrilled to drive the field of social neuroscience forward.
To date, dopamine (DA) neurons within the dorsal raphe nucleus (DRN) represent the first-identified cellular substrate for the aversive state associated with social isolation, though much is yet unknown regarding the associated circuitry. Therefore we designed experiments that will determine 1) the neuroanatomical connections of this specific subset of DA neurons residing within the DRN, 2) provide novel biological insight into how DA influences social interaction and responds to social isolation, and 3) unravel the relationship between DRN DA function and social rank, to further our understanding of the individual differences in social experiences between individuals.
