Cell Type-Specific Alterations in the Nucleus Accumbens by Repeated Exposures to Cocaine
Cell Type-Specific Alterations in the Nucleus Accumbens by Repeated Exposures to Cocaine
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DOI：
10.1016/j.biopsych.2011.01.013
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发表时间：
2011-06-01
影响因子：
10.6
通讯作者：
Kim, Joung-Hun
中科院分区：
文献类型：
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作者：
Kim, Juhyun;Park, Bong-Hyun;Kim, Joung-Hun
背景：伏隔核（NAc）是一个关键参与精神兴奋剂诱导的神经适应的大脑区域。NAc神经元主要由中棘神经元（medium spiny neuron, MSNs）组成，根据其D1多巴胺受体（D1R-MSNs）或D2多巴胺受体（D2R-MSNs）的表达，通常分为两大亚群。虽然已知NAc微MSN在暴露于滥用药物后其特征会发生广泛的改变，但每种类型的微MSN特有的功能和结构变化尚未完全解决。方法：在D1R或D2R启动子的控制下，将可卡因反复注射到表达增强绿色荧光蛋白的转基因小鼠体内，通过全细胞记录分析各类型MSN的生理特性。我们还以细胞类型特异性的方式分析了可卡因诱导的重组慢病毒个体msn脊柱密度的变化，并通过重组狂犬病毒的途径特异性标记证实了这一发现。结果：反复给药后，D1R-MSNs的膜兴奋性降低，微兴奋性突触后电流频率增加，而D2R-MSNs的微兴奋性突触后电流频率降低，但兴奋性无变化。有趣的是，微型抑制性突触后电流在D1R-MSNs中下降，但在D2R-MSNs中未受影响。此外，形态学分析显示，慢性可卡因暴露后，d1r - msn的脊柱密度选择性增加。结论：本研究提供了第一个实验证据，证明NAc msnn通过以细胞类型特异性的方式改变其内在、突触和结构特征，对精神兴奋剂诱导的神经适应有不同的贡献。
Background: The nucleus accumbens (NAc) is a brain region critically involved in psychostimulant-induced neuroadaptations. A major proportion of NAc neurons consists of medium spiny neurons (MSNs), commonly divided into two major subsets on the basis of their expression of D1 dopamine receptors (D1R-MSNs) or D2 dopamine receptors (D2R-MSNs). Although NAc MSNs are known to undergo extensive alterations in their characteristics upon exposure to drugs of abuse, the functional and structural changes specific to each type of MSN have yet to be fully resolved.Methods: We repeatedly injected cocaine into transgenic mice expressing enhanced green fluorescent protein under the control of promoters for either D1R or D2R and then analyzed the physiological characteristics of each type of MSN by whole-cell recording. We also analyzed cocaine-induced changes of spine densities of individual MSNs with recombinant lentivirus in a cell type-specific manner and corroborated findings by use of a pathway-specific labeling using recombinant rabies virus.Results: The D1R-MSNs exhibited decreased membrane excitability but increased frequency of miniature excitatory postsynaptic currents after repeated cocaine administration, whereas D2R-MSNs displayed a decrease in miniature excitatory postsynaptic current frequency with no change in excitability. Interestingly, miniature inhibitory postsynaptic currents decreased in D1R-MSNs but were unaffected in D2R-MSNs. Moreover, morphological analyses revealed a selective increase in spine density in D1R-MSNs after chronic cocaine exposure.Conclusions: This study provides the first experimental evidence that NAc MSNs differentially contribute to psychostimulant-induced neuroadaptations by changing their intrinsic, synaptic, and structural characteristics in a cell type-specific fashion.