UC San Diego

Cognitive control processes do not solely rely on the prefrontal cortex (PFC) proper. Mediodorsal thalamus (MD), the higher-order thalamic region known to be prominently connected with the PFC, has been recognized as an important node in the cortico-striatal-thalamic-cortical loops mediating flexible goal-directed behavior, both in clinical and basic research. Previously, studies trying to understand MD activity and function have largely examined or manipulated the structure as a whole. Recently, there has been an increasing appreciation of, and methods to target, the subpopulations within the MD as they relate to the functions of their respective PFC targets; but most in vivo studies focus on MD projections into medial and dorsal PFC. The lateral orbitofrontal cortex (lOFC) also receives input from the MD, and has been implicated in various aspects of goal-directed decision-making such as outcome valuation and maintaining an up-to-date internal representation of tasks and the contingencies therein; yet MD’s contributions to lOFC functions have remained unclear.In this dissertation, I sought to image and manipulate the endogenous activity pattern of the MD projection population into lOFC during the learning and performance of a self-initiated goal-directed task, which to our knowledge is the first time this MD-PFC subcircuit has been examined in this manner in vivo. We found that the activity of the MD terminal population in lOFC was differentially sensitive to trials based on the probabilistic outcome of instrumental actions. In concert, we found that animals’ expectation built across learning and changing task requirements, with expectation-modulated instrumental performance affected by optogenetically inhibiting the activity of lOFC projecting MD somas. We did not find evidence of motivational state-induced outcome value representation in the MD-lOFC terminal population; however, attenuating the activity of MD-lOFC projection neurons during outcome revaluation and, in particular, the use of updated outcome value in extinction did compromise adaptive instrumental behavior. These findings suggest that MD input population into lOFC provides prospective information that modulates instrumental actions within the overall cognitive control framework of monitoring interactions with the world, comparing expectations with actual experiences, and adapting an internal model of the world in order to optimize goal-directed behaviors.