Miranda Nicole C, Aquino Yasmin C, Macedo Tainá O, Oliveira Luiz M, Albernaz-Mariano Kairo A, Munhoz Carolina D, Ramirez Jan-Marino, Moreira Thiago S, Takakura Ana C
Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, 05508-000, São Paulo, SP, Brazil.
Center for Integrative Brain Research, Seattle Children's Research Institute, 1900 9th Avenue, JMB10, Seattle, Washington, 98101, USA.
Exp Neurol. 2025 May;387:115193. doi: 10.1016/j.expneurol.2025.115193. Epub 2025 Feb 26.
The substantia nigra pars compacta (SNpc), a midbrain region enriched with dopaminergic neurons projecting to the dorsal striatum, is essential for motor control and has been implicated in respiratory modulation. In Parkinson's disease (PD) models, the loss of SNpc dopaminergic neurons correlates with baseline respiratory deficits, suggesting a potential link between dopaminergic dysfunction and respiratory impairments. To explore this, we used adult transgenic mice (Vglut Ai6 and Vgat Ai6) to map neurotransmitter phenotypes, as well as DAT mice for pharmacogenetic modulation of SNpc dopaminergic neurons using excitatory (Gq) or inhibitory (Gi) designer receptors exclusively activated by designer drugs (DREADDs). Neuroanatomical tracing revealed SNpc projections to key respiratory nuclei, including the caudal and rostral ventral respiratory groups (cVRG and rVRG), Bötzinger complex (BötC), nucleus of the solitary tract (NTS), raphe magnus (RMg), and dorsal raphe (DR). While SNpc neurons were not activated by hypercapnia (7 % CO₂) or hypoxia (8 % O₂), pharmacogenetic stimulation of SNpc neurons altered respiratory parameters under both baseline and chemosensory challenge conditions. However, dopamine precursor treatment in PD models did not reverse respiratory deficits. These findings suggest that SNpc dopaminergic neurons can modulate respiration when selectively stimulated, but we did not find evidence for an endogenous role in respiratory chemosensitivity. This study reinforces the complexity of dopaminergic contributions to respiratory control in PD and suggests that targeting these neurons may not be sufficient to restore respiratory function, emphasizing the need for broader therapeutic strategies.
黑质致密部（SNpc）是中脑的一个区域，富含向背侧纹状体投射的多巴胺能神经元，对运动控制至关重要，并且与呼吸调节有关。在帕金森病（PD）模型中，SNpc多巴胺能神经元的丧失与基线呼吸缺陷相关，这表明多巴胺能功能障碍与呼吸障碍之间可能存在联系。为了探究这一点，我们使用成年转基因小鼠（Vglut Ai6和Vgat Ai6）来绘制神经递质表型，以及使用仅由设计药物（DREADDs）特异性激活的兴奋性（Gq）或抑制性（Gi）设计受体对SNpc多巴胺能神经元进行药物遗传学调节的DAT小鼠。神经解剖学追踪显示SNpc投射到关键的呼吸核团，包括尾侧和嘴侧腹侧呼吸组（cVRG和rVRG）、包钦格复合体（BötC）、孤束核（NTS）、中缝大核（RMg）和背侧中缝核（DR）。虽然SNpc神经元不会被高碳酸血症（7% CO₂）或低氧（8% O₂）激活，但在基线和化学感受性刺激条件下，对SNpc神经元的药物遗传学刺激都会改变呼吸参数。然而，在PD模型中进行多巴胺前体治疗并不能逆转呼吸缺陷。这些发现表明，SNpc多巴胺能神经元在被选择性刺激时可以调节呼吸，但我们没有找到其在呼吸化学感受性中发挥内源性作用的证据。这项研究强化了多巴胺能对PD呼吸控制作用的复杂性，并表明靶向这些神经元可能不足以恢复呼吸功能，强调了需要更广泛治疗策略的必要性。
