UCLA

Adaptive decision making requires the accurate anticipation or expectation of rewarding events. To survive in our environment, we must retrieve and use detailed associative memories of reward-predictive cues and actions taken to reach a goal to inform and guide our decisions. Often times, this cognitive process and underlying neural mechanisms can go awry, leading to maladaptive reward representation and improper choice behavior. Here, we elucidate the basic brain mechanisms of reward-expectation guided behaviors by employing neuroanatomical tracing alongside targeted pharmacological and chemogenetic manipulations of neural circuitry. The data presented here reveal novel contributions of a basolateral amygdala (BLA) opioid receptor system and of specific amygdala-cortical projection pathways to cue-guided behavior.

First, we reveal that the endogenous activation of mu-, but not delta-opioid receptors in the BLA are needed for a reward-predictive cue to guide action selection. BLA mu-opioid receptor antagonism did not disrupt the ability of a reward itself to influence actions, suggesting a selective role for this receptor in mediating cue-outcome memory retrieval. Next, we sought to understand the role of the BLA within a larger neural network, so we first used anterograde and retrograde tract tracers to anatomically map populations of BLA projection neurons to the medial (mOFC) and lateral (lOFC) orbitofrontal cortices, and also identified reciprocal overlap in BLA-OFC (orbitofrontal) circuitry within the frontal cortex. We found spatially distinct populations of BLA→mOFC and BLA→lOFC neurons and dense overlap between OFC cell bodies and BLA terminals in the mOFC and lOFC. Thereafter, we causally manipulated pathways within the BLA-OFC network using a novel projection-specific chemogenetic approach during a series of behavioral tasks designed to assess the retrieval and use of cue- and action-outcome memories. BLA→lOFC projections were required for cue-guided action selection and responding according to a reward’s current value, while BLA→mOFC projections were only required for the latter. Much like the BLA→lOFC pathway, mOFC→BLA projections were needed for reward-predictive cues to guide action selection, and for such cues to influence responding according to a reward’s current value. lOFC inputs to the BLA were not needed for cue-guided action selection, and no projection was found to be necessary for action selection based on a reward’s current value. Taken together, these data provide evidence that distinct projection pathways in the BLA-OFC network coordinate unique and overlapping aspects of reward expectation-guided behaviors, particularly when these behaviors are informed by reward-predictive environmental cues. Often times, mental illness is characterized by improper reward expectation or foresight because patients are deficient in mentally representing anticipated rewards and in reward valuation. Therefore, the findings presented in this work may contribute to our understanding and treatment of psychiatric disease, such as addiction, and suggest that they may arise due to dysfunctional amygdala-OFC circuits.