Unraveling the neural mechanism underlying context-dependent decision making

PROJECT SUMMARY Humans live in a complex and dynamic environment. In our daily lives, many decisions depend on contextual information. For example, when drivers enter a two-way street in the US, they will stay on the right side of the road. Once they travel to the UK (a different context), they will have to adjust their actions and drive on the left side to follow local traffic rules. This capacity for flexible decision making is thought to be a critical part of cognitive function and is compromised in psychiatric and neurological disorders, such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder, and obsessive-compulsive disorder (OCD). How does a healthy brain process contextual information and flexibly modulate the behavioral response? How is this neural computation altered in patients with cognitive inflexibility? Neuroimaging studies in humans have indicated that the frontal lobe is responsible for this executive function; however, mechanistic studies in animal models have shown mixed results. Our lab takes advantage of the rapidly developing genetic and imaging tools available in mouse models to study the neural mechanism underlying context-dependent decision making. We have recently discovered that the premotor cortex (anterior lateral motor cortex, ALM) encodes both contextual cues and behavioral choices using an olfactory-guided delayed match to sample (DMS) task. More importantly, neural processing in the ALM (but not orbitofrontal cortex) is required for animals to optimally perform this task. In this proposal, I aim to unravel the neural mechanism and computation underlying flexible decision making at both the subcellular and network levels. I first aim to develop a new context-dependent olfactory decision (CDOD) task to address a potential confounder in our previous work and establish a robust and simple behavioral paradigm to study flexible decision in mouse models. Next, I will elucidate whether and how the context selective neurons in the ALM, including pyramidal neurons and subtypes of interneurons, mediate the flexible response in choice neurons by using 2-photon imaging, targeted 3D photostimulation, and computational modeling. I hypothesize that the context selective neurons in the ALM mediate the functional state of the choice neurons through dendritic gating to regulate the flexible behavioral response. Furthermore, I will test the causal role of context specific neurons in decisions using large-scale 3D photoinhibition. Lastly, I aim to identify the upstream brain substrates that enable the processing of context information in ALM. Answering these questions will contribute to the core goal of NIMH by advancing our knowledge about the neural mechanism behind flexible decision-making, which is altered in mental illnesses such as ASD and OCD. Using the proposed experiments in the olfactory system as an entry point, I hope to provide insights into the fundamental cognitive functions involving perception and decision-making.