Prefrontal parvalbumin neurons as a target for enhancing cognition in non-pathological and 22q11.2 microdeletion syndrome mice.

To achieve goals in a dynamic environment, the prefrontal cortex (PFC) facilitates various cognitive functions that allow an organism to detect and discriminate information, identify changes in context, and apply this information to representations of known rules and internal states. A failure of organized communication in the PFC is thought to contribute to the emergence of cognitive impairments in psychiatric diseases, with attentional deficits occurring as a fundamental symptom across various conditions. The 22q11.2 microdeletion syndrome is a rare genetic condition that confers a high risk for developing psychiatric and neurodevelopmental disorders, and mouse models have been shown to display attention impairments and PFC pathology that are relevant to clinical populations. Abnormalities in prefrontal parvalbumin-expressing neurons (PVNs) are part of the observed pathophysiology, and studies in rodents have shown that the direct manipulation of these cells can induce behavioral deficits that align with the cognitive symptoms seen in psychiatric diseases. PVNs are a subclass of GABAergic inhibitory cells that facilitate high frequency oscillations that are associated with information processing in the cortex. Because PVNs have such a pivotal role in organizing the input of information to the PFC, their dysfunction could contribute to the manifestation of a variety of cognitive and behavior impairments in disease states. In the present study, we expanded on the role of PVNs in supporting cognition by investigating their involvement in multiple components of attentional functions using a translationally relevant task of focused visual attention, in both non-pathological mice and a model of the 22q11.2 microdeletion syndrome. Using genetically-encoded calcium sensors, fiber photometry, and optogenetics, we describe a novel assessment of how PVN activity is modulated by learning and acute changes in task demands. Interestingly, we observed that task-evoked prefrontal PVN activity was reduced in mice that exhibited poorer attention and in 22q11.2 mutant mice. While PVN activity was shaped across learning in non-pathological mice, mutant mice exhibited a lack of signal dynamics that coincided with attentional deficits. Importantly, we observed that task performance in both poor performing wild-types and 22q11.2 mutants could be alleviated by high frequency (gamma band range) PVN stimulation. Thus, PVNs appear to be involved in the acquisition of task rules and execution of attention and continue to be a promising therapeutic target for cognitive dysfunction in disease.