Uncovering cell type-specific prefrontal neural mechanisms of visuospatial selective attention in freely behaving mice using a high-throughput touchscreen-based training system

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PROJECT SUMMARY Selective spatial attention, the ability to select and preferentially process information at the most important spatial location, is essential for adaptive behavior. Although extensive research in primates has established the necessity of the prefrontal cortex (and specifically, the frontal eye field, FEF) for the control of selective visual attention, the underlying cell-type and projection-specific neural circuit mechanisms remain elusive. We recently developed rigorous touchscreen-based tasks for primate-like visuospatial selective attention in freely behaving mice in order to investigate circuit mechanistic questions in a genetically tractable model and in a naturalistic (unrestrained) setting. However, investigating the cell-type and projection-specific circuit logic of attention in mice (using these tasks) is a large-scale effort that critically requires an affordable, high-throughput system for the parallelized training of large numbers of mice. Specifically, for touchscreen behaviors, which are used extensively in the behavioral neuroscience community, such a system does not exist either commercially or as open-source. Here, in Aim 1, we propose to develop and establish a low cost, high-throughput, touchscreen-based hardware and software platform for parallelized training of 20 mice at a time on complex visually guided behaviors (including our attention tasks). We hypothesize that this open-source system will cost <1/10th the price, and occupy <1/3rd the space, of current commercial systems, and offer flexible, easy-to-use software for stimulus and experimental control. Preliminary data - hardware and software prototypes, establish viability of this aim. Next, in Aim 2, we will use this high-throughput system to investigate in freely behaving mice, the causal role of somatostatin-positive (SOM+) inhibitory neurons in the cingulate subdivision (Cg) of the mouse prefrontal cortex (considered to be an analog of the FEF), in the control of visuospatial selective attention. We will do so with cell- type specific chemogenetic silencing of SOM+ Cg interneurons in mice trained on our mouse flanker task of attention, which dissociates the locus of attention from the locus of behavioral report (total of 35 SOM-cre mice). We will combine behavioral testing with 3-D head-tracking (and eye-tracking). We hypothesize that Cg/SOM+ neurons control stimulus competition and target selection across space, and that their disruption will impair target selection accuracy without producing purely sensory or motor deficits. Results from this work will have three major impacts. (a) They will shed new light on the functional role of Cg/SOM+ interneurons in attention control. (b) They will set the stage for our planned R01 aimed at detailed cell-type and projection-specific dissection of cingulate sub-circuits (using optogenetics) and cingulate neuronal representations (using endoscopic Ca++ imaging) for visuospatial selective attention in freely behaving mice. (c) Equally importantly, the high-throughput touchscreen training platform developed here will be a potent open-source tool for the broader behavioral neuroscience community investigating the neural circuit basis of other visually guided cognitive functions and dysfunctions as well, such as cognitive control, decision-making, and addiction, in freely moving mice.