Antidepressant-like effects of cortical deep brain stimulation coincide with pro-neuroplastic adaptations of serotonin systems.
Antidepressant-like effects of cortical deep brain stimulation coincide with pro-neuroplastic adaptations of serotonin systems.
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DOI：
10.1016/j.biopsych.2013.12.009
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发表时间：
2014-08-01
影响因子：
10.6
通讯作者：
Berton, Olivier
中科院分区：
文献类型：
--
作者：
Veerakumar, Avin;Challis, Collin;Gupta, Preetika;Da, Jennifer;Upadhyay, Aseem;Beck, Sheryl G.;Berton, Olivier
皮质深部脑刺激(DBS)是治疗难治性抑郁症的一种有前景的治疗选择，但其作用模式仍是个谜。5-羟色胺(5-HT)系统由腹内侧额叶皮质(VmPFC)DBS间接参与。由此导致的5-羟色胺系统的神经可塑性变化可能与vmPFC DBS的长期治疗活性相一致。我们通过评估vmPFC DBS在慢性社会失败应激(CSDS)抑郁症模型(每组8-13只小鼠)中的抗抑郁药样活性来验证这一假说。C-Fos免疫标记法定位vmPFC DBS诱导的全电路激活。采用全细胞记录、躯体树突三维重建和5-羟色胺突触前突触形态计量学分析的方法，研究了慢性vmPFC DBS对中缝背核(DRN)5-羟色胺(5-HT)细胞生理和形态的影响。急性DBS在vmPFC和包括DRN在内的几个远端单突触连接区域局部驱动c-Fos的表达。慢性DBS逆转了CSDS诱导的社交回避，恢复了5-羟色胺神经元兴奋性/抑制性输入失衡的平衡，并逆转了CSDS后观察到的5-羟色胺低兴奋性。此外，vmPFC DBS还逆转了CSDS诱导的5-羟色胺在DRN内的树枝状分支，并增加了齿状回和vmPFC内5-羟色胺突触前终末的大小和密度。我们验证了一种新的临床前范例，以检验vmPFC DBS抗抑郁药样活性的细胞机制，并确定与这种治疗相一致的戏剧性电路介导的细胞适应。这些5-羟色胺神经元的神经可塑性变化可能有助于报告的慢性皮质型DBS治疗患者情绪的进行性改善。
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. 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 per group). Circuit-wide activation induced by vmPFC DBS was mapped using 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 using whole-cell recording, somatodendritic 3-D reconstructions and morphometric analyses of presynaptic boutons along 5-HT axons. 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. 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 which coincide with this treatment. These neuroplastic changes of 5-HT neurons may contribute to the progressive mood improvements reported in patients treated with chronic courses of cortical DBS.
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影响因子：
4.8
作者：
Falowski SM;Sharan A;Reyes BA;Sikkema C;Szot P;Van Bockstaele EJ
通讯作者：
Van Bockstaele EJ
影响因子：
10.6
作者：
Hamani, Clement;Machado, Danilo C.;Nobrega, Jose N.
通讯作者：
Nobrega, Jose N.
影响因子：
5.3
作者：
Celada, P;Puig, MV;Artigas, F
通讯作者：
Artigas, F
DOI：
10.1523/jneurosci.3237-12.2013
发表时间：
2013-04-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Halpern CH;Tekriwal A;Santollo J;Keating JG;Wolf JA;Daniels D;Bale TL
通讯作者：
Bale TL
影响因子：
4.8
作者：
Hamani, Clement;Diwan, Mustansir;Nobrega, Jose N.
通讯作者：
Nobrega, Jose N.