The aim of the current proposal is to test the hypothesis that signaling through 5-HT1A receptors in the medial prefrontal cortex during adolescence is important for establishing lifelong motivation. Prior work suggests that disruption of the serotonin system during early post-natal development in animal models results in altered anxiety and mood related behaviors in the full-grown adult animal. One receptor that is particularly relevant in this regard is the 5-HT1A receptor. Recent data from our lab suggests that loss of serotonin signaling through 5-HT1A receptors in the medial prefrontal cortex during adolescence but not during adulthood, results in decreased motivation related behavioral setpoints. We hypothesize that this is true for both appetitive and avoidance motivation. The current proposal both examines mechanisms through which altered serotonin signaling through 5-HT1A receptors in adolescence leads to changes in motivation and further elucidates the specific nature of the reinforcement related behavior that is affected. In addition to a loss of function, we will use a biased 5-HT1A agonist as a gain of function approach bi-directionally modulate 5-HT1A signaling Using slice physiology, we will assess whether 5-HT1A expressing neurons alter their intrinsic properties as a result of the disrupted 5-HT1A mediated signaling, or whether there are compensatory changes in circuit properties resulting from the disruption. Using fiber photometry, we will determine how the medial prefrontal cortex engages with other circuit nodes like the dorsal raphe nucleus in tasks that tax motivational systems, with the goal of understanding the circuit basis for the disrupted behavior. Finally, we will directly assess whether the sensitivity of mPFC pyramidal neurons to inputs during adolescence is the critical factor in establishing later motivation. We will do this by manipulating mPFC principal neuron activity during the sensitive period in adolescence using DREADDS. Understanding how mPFC plasticity in adolescence can be harnessed to modulate motivation is a potentially promising strategy for addressing disorder that emerge in adolescence and often include a prominent motivational component. !
This project addresses a number of issues that of central importance for understanding how behavioral set-points for motivated behaviors are regulated during the critical transition between adolescence and full maturity. Specifically, using a mouse model, this project will examine how serotonin, acting through 5-HT1A receptors affects maturation of medial pre-frontal cortex dependent circuitry in adolescence to affect lifelong motivational states. This work has implications for our understanding of human conditions where motivation is dysregulated such as depression, and may reveal new developmentally specific approaches to treating such problems.
