Institute for Healthy Aging and Center for Neuroscience Discovery, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.
Department of Cell Systems and Anatomy, Barshop Institute for Aging and Longevity Studies, UT Health San Antonio, San Antonio, TX, 78229, USA.
Mol Neurobiol. 2019 Apr;56(4):2728-2740. doi: 10.1007/s12035-018-1256-9. Epub 2018 Jul 28.
Reduced movement frequency or physical activity (bradykinesia) occurs with high prevalence in the elderly. However, loss of striatal tyrosine hydroxylase (TH) in aging humans, non-human primates, or rodents does not reach the ~ 80% loss threshold associated with bradykinesia onset in Parkinson's disease. Moderate striatal dopamine (DA) loss, either following TH inhibition or decreased TH expression, may not affect movement frequency. In contrast, moderate DA or TH loss in the substantia nigra (SN), as occurs in aging, is of similar magnitude (~ 40%) to nigral TH loss at bradykinesia onset in Parkinson's disease. In aged rats, increased TH expression and DA in SN alone increases movement frequency, suggesting aging-related TH and DA loss in the SN contributes to aging-related bradykinesia or decreased physical activity. To test this hypothesis, the SN was targeted with bilateral guide cannula in young (6 months old) rats, in a within-subjects design, to evaluate the impact of nigral TH inhibition on movement frequency and speed. The TH inhibitor, α-methyl-p-tyrosine (AMPT) reduced nigral DA (~ 40%) 45-150 min following infusion, without affecting DA in striatum, nucleus accumbens, or adjacent ventral tegmental area. Locomotor activity in the open-field was recorded up to 3 h following nigral saline or AMPT infusion in each test subject. During the period of nigra-specific DA reduction, movement frequency, but not movement speed, was significantly decreased. These results indicate that DA or TH loss in the SN, as observed in aging, contributes as a central mechanism of reduced movement frequency.
运动频率或体力活动减少（运动迟缓）在老年人中普遍存在。然而，在衰老的人类、非人类灵长类动物或啮齿动物中，纹状体酪氨酸羟化酶（TH）的丧失并未达到与帕金森病运动迟缓发作相关的80%丧失阈值。中等程度的纹状体多巴胺（DA）丧失，无论是在 TH 抑制后还是在 TH 表达减少后，可能不会影响运动频率。相比之下，在衰老过程中发生的中脑黑质（SN）中等程度的 DA 或 TH 丧失，与帕金森病运动迟缓发作时 SN 中发生的黑质 TH 丧失相似（40%）。在老年大鼠中，SN 中 TH 表达和 DA 的增加单独增加运动频率，这表明与衰老相关的 SN 中 TH 和 DA 的丧失导致与衰老相关的运动迟缓或体力活动减少。为了验证这一假设，在年轻（6 个月大）大鼠中，采用双侧导向套管，在一个被试内设计中，评估黑质 TH 抑制对运动频率和速度的影响。TH 抑制剂α-甲基-对酪氨酸（AMPT）在输注后 45-150 分钟内降低黑质 DA（~40%），而不影响纹状体、伏隔核或相邻腹侧被盖区的 DA。在每个测试对象中，在黑质盐水或 AMPT 输注后 3 小时内记录旷场中的运动活动。在黑质特异性 DA 减少期间，运动频率而非运动速度显著降低。这些结果表明，SN 中观察到的 DA 或 TH 丧失是运动频率降低的中枢机制之一。
