Testing different paradigms to optimize antidepressant deep brain stimulation in different rat models of depression.
Testing different paradigms to optimize antidepressant deep brain stimulation in different rat models of depression.
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在不同的抑郁症大鼠模型中测试不同的范例以优化抗抑郁深部脑刺激
DOI：
10.1016/j.jpsychires.2016.06.016
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发表时间：
2016
影响因子：
4.8
通讯作者：
Winter C
中科院分区：
文献类型：
--
作者：
Rummel J;Voget M;Hadar R;Ewing S;Sohr R;Klein J;Sartorius A;Heinz A;Mathé AA;Vollmayr B;Winter C
几个目标的脑深部电刺激（DBS）在大约60%的难治性抑郁症（TRD）患者中诱导了有益的反应。其余40%表明这些刺激部位对所有TRD患者均不具有治疗相关性，因此应根据个体症状特征选择DBS靶点。我们在这里使用了两种已知具有不同遗传背景和行为反应的抑郁症动物模型：治疗反应性弗林德斯敏感系（FSL）和治疗难治性先天习得性无助大鼠（cLH），以研究特定DBS对i）不同脑部位ii）不同刺激参数和iii）疾病不同表达的影响。假刺激/DBS被施加慢性-间歇或慢性-连续的腹内侧前额叶皮层（vmPFC，啮齿动物相当于膝下扣带），丘脑底核（Nacc）或丘脑底核（Nacc），和不同的抑郁症相关的行为，即快感缺乏，不动/行为绝望和习得性无助的影响进行了研究。使用体内微透析和死后高效液相色谱法（HPLC）分析行为有效与无效DBS的生化底物。我们发现i）vmPFC-DBS优于Nacc-DBS，ii）STN-DBS增加抑郁状态，iii）与慢性间歇性DBS相比，慢性连续性DBS未增加获益，iv）DBS疗效取决于模型化的疾病表达，iv）抗抑郁药DBS与5-羟色胺周转增加以及5-羟色胺含量的部位特异性降低相关。报告的vmPFC DBS的有效性有限，这表明未来的研究可能会考虑特定的疾病表达、不同DBS靶点的研究和替代参数设置。
Deep brain stimulation (DBS) of several targets induces beneficial responses in approximately 60% of patients suffering from treatment-resistant depression (TRD). The remaining 40% indicate that these stimulation sites do not bear therapeutic relevance for all TRD patients and consequently DBS-targets should be selected according to individual symptom profiles. We here used two animal models of depression known to have different genetic backgrounds and behavioral responses: the therapy-responsive Flinders sensitive line (FSL) and the therapy-refractory congenitally learned helpless rats (cLH) to study symptom-specific DBS effects i) of different brain sites ii) at different stimulation parameters, and iii) at different expressions of the disease. Sham-stimulation/DBS was applied chronic-intermittently or chronic-continuously to either the ventromedial prefrontal cortex (vmPFC, rodent equivalent to subgenual cingulate), nucleus accumbens (Nacc) or subthalamic nucleus (STN), and effects were studied on different depression-associated behaviors, i.e. anhedonia, immobility/behavioral despair and learned helplessness. Biochemical substrates of behaviorally effective versus ineffective DBS were analyzed using in-vivo microdialysis and post-mortem high-performance liquid chromatography (HPLC). We found that i) vmPFC-DBS outperforms Nacc-DBS, ii) STN-DBS increases depressive states, iii) chronic-continuous DBS does not add benefits compared to chronic-intermittent DBS, iv) DBS-efficacy depends on the disease expression modeled and iv) antidepressant DBS is associated with an increase in serotonin turnover alongside site-specific reductions in serotonin contents. The reported limited effectiveness of vmPFC DBS suggests that future research may consider the specific disease expression, investigation of different DBS-targets and alternative parameter settings.