Deep brain stimulation changes locus coeruleus responses to social stress from activation to inhibition

Deep Brain Stimulation (DBS) of the subgenual cingulate cortex (SCC) stands as an innovative therapeutic approach for treatment-resistant depression. Previous preclinical investigations utilizing DBS targeted at the ventromedial prefrontal cortex (vmPFC), considered the rodent equivalent of the human SCC, have demonstrated antidepressant-like effects, as well as enhancement in the activity of the locus coeruleus (LC)-norepinephrine (NE) system and pontine-cortical network oscillations. Given the association between social stress and depression and other psychiatric disorders, we assessed the impact of vmPFC DBS on social stress-induced changes in LC neuronal activity in awake rats. Spontaneous and auditory-evoked LC single unit activity were compared between control and DBS male rats during the first (acute) and fifth (repeated) day of social defeat stress. In stark contrast to LC activation observed in controls, both acute and repeated stress robustly inhibited LC neurons of DBS rats. While both groups experienced an acute stress-induced reduction in auditory-evoked LC discharge, the duration of the evoked response was only decreased in control animals. LC auditory-evoked activity was increased after repeated stress and DBS effectively counteracted these stress-induced alterations. These findings suggest that DBS treatment shifts stress-induced regulation of LC activity such that it favors the engagement of inhibitory modulation. This may serve to promote resistance of the LC-NE system to stress-induced excitation and contribute to the mitigation of neuropsychiatric consequences of stress.