Antidepressant-like effects of cortical deep brain stimulation coincide with pro-neuroplastic adaptations of serotonin systems.
BACKGROUND
Cortical deep brain stimulation (DBS) is a promising therapeutic option for treatment-refractory depression, but its mode of action remains enigmatic. Serotonin (5-HT) systems are engaged indirectly by ventromedial prefrontal cortex (vmPFC) DBS. Resulting neuroplastic changes in 5-HT systems could thus coincide with the long-term therapeutic activity of vmPFC DBS.


METHODS
We tested this hypothesis by evaluating the antidepressant-like activity of vmPFC DBS in the chronic social defeat stress (CSDS) model of depression (n = 8-13 mice/group). Circuit-wide activation induced by vmPFC DBS was mapped with c-Fos immunolabeling. The effects of chronic vmPFC DBS on the physiology and morphology of genetically identified 5-HT cells from the dorsal raphe nucleus (DRN) were examined with whole-cell recording, somatodendritic three-dimensional reconstructions and morphometric analyses of presynaptic boutons along 5-HT axons.


RESULTS
Acute DBS drove c-Fos expression locally in the vmPFC and in several distal monosynaptically connected regions, including the DRN. Chronic DBS reversed CSDS-induced social avoidance, restored the disrupted balance of excitatory/inhibitory inputs onto 5-HT neurons, and reversed 5-HT hypoexcitability observed after CSDS. Furthermore, vmPFC DBS reversed CSDS-induced arborization of 5-HT dendrites in the DRN and increased the size and density of 5-HT presynaptic terminals in the dentate gyrus and vmPFC.


CONCLUSIONS
We validate a new preclinical paradigm to examine cellular mechanisms underlying the antidepressant-like activity of vmPFC DBS and identify dramatic circuit-mediated cellular adaptations that coincide with this treatment. These neuroplastic changes of 5-HT neurons might contribute to the progressive mood improvements reported in patients treated with chronic courses of cortical DBS.
['Veerakumar|Avin|A|', 'Challis|Collin|C|', 'Gupta|Preetika|P|', 'Da|Jennifer|J|', 'Upadhyay|Aseem|A|', 'Beck|Sheryl G|SG|', 'Berton|Olivier|O|']
D000222:Adaptation, Physiological D000818:Animals D001921:Brain D046690:Deep Brain Stimulation D003863:Depression D065847:Dorsal Raphe Nucleus D053444:Inhibitory Postsynaptic Potentials D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D017397:Prefrontal Cortex D059326:Serotonergic Neurons
Deep brain stimulation depression prefrontal cortex neuroplasticity social defeat dorsal raphe