PROJECT SUMMARY Attention is comprised of several component processes, including sustained attention, selective attention, and attentional flexibility. The first phase, the initial focusing of attention, precludes engagement of other components making it an important building block of many of our more complex behaviors. Additionally, attention impairments often present as a comorbidity in conditions including but not limited to schizophrenia, autism, depression, and epilepsy, making identifying therapeutic targets a significant public health concern. Convergent data point to the medial prefrontal cortex (mPFC) as a hub for supporting attentional shifting along with other key structures, while its role in the initial engagement of attention is less clear. Somehow, mPFC pyramidal neurons integrate information from multiple sources, represent task rules, cue, and response-related information in dynamically active ensembles, and select appropriate behavioral responses. Previous physiological data suggests this astounding computational feat is made possible due to the powerful regulation of pyramidal neuron activity by cortical inhibitory interneurons, but many studies lacked the ability to monitor distinct cell-classes with specificity. Using fiber photometry of GCaMP-mediated Ca2+ signals in mPFC parvalbumin-expressing interneurons (PVINs), we have collected preliminary data demonstrating that PVINs play a novel role in cue-perception during a visual attentional engagement task (AET). Specifically, we have observed that cue-evoked population increases in PVIN activity are necessary, sufficient, and can be predictive for successful attentional engagement. We hypothesize that this may represent a universal mechanism of attention that is consistently disrupted across diseases with attentional impairments. PVINs however, do not operate in isolation, and mPFC pyramidal neurons are also regulated by long-range inputs from the mediodorsal thalamus (MD) among others, and local circuit interactions with other interneuron subtypes, such as somatostatin (SOM) and vasoactive intestinal polypeptide (VIP) expressing interneurons, all of which have also been linked to cognition and psychiatric disease dysfunction. Separate studies have identified distinct disinhibitory circuits involving VIP and SST interneurons, and SST and PV interneurons that can regulate mPFC-dependent behaviors. However, the precise circuit motifs which regulate attentional processes are largely uncharacterized. Specifically, how individual interneurons in specific classes represent information during attentional assays capturing distinct components of attention remains to be determined. Through the K99 phase, I will receive critical training in in vivo Ca2+ imaging and design and implementation of attentional tasks to test my overall hypothesis that PVINs provide broad inhibition to suppress distracting information during attentional engagement, while the R00 phase will examine how separate disinhibitory circuit motifs allow pyramidal neuron ensembles to signal cue and response information to appropriately guide separate attention functions.

PROJECT NARRATIVE Attention is critical in our everyday life and serves as an important building block of many of our more complex behaviors. The proposed research will identify the cellular and circuit level signatures of successful attention through examination of neuronal activity in typically functioning mice and mutant mouse lines with attention impairments. Results generated from this proposal will answer fundamental questions about how the brain supports attention and provide a basis for the development of effective therapeutics for attentional impairments across disease states.