Investigating the role of frontal parvalbumin interneuron maturation in attentional development

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

Project Summary Frontal cortical circuits undergo a protracted developmental process from adolescence to early adulthood to establish cognitive functions such as attention and working memory. This developmental process is disrupted in neurodevelopmental and psychiatric disorders. It remains poorly understood how key frontal circuits and their associated brain networks are differentially recruited during cognitive behavior between adolescents and adults, and how the dysregulation of frontal circuit development contributes to cognitive impairments. Identifying the specific types of neurons in the frontal cortex that are crucial for attention development could lead to the discovery of new therapeutic targets for treating cognitive impairments. Our long-term goals are to characterize the neural circuit mechanisms of frontal cortex maturation that are essential for cognitive function, and to identify therapeutic targets for mitigating cognitive impairments. Attention requires recruitment of the anterior cingulate cortex area (ACA), a subregion of the frontal cortex. In adults, an increase in gamma oscillations between the frontal cortex and sensory cortical areas is also crucial for attention. Among various cell types within the ACA, parvalbumin- expressing interneurons (PVIs) exhibit neural activity that synchronizes with gamma oscillations, and this synchronous activity is known to play a crucial role in attention control. Notably, ACA-PVIs undergo maturation from adolescence to early adulthood, coinciding with the acquisition of improved attentional abilities, and adolescent stress is known to negatively affect the maturation of ACA-PVIs. However, assessing attentional performance in young mice is technically challenging because it typically takes months for mice to learn conventional attentional behavior tasks. As a result, it is entirely unknown how the developmental changes of ACA-PVIs are associated with in vivo network activity and attentional behavior across adolescence, and how stress during adolescence affects PVIs and associated downstream neural activity during attentional behaviors in adulthood. Our preliminary study overcame this challenge by applying an improved fast attentional testing protocol which enabled the recording and manipulation of neural activity in adolescent mice performing the attentional behavior task. Here, we will test the hypothesis that maturation of attentional performance following adolescence depends on increasing recruitment of ACA-PVIs to synchronize ACA and visual cortex (VIS) activity. We will also test the hypothesis that social stress during adolescence reduces recruitment of ACA-PVIs in adulthood, leading to a decline in attentional performance, and that stress-induced attention deficits can be alleviated through genetic manipulation of ACA-PVI maturation. To test these hypotheses, we will integrate techniques for manipulating and monitoring cell-specific activity in developing mice with the aforementioned attentional testing protocol.