Elsevier

Biological Psychiatry

Volume 76, Issue 3, 1 August 2014, Pages 203-212
Biological Psychiatry

Archival Report
Antidepressant-like Effects of Cortical Deep Brain Stimulation Coincide With Pro-neuroplastic Adaptations of Serotonin Systems

https://doi.org/10.1016/j.biopsych.2013.12.009Get rights and content

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.

Section snippets

Animals

Eight- to twelve-week-old male wild-type (for behavior and c-Fos experiments) or Pet1-tdTomato transgenic mice (for electrophysiology and morphology experiments) bred onto a C57BL/6 background were used for all experiments (generation of transgenic mice is described in Supplement 1). Mice were housed on a 12-hour light/dark cycle with food and water available ad libitum, except during DBS or sham stimulation. All studies were conducted strictly according to protocols approved by the University

Antidepressant-Like Effect of Chronic vmPFC DBS in Stress-Susceptible Mice

We first investigated the behavioral effect of chronic vmPFC DBS in the CSDS paradigm (Figure 1A). Histological analyses confirmed that DBS electrodes were placed in the vmPFC during experiments (Figure 1B). A social interaction test conducted on Day 11 before surgery verified that interaction times were decreased in defeat-susceptible mice (main effect of defeat F1,36 = 167.11, p = 4.33 × 10−15) (Figure 1C, left). When social interaction was retested on Day 25 after 7 days of chronic vmPFC

Discussion

In this study we have demonstrated that chronic vmPFC DBS reverses social avoidance in a mouse model of depression and induces striking neuroadaptations in brainstem 5-HT neurons that reverse CSDS-induced maladaptive plasticity and point to a sustained increase in 5-HT activity upon repeated courses of DBS.

We first built on previous studies of cortical DBS in the chronic mild stress model 7, 31 by demonstrating the efficacy of DBS in modulating CSDS-induced social avoidance, which models

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