Avin Veerakumar1, Collin Challis2, Preetika Gupta2, Jennifer Da3, Aseem Upadhyay3, Sheryl G Beck4, Olivier Berton5. 1. Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania. 2. Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Neuroscience Graduate Group, Perelman School of Medicine, Philadelphia, Pennsylvania. 3. Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania. 4. Department of Neuroscience Graduate Group, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Anesthesiology, Children's Hospital of Philadelphia Research Institute and Perelman School of Medicine, Philadelphia, Pennsylvania. 5. Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Neuroscience Graduate Group, Perelman School of Medicine, Philadelphia, Pennsylvania. Electronic address: bertonol@mail.med.upenn.edu.
Abstract
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.
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.
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