| Neural encoding of associative learning by orbitofrontal cortex circuits Dysfunction of the orbitofrontal cortex (OFC) can cause impulsive decision-making, and is implicated in neuropsychiatric disorders including addiction, obsessive compulsive disorder, major depression, attention deficit hyperactivity disorder and schizophrenia. Nevertheless, the function of OFC neural circuits, and how their impairment relates to these disorders is unknown. Impulsive decision-making is characterized by an inability to optimize decisions based on their predicted outcome. It may thus arise due to the dysfunction of both Pavlovian systems, which learn stimulus-outcome associations, and instrumental systems, which learn stimulus-action- outcome associations. OFC is thought to convey both these types of associations, including to the ventral tegmental area (VTA)?a key regulator of learning. Thus, impulsive decision-making may be a consequence of differential aberrations in these learning systems within OFC. Hence, understanding how these associations are learned and maintained by OFC neural circuits may be fundamental to unraveling its function in health and disease. To understand how genetically or projection-defined neurons learn and maintain information, it is imperative to longitudinally track the evolution of their activity during and after learning. Recent state-of-the-art imaging and genetic/viral methods have now made this possible. Using these techniques, I present pilot data demonstrating that I have longitudinally tracked the activity of thousands of OFC neurons, including those projecting to VTA, as mice learned the associations between stimuli and rewards. However, whether the activity patterns uncovered in these experiments are relayed onto these OFC output neurons from elsewhere, or are a product of local computation is unknown. Hence, I first propose to study how input from the medial thalamus, a structure shown to encode associative information, is integrated by the OFC circuit to affect output activity. As part of this goal, I will train to perform patch-clamp electrophysiology in the first aim to establish functional connectivity of this input with specific genetically and projection-defined cell types within OFC. In the second aim, I will optogenetically silence the medial thalamus-to-OFC pathway while longitudinally tracking response evolution of VTA projecting OFC neurons during the learning of stimulus-reward associations. Lastly, I propose to transition my independent research to study how specific cell-types in OFC learn instrumental associations to guide decision-making, through a delay discounting task often used to measure impulsivity. Given my graduate training in rat instrumental behavior and theoretical background in intertemporal decision-making, these proposed aims will help me establish a unique line of research. Further, the technical and managerial training gathered during the K99 phase, and the support of my advisory committee and institution, will help me transition to an independent faculty position in academic research.
Aberrant reward learning and decision-making have debilitating consequences across a wide range of neuropsychiatric disorders including addiction, major depression, obsessive compulsive disorder, schizophrenia, anxiety, and attention deficit hyperactivity disorder. Completion of the aims proposed here is expected to be impactful as it will shed light on the nature of neural encoding and plasticity within precisely identified brain circuit elements during normal reward learning and decision-making. Identifying these mechanisms is important as without such mechanistic studies, we are unlikely to gain significant insight into the nature of aberrant functioning of these circuits?a common theme across these disorders.
