Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons.
Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons.
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作者：
大脑奖励回路中的中脑被盖区（VTA）多巴胺（DA）神经元在介导压力反应中起着至关重要的作用，包括确定对社会压力诱导的行为异常的敏感性与弹性。腹侧被盖区DA神经元在体内表现出两种放电模式：低频强直放电和高频相位放电。众所周知，神经元的相位放电编码奖励信号，被反复的社会失败压力上调，这是一种高度有效的抑郁症小鼠模型。令人惊讶的是，这种病理生理学效应仅在易感小鼠中观察到，在弹性个体中放电率没有明显变化。然而，直接的证据链接在实时DA神经元相位放电促进易感（抑郁样）表型是缺乏的。在这里，我们利用光遗传学的时间精确性和细胞类型和投射通路特异性来证明这些神经元的增强的相位放电介导了自由行为小鼠对社会失败压力的易感性。我们表明，光遗传学诱导阶段性，但不是紧张性，发射，在腹侧被盖区DA神经元的小鼠经历了一个阈下社会失败的范例迅速诱导易感表型的社会回避和减少蔗糖偏好。这些神经元的光遗传相位刺激也迅速诱导易感表型在以前的弹性小鼠已受到反复的社会失败的压力。此外，我们显示的差异，在促进压力敏感性的投射途径特异性：阶段性激活的腹侧被盖区神经元投射到丘脑核（NAc），但不内侧前额叶皮层（mPFC），诱导社会失败压力的敏感性。相反，VTA-NAc投射的光遗传学抑制诱导恢复力，而VTA-mPFC投射的抑制促进易感性。总的来说，这些研究揭示了抑郁症的新的放电模式和神经回路特异性机制。
Ventral tegmental area (VTA) dopamine (DA) neurons in the brain’s reward circuit play a crucial role in mediating stress responses including determining susceptibility vs. resilience to social stress-induced behavioural abnormalities. VTA DA neurons exhibit two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no change in firing rate apparent in resilient individuals. However, direct evidence linking—in real-time—DA neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here, we took advantage of the temporal precision and cell type- and projection pathway-specificity of optogenetics to demonstrate that enhanced phasic firing of these neurons mediates susceptibility to social defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing, in VTA DA neurons of mice undergoing a subthreshold social defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social defeat stress. Furthermore, we show differences in projection pathway-specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, while inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing pattern- and neural circuit-specific mechanisms of depression.
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影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
使用ChannelRhopopsin-2的细胞型特异性表达，对体内神经元的靶向光遗传学刺激和记录。
影响因子：
14.8
作者：
通讯作者：
--
DOI：
10.1186/1744-9081-6-24
发表时间：
2010-04-23
期刊：
Behavioral and brain functions : BBF
影响因子：
--
作者：
Schultz W
通讯作者：
Schultz W
DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
82.9
作者：
Hommel, JD;Sears, RM;DiLeone, RJ
通讯作者：
DiLeone, RJ