Understanding how social interactions influence reward-seeking behaviors: Developmental mechanisms

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SUMMARY Social interactions impact everyday decisions, even decisions lacking explicit social content. How mammals process social information is intensively investigated. Still, how prior social experiences influence later decision making is not well-understood, likely due in part to a dearth of assays for use in malleable model organisms. My team developed a task referred to as social incentivization of future choice (SIFC). Mice are trained to respond in operant conditioning chambers for two equally preferred foods, then one food is paired with the opportunity to interact with a novel conspecific. The other food is paired with a novel object. We find that mice will later respond more for the conspecific-associated food, even in the absence of that conspecific. Thus, prior social experience appears to confer value to familiar rewards and incentivize choosing that reward over another – akin to one repeatedly favoring a particular restaurant because it’s where one had a first date. The medial orbitofrontal cortex (MO) is necessary for generating reward-seeking actions when the motivating features of possible rewards are not available and must be envisioned – as in SIFC, when mice must recall social interactions. Brain-derived Neurotrophic Factor (BDNF) is integral to MO development, and we recently found that neuronal Bdnf depletion in the MO early in life obstructs SIFC. Many unanswered questions remain. We will: Aim 1: Determine whether BDNF in the developing MO impacts social value processing via MO-BLA connections. We will test the hypothesis that MO-BLA connections require neuronally-derived BDNF for maturation, such that Bdnf silencing in developing MO neurons, but not other cell types, will: 1) diminish MO terminal densities in the BLA and 2) occlude learning-dependent dendritic spine plasticity on excitatory BLA neurons. 3) We will test the hypothesis that dendritic spine plasticity in the BLA is necessary for SIFC to occur. Aim 2: Dissociate the roles of pre- vs. post-synaptic trkB in SIFC. BDNF is subject to anterograde transport; thus, where BDNF must bind to its ubiquitously expressed high-affinity receptor, tropomyosin receptor kinase B (trkB), to control SIFC remains unclear. We will test the hypothesis that BDNF-trkB in the MO and not BLA is necessary for mice to integrate social information into decision-making behavior. We will then replace trkB activity during specific developmental epochs to identify critical periods of action. In a sub-aim, we will compare any effects in the SIFC task to those in a traditional Pavlovian-to-instrumental transfer (PIT) task to reveal dissociable effects of neurotrophin signaling on social vs. non-social PIT behavior, if they exist. Aim 3: Recover SIFC following social isolation. Early-life adversity can profoundly impact cognitive and social function later in life. We find that adolescent social isolation causes the premature up-regulation of trkB full-length isoforms and stress-related co-factors and obstructs SIFC. We will test the hypothesis that select factors in the BLA causally influence SIFC, with overexpression obstructing SIFC and inhibition normalizing social decision-making.