Shifts in attentional demand are accompanied by sex-specific patterns of insula-frontal cortical interactions in mice.

The insula is a brain region that is correlated with the cognitive process of attention in humans. Aberrant insula function is also implicated in attentional impairments in several psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia. Although the insula's role in attention has been well-studied in humans, we do not yet have an understanding of how the insula communicates with other brain areas to promote attentional processing. Here, we show that neurons in the mouse insula send direct axonal projections to the frontal cortex, and that these two brain areas functionally interact in different ways between male and female mice performing a touchscreen-based attention task. Specifically, we recorded and analyzed local field potentials (LFPs) from the insula and frontal cortex while mice performed variants of a rodent analogue of the continuous performance test of attention, or rCPT. In male mice, we found that activity in the frontal cortex preceded insular activity when the task was well-learned, but that insula-frontal cortex synchrony decreased when the need to inhibit responding was high. In female mice, synchrony between the insula and frontal cortex was largely bidirectional, but was high during all session types. We further demonstrate that patterns of theta-gamma coupling between the frontal cortex and insula distinguish between correct choices and errors during the rCPT, and that these patterns diverge between sexes. Our results suggest that functional differences in insula-frontal cortical circuitry at least partially underlie sex differences in attention-guided behavior in mice. Highlights: We measured local field potentials (LFPs) in the mouse insula and frontal cortex during a translationally-relevant touchscreen-based task of attentionManipulation of stimulus frequency during the task increased the demand on vigilance and response inhibitionIn male mice, frontal cortex-driven synchrony in slow frequency bands reflected task rules, while theta-gamma coupling reflected errors when demand on response inhibition was increasedIn female mice, bidirectionally-driven synchrony in slow frequency bands also reflected task rules, while theta-gamma coupling reflected errors when demand on vigilance was increased.