Role of brain Avpr1a-expressing neurons in modulation of social behavior

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Project Summary The importance of understanding the neurobiology of social behavior is underscored by the fact that social interactions permeate nearly every aspect of human life. How we are raised, our interactions with peers, romantic relationships, parenting our own children. All these relationships impact our quality of life, and atypical social interactions can have devastating consequences both for individuals and their social networks. The negative impact of disrupted social behavior can lead to and exacerbate health problems, whereas positive social interactions and supportive environments can improve health outcomes. Better understanding of neural mechanisms underlying social behavior, a key objective of strategic goals laid out by the National Institute of Mental Health, will help identify targets for treatment of underlying causes that disrupt behavior and motivate new ways of using social interaction itself as a therapeutic intervention to improve health outcomes. Decades of research have shown unequivocally that the neuropeptide arginine vasopressin (Avp) impacts both pro- social (e.g., parental care, juvenile play, pair-bonding, and social memory) and anti-social (e.g., aggression and territorial flank-marking) behaviors in numerous mammalian species, but mechanisms by which Avp impacts social behavior are not fully understood creating a critical gap in knowledge. Anatomical studies of Avp neuron projections suggest that Avp producing neurons in the bed nucleus of the stria terminalis (BNST) and medial amygdala are likely to be involved in the regulation of prosocial behavior given that their targets include brain regions associated with motivated behavior, emotional state, and reward (e.g., the mediodorsal thalamus, the target of proposed studies). A central hypothesis is that activation of Avp-responsive (i.e., Avp 1A receptor- expressing, Avpr1a) neurons in brain regions controlling motivation and emotion promote pro-social behavior (i.e., increase interest in social stimuli and engagement in non-aggressive behaviors) and decrease anti-social behavior (i.e., social avoidance and display of aggressive behaviors). To test this hypothesis and discover underlying mechanisms, 3 Aims are proposed. Proposed experiments make use of a newly characterized mouse model that allows genetic access to Avpr1a-expressing cells enabling selective targeting and differentiation between Avpr1a and non-Avpr1a neurons. In Aim 1, electrophysiological, transcriptomic, and viral tracing strategies will be used to identify the fundamental electrical behavior, gene expression patterns, and connectivity of mediodorsal thalamus Avpr1a neurons, a previously unexplored neuronal subtype. The mediodorsal thalamus is a down stream target of the dopamine reward system, is innervated by the BNST Avp system, and through its projections to the medial prefrontal cortex influences memory, cognitive flexibility, and decision-making, all critical to the expression of social behaviors. Then, a chemogenetic loss-of-function strategy will be used to directly assess the role of the mediodorsal thalamus Avpr1a neuron subtype during social interactions (Aim 2) and tests of cognitive behavior (Aim 3).