title: Antidepressant-like effects of cortical deep brain stimulation coincide with pro-neuroplastic adaptations of serotonin systems.
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.
authors: Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Avin
authors: A
authors: Veerakumar
authors: Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Neuroscience Graduate Group, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Collin
authors: C
authors: Challis
authors: Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Neuroscience Graduate Group, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Preetika
authors: P
authors: Gupta
authors: Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Jennifer
authors: J
authors: Da
authors: Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Aseem
authors: A
authors: Upadhyay
authors: 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.
authors: Sheryl G
authors: SG
authors: Beck
authors: 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.
authors: Olivier
authors: O
authors: Berton
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D046690:Deep Brain Stimulation; D003863:Depression / Q000628:therapy*; D065847:Dorsal Raphe Nucleus / Q000378:metabolism / Q000503:physiopathology*; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology*; D059326:Serotonergic Neurons / Q000502:physiology*
keywords: Deep brain stimulation; depression; dorsal raphe; neuroplasticity; prefrontal cortex; social defeat