Intranasal dopamine stabilizes prefrontal cortical CaMKIIα-positive neuronal population dynamics during object discrimination

Abstract

Abstract Dopamine (DA) is a key modulator of prefrontal cortex function, yet how distinct dopaminergic states shape the temporal organization of cortical population activity during behavior remains poorly understood. We combined in vivo fiber photometry of dorsomedial prefrontal cortex (dmPFC) putative glutamatergic neurons with an object-based attention (OBAT) task in male mice to examine this question. Intranasal DA (IN-DA), which accesses the brain directly via nose-to-brain pathways, left locomotion and exploratory behavior unchanged. Although both vehicle- and IN-DA- treated mice showed a preference for the novel object, this preference reached statistical significance only in the IN-DA group. IN-DA selectively amplified calcium activity within the familiar-object zone and enhanced movement-normalized calcium spike rates. Strikingly, IN-DA reduced both the mean and variability of calcium transient intervals, reflecting a shift toward more frequent and temporally regular events during object processing. To model the network consequences of supraphysiological dopaminergic drive, we administered the psychostimulant amphetamine as a proxy for dopaminergic excess. In contrast to the stabilizing effects of IN-DA, amphetamine induced locomotor hyperactivity accompanied by a collapse of temporal structure, characterized by prolonged inter-transient intervals and markedly increased variability. Together, these findings demonstrate that dopaminergic modulation shapes not only the magnitude but also the temporal organization of dmPFC population activity. At the network level, physiological DA promotes a temporally stable prefrontal state, whereas dopaminergic excess destabilizes it. This provides population-level evidence for the inverted-U relationship between DA signaling and prefrontal function.