Frequency specific optogenetic stimulation of the locus coeruleus induces task-relevant plasticity in the motor cortex

Abstract

The locus coeruleus (LC) is the primary source of neocortical noradrenaline (NA), which is known to be involved in diverse brain functions including sensory perception, attention, and learning. Previous studies have shown that LC stimulation paired with sensory experience can induce task-dependent plasticity in sensory neocortex and in the hippocampus. However, it remains unknown whether LC activation similarly impacts neural representations in the agranular motor cortical regions that are responsible for movement planning and production. In this study, we test whether optogenetic stimulation of the LC paired with motor performance is sufficient to induce task-relevant plasticity in the somatotopic cortical motor map. Male and female TH-Cre+ rats were trained on a skilled reaching lever pressing task emphasizing the use of the proximal forelimb musculature, and a viral approach was used to selectively express ChR2 in noradrenergic LC neurons. Once animals reached criterial behavioral performance, they received five training sessions in which correct task performance was paired with optogenetic stimulation of the LC delivered at 3, 10, or 30 Hz. After the last stimulation session, motor cortical mapping was performed using intracortical microstimulation. Our results show that lever pressing paired with LC stimulation at 10 Hz, but not at 3 or 30 Hz, drove expansion of the motor map representation of the task-relevant proximal forelimb musculature. These findings demonstrate that phasic, training-paired activation of the LC is sufficient to induce experience-dependent plasticity in agranular motor cortex, and that this LC-driven plasticity is highly dependent on the temporal dynamics of LC activation.Significance StatementNoradrenergic input from the locus coeruleus (LC) is known to modulate cortical arousal, attention, and sensory perception. The impacts of noradrenergic signaling on motor cortical networks, however, remain relatively poorly understood. In the current study, we demonstrate that brief, movement-paired LC activation is sufficient to induce experience-dependent plasticity in the motor cortex. Further, this LC-driven motor cortical plasticity is highly dependent on the frequency of LC stimulation, exhibiting an inverted U-shaped relationship with increasing stimulation frequency. These findings point to the temporal dynamics of noradrenergic signaling as an important driver of motor cortical network optimization and experience-dependent plasticity, with implications for targeting this key neuromodulatory system to aid patients with motor deficits.