Top-down control of sustained attention by medial prefrontal cortex-locus coeruleus (mPFC-LC) projection neurons during the rodent continuous performance test (rCPT).

The medial prefrontal cortex (mPFC) plays a pivotal role in attention by exerting top-down control to allocate cognitive resources toward behaviorally relevant stimuli based on learned context and expectations. mPFC neurons project to multiple cortical and subcortical regions, including the locus coeruleus (LC)-the brain's primary source of norepinephrine (NE). The mPFC also receives inputs from the LC, which release NE to modulate mPFC neuronal activity and downstream cellular signaling. While enhanced functional connectivity between the mPFC and LC in mice during sustained attention tasks suggest an important role for the mPFC-LC circuit, and in particular for mPFC neurons projecting to the LC (mPFC-LC projectors), functional evidence directly implicating this population in attention is lacking. Here, we investigated the role of the mPFC-LC projectors in attention by comparing selective chemogenetic manipulation of these neurons to broad chemogenetic manipulation of mPFC neurons. Selective activation of mPFC-LC projectors in mice performing the rodent continuous performance test (rCPT), a translational sustained attention task, robustly improves attentional performance by enhancing discrimination while non-selective activation of mPFC neurons increases attentional performance by increasing responsiveness. Behavioral effects of mPFC-LC projector activation were mediated by recruitment of a microcircuit involving LC-NE neurons and glutamate and GABA peri-LC neurons that resulted in an increase in NE tone within the mPFC. while effects of non-selective activation of mPFC neurons were mediated by engaging downstream targets such as the nucleus accumbens (NAc) as well as the LC/peri-LC region. These findings demonstrate that subpopulations of mPFC neurons engaging distinct downstream targets control different domains of attentional performance, providing a circuit-level framework for understanding the mechanisms of sustained attention and for developing targeted therapies for attentional deficits across neuropsychiatric disorders.