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

Abstract 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, functional evidence directly implicating this circuit in attention is lacking. Here, we investigated the role of the mPFC–LC circuit in attention by comparing selective chemogenetic manipulation of mPFC neurons that project to the LC (mPFC-LC projectors) to non-specific 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 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. Competing Interest Statement GVC is a scientific advisor for LongTermGevity, Inc. and owns stock options in the company. LongTermGevity, Inc. was not involved in the funding, design, or execution of these studies. No other authors have financial relationships with commercial interests, and the authors declare no competing interests. Footnotes Updated figure 4 and figure 5