Identifying neurobiological mechanisms of aging-related parkinsonism, and lifestyle interventions that mitigate them, remain critical knowledge gaps. No aging study, from rodent to human, has reported loss of any dopamine (DA) signaling marker near the magnitude associated with onset of parkinsonian signs in Parkinson’s disease (PD). However, in substantia nigra (SN), similar loss of DA signaling markers in PD or aging coincide with parkinsonian signs. Alleviation of these parkinsonian signs may be possible by interventions such as calorie restriction (CR), which augment DA signaling markers like tyrosine hydroxylase (TH) expression in the SN, but not striatum. Here, we interrogated respective contributions of nigral and striatal DA mechanisms to aging-related parkinsonian signs in aging (18 months old) rats in two studies: by the imposition of CR for 6 months, and inhibition of DA uptake within the SN or striatum by cannula-directed infusion of nomifensine. Parkinsonian signs were mitigated within 12 weeks after CR and maintained until 24 months old, commensurate with increased D₁ receptor expression in the SN alone, and increased GDNF family receptor, GFR-α1, in the striatum, suggesting increased GDNF signaling. Nomifensine infusion into the SN or striatum selectively increased extracellular DA. However, only nigral infusion increased locomotor activity. These results indicate mechanisms that increase components of DA signaling in the SN alone mitigate parkinsonian signs in aging, and are modifiable by interventions, like CR, to offset parkinsonian signs, even at advanced age. Moreover, these results give evidence that changes in nigral DA signaling may modulate some parameters of locomotor activity autonomously from striatal DA signaling.

确定与衰老相关的帕金森病的神经生物学机制，以及减轻它们的生活方式干预，仍然是关键的知识缺口。从啮齿动物到人类的衰老研究均未报告任何多巴胺 (DA) 信号标志物的丢失程度接近与帕金森氏病 (PD) 中帕金森病症状发作相关的程度。然而，在黑质 (SN) 中，PD 或衰老中 DA 信号标志物的类似丢失与帕金森病征一致。可以通过卡路里限制 (CR) 等干预措施缓解这些帕金森病征，这会增加 DA 信号标志物，如 SN 中的酪氨酸羟化酶 (TH) 表达，但不会增加纹状体中的表达。在这里，我们在两项研究中询问了黑质和纹状体 DA 机制对衰老（18 个月大）大鼠中与衰老相关的帕金森症状的各自贡献：通过实施 CR 6 个月，并通过套管定向输注诺米芬辛抑制 SN 或纹状体内的 DA 摄取。帕金森症状在 CR 后 12 周内减轻，并维持到 24 个月大，与增加的 D 相称_{仅 SN 中的1}受体表达，以及纹状体中 GDNF 家族受体 GFR-α1 的增加，表明 GDNF 信号传导增加。将诺米芬辛输注到 SN 或纹状体中可选择性地增加细胞外 DA。然而，只有黑质输注增加了运动活动。这些结果表明，仅增加 SN 中 DA 信号成分的机制就可以减轻衰老过程中的帕金森病征，并且可以通过干预措施（如 CR）进行修改，以抵消帕金森病征，即使在高龄时也是如此。此外，这些结果证明，黑质 DA 信号的变化可能会根据纹状体 DA 信号自主调节运动活动的某些参数。