Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability.
Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability.
复制标题
DOI：
10.1523/jneurosci.5017-09.2010
复制
发表时间：
2010-04-14
期刊：
影响因子：
--
通讯作者：
Holmes A
中科院分区：
文献类型：
--
作者：
Mozhui K;Karlsson RM;Kash TL;Ihne J;Norcross M;Patel S;Farrell MR;Hill EE;Graybeal C;Martin KP;Camp M;Fitzgerald PJ;Ciobanu DC;Sprengel R;Mishina M;Wellman CL;Winder DG;Williams RW;Holmes A
压力是许多神经精神疾病的主要危险因素。然而，对压力的敏感性，以及压力对行为影响的定性性质，在个体之间存在显着差异。这部分是由于遗传因素的调节作用。近交系小鼠品系提供了相对稳定和有限的遗传和环境变异范围，这对于解开基因x应激相互作用是有价值的。在这里，我们筛选了一组近交系的焦虑和抑郁相关的表型在基线（性状）和暴露于重复约束。DBA/2 J和C57 BL/6 J两个品系在特质和限制诱导的焦虑相关行为（黑暗/光照探索，高架十字迷宫）方面存在差异。杏仁核，内侧前额叶皮层和海马的基因表达分析显示，在DBA/2 J和C57 BL/6 J在基线和重复约束后的表达不同。限制在包括谷氨酸受体（例如，Grin1，Grik1）.为了阐明这些应变差异的神经元相关性，我们进行了杏仁核主神经元谷氨酸兴奋性神经传递的离体分析。重复约束增强杏仁核兴奋性突触后信号传导和改变的metaplasticity（时间总和的NMDAR电流）在DBA/2 J，但不是C57 BL/6 J。此外，我们发现，C57 BL/6 J样的变化，在焦虑相关的行为限制后，在无效突变体缺乏调节NMDA受体亚基Grin 2a，但不是AMPA受体亚基Gria 1。Grin 2a无效突变体在非约束条件下表现出杏仁核主神经元上树突棘的显著（~30%）损失。总的来说，我们的数据支持一个模型，其中皮质边缘回路中的多巴胺能神经可塑性的遗传变异是对压力反应的表型变异的基础。
Stress is a major risk factor for numerous neuropsychiatric diseases. However, susceptibility to stress, and the qualitative nature of stress effects on behavior, differs markedly among individuals. This is partly due to the moderating influence of genetic factors. Inbred mouse strains provide a relatively stable and restricted range of genetic and environmental variability that is valuable for disentangling gene x stress interactions. Here, we screened a panel of inbred strains for anxiety- and depression-related phenotypes at baseline (trait) and following exposure to repeated restraint. Two strains, DBA/2J and C57BL/6J, differed in trait and restraint-induced anxiety-related behavior (dark/light exploration, elevated plus-maze). Gene expression analysis of amygdala, medial prefrontal cortex and hippocampus revealed divergent expression in DBA/2J and C57BL/6J both at baseline and after repeated restraint. Restraint produced strain-dependent expression alterations in various genes including glutamate receptors (e.g., Grin1, Grik1). To elucidate neuronal correlates of these strain differences, we performed ex vivo analysis of glutamate excitatory neurotransmission in amygdala principal neurons. Repeated restraint augmented amygdala excitatory postsynaptic signaling and altered metaplasticity (temporal summation of NMDAR currents) in DBA/2J but not C57BL/6J. Furthermore, we found that the C57BL/6J-like changes in anxiety-related behavior after restraint were absent in null mutants lacking the modulatory NMDA receptor subunit Grin2a, but not the AMPA receptor subunit Gria1. Grin2a null mutants exhibited significant (~30%) loss of dendritic spines on amygdala principal neurons under non-restraint conditions. Collectively, our data support a model in which genetic variation in glutamatergic neuroplasticity in corticolimbic circuitry underlies phenotypic variation in responsivity to stress.