Pharmacological and Physiological Characteristics of Synaptic Transmissions From the Medial Prefrontal Cortex Onto Noradrenergic Neurons and Inhibitory Interneurons in the Mouse Locus Coeruleus

Abstract

The locus coeruleus (LC) is the brain's primary source of norepinephrine. It modulates the brain's overall state of arousal. Recent evidence suggests that the LC also regulates immediate attentional responses by resetting related cortical networks to optimize behavioral outcomes. Cortical regions associated with high cognitive function, such as the medial prefrontal cortex (mPFC), are theorized to influence LC output directly to regulate behavior. However, the available evidence is insufficient for a comprehensive understanding of the underlying mechanisms and properties. To address this gap in knowledge, we employed a combination of ex vivo whole‐cell recording and optogenetic techniques to investigate the synaptic transmission of inputs from the mPFC to noradrenergic (NA) neurons in the LC, as well as to inhibitory interneurons (iINs) that synapse onto NA neurons. Our findings suggest that the mPFC forms monosynaptic connections with both LC‐NA neurons and LC‐iINs. These synaptic connections demonstrate disparities in glutamate release properties specific to cell type. Compared to LC‐iINs, mPFC fibers synapsing onto LC‐NA neurons exhibit a higher paired‐pulse ratio, indicating lower release probability, and demonstrate presynaptic enhancement of glutamate release efficacy when stimulated by a paradigm mimicking mPFC unit activity during decision‐making behavior. We propose that the simultaneous connections onto LC‐NA neurons and LC‐iINs, along with cell type–specific differences in transmitter release plasticity, may enable the mPFC to effectively multiplex information to the LC for adaptive behavioral regulation.