Resolving the diversity of prefrontal neuron activity within and across behavioral tasks in mice

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A striking feature of prefrontal cortex (PFC) neurons is their functional diversity, which likely is crucial to their ability to control behavior in an adaptive and flexible manner. This diversity is manifest in two ways. First, the activity of PFC neurons is modulated by a wide variety of cognitive and behavioral tasks. Second, within any given task, PFC neurons display a variety of behavioral and task-related firing patterns that defy easy characterization. The overall goal of the current proposal is to uncover organizing principles underlying these two aspects of response diversity in PFC neurons. First, we will examine to what extent the diversity in task-related firing patterns of PFC neurons can be explained by their different projection targets, addressing core hypothesis 2 of the consortium. To this end, we will use calcium imaging to compare the working memory-related activity patterns of PFC neurons projecting to different cortical and subcortical areas. We hypothesize that neurons projecting to different targets will display different task-related response properties, revealing the unique signals relayed by the mPFC to each of its downstream targets. We will also extensively characterize the anatomical organization of projection-defined mPFC populations. Second, we will examine to what extent different behaviors that have been associated with the PFC engage independent or overlapping ensembles of PFC neurons and thus address core hypothesis 1 of the consortium. To this end, we will perform longitudinal calcium recordings of the same PFC neuron population in mice while they perform multiple behavioral tasks, including working memory and sensory decision-making. We hypothesize that PFC neurons will be organized into ensembles that are recruited either during single tasks or active across multiple tasks, reflecting common neural computations. We will also examine how task-related activity patterns and ensembles in the PFC are dynamically formed and modified during the sequential learning of different behavioral tasks. Thus, by comparing PFC neuronal activity across behavioral tasks and projection targets, we hope to gain insights into the factors that shape the response diversity of PFC neurons and their organization into ensembles guiding flexible behavior.