Portland VA Medical Center, Portland, OR 97239, USA.
Neurobiol Dis. 2012 Mar;45(3):1051-67. doi: 10.1016/j.nbd.2011.12.024. Epub 2011 Dec 14.
Environmental enrichment has been shown to be both neuroprotective and neurorestorative in 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models of Parkinson's disease (PD). However, whether social interaction or novel physical stimulation is responsible for this recovery is controversial. In the current study, we have investigated the effects of only social enrichment (SocE) in progressively MPTP-lesioned mice. After mice were lesioned using a progressively increased dose (4 mg/kg, 8 mg/kg, 16 mg/kg and 32 mg/kg; each dose daily for 5 days), the MPTP-induced behavioral deficits, after the 32 mg/kg dose, were reversed with acute L-DOPA. This acute behavioral recovery suggests that this progressive MPTP-induced neurodegeneration is an appropriate murine model of PD. Mice were housed four per cage for the first 2 weeks of progressive lesioning or vehicle treatment. After the 8 mg/kg MPTP dose (prior to SocE intervention) mice showed a significant decrease in rearing and foot fault behaviors (FF/BB) compared to the vehicle group. Additionally, there was a 38% decrease in mean number of tyrosine hydroxylase immunoreactive (TH-ir) substantia nigra pars compacta (SNpc) neurons/section, and a 50% decrease in the optical density of TH-ir dorsolateral caudate putamen (CPu) terminals compared to the vehicle group. Mice were then housed either two (socially limited environment; SLE) or twelve (SocE) mice per cage during continued MPTP lesioning for the next 2 weeks at 16 mg/kg and 32 mg/kg MPTP. MPTP treatment was then discontinued, while mice remained in the SLE or SocE cages for an additional week. Rearing behavior was further impaired in SLE-MPTP mice following progressive MPTP, accompanied by additional decreases in the mean number of TH-ir SNpc neurons/section and CPu TH-ir terminals. CPu TH and dopamine transporter (DAT) protein expression, as well as dopamine tissue and TH protein levels was significantly decreased compared to either vehicle group. However, the deficit in rearing behavior in SLE-MPTP mice was reversed with acute L-DOPA following the intervention period. SocE-MPTP mice showed rearing and FF/BB behaviors similar to vehicle levels, although FF/BB was not significantly different from pre-intervention levels. The reversal from pre-intervention rearing deficits was correlated with an attenuated decrease in the mean number of SNpc TH-ir neurons/section and CPu TH and DAT protein, and with a blocked decrease in CPu TH-ir terminals compared to pre-intervention levels. Our findings show that SocE mice not only resist further nigrostriatal lesioning and FF/BB deficit, but rearing behavior is recovered to the level of the vehicle group despite continued MPTP treatment. In contrast, SLE mice showed continued loss of nigrostriatal TH-ir and decline of motor behaviors with progressive MPTP. The data suggest that non-pharmacological intervention that started at an early stage of dopamine loss is effective at slowing or blocking further nigrostriatal degeneration.
环境丰富已被证明在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）帕金森病（PD）小鼠模型中具有神经保护和神经修复作用。然而，社交互动还是新的物理刺激负责这种恢复仍存在争议。在当前的研究中，我们仅研究了社交丰富（SocE）对逐渐 MPTP 损伤的小鼠的影响。在使用逐渐增加的剂量（4mg/kg、8mg/kg、16mg/kg 和 32mg/kg；每天一次，连续 5 天）对小鼠进行损伤后，32mg/kg 剂量后的急性 L-DOPA 逆转了 MPTP 诱导的行为缺陷。这种急性行为恢复表明，这种逐渐 MPTP 诱导的神经退行性变是 PD 的一种合适的小鼠模型。在逐渐损伤或载体处理的前 2 周，将小鼠每 4 只饲养在一个笼子中。在接受 8mg/kg MPTP 剂量（SocE 干预前）后，与载体组相比，小鼠的后肢离地和抬脚行为（FF/BB）显著减少。此外，与载体组相比，酪氨酸羟化酶免疫反应性（TH-ir）黑质致密部（SNpc）神经元/节的平均数量减少了 38%，TH-ir 背外侧纹状体（CPu）末梢的光密度减少了 50%。然后，在接下来的 2 周内，将小鼠分别以每笼 2 只（社交受限环境；SLE）或 12 只（SocE）继续接受 16mg/kg 和 32mg/kg MPTP 损伤。然后停止 MPTP 治疗，而小鼠在 SLE 或 SocE 笼中再额外饲养 1 周。在逐渐接受 MPTP 治疗后，SLE-MPTP 小鼠的后肢离地行为进一步受损，SNpc TH-ir 神经元/节和 CPu TH-ir 末梢的平均数量进一步减少。与任一载体组相比，CPu TH 和多巴胺转运蛋白（DAT）蛋白表达以及多巴胺组织和 TH 蛋白水平均显著降低。然而，在干预期后，SLE-MPTP 小鼠的后肢离地行为缺陷通过急性 L-DOPA 得到逆转。SocE-MPTP 小鼠的后肢离地和抬脚行为与载体水平相似，尽管抬脚行为与干预前水平无显著差异。与干预前相比，后肢离地行为的恢复与 SNpc TH-ir 神经元/节和 CPu TH 和 DAT 蛋白平均数量的减少减弱以及 CPu TH-ir 末梢减少相吻合。我们的研究结果表明，SocE 小鼠不仅能抵抗进一步的黑质纹状体损伤和抬脚行为缺陷，而且在继续接受 MPTP 治疗的情况下，后肢离地行为恢复到载体组的水平。相比之下，SLE 小鼠在逐渐接受 MPTP 治疗后，黑质纹状体的 TH-ir 持续减少，运动行为下降。数据表明，在多巴胺丢失的早期开始进行非药物干预可有效减缓或阻断进一步的黑质纹状体变性。
