Lin Minshan, Calabrese Giulia Benedetta, Incognito Anthony V, Moore Matthew T, Agarwal Aambar, Wilson Richard J A, Zagoraiou Laskaro, Sharples Simon A, Miles Gareth B, Philippidou Polyxeni
Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.
School of Psychology and Neuroscience, University of St Andrews, St Andrews, United Kingdom.
bioRxiv. 2025 Jan 20:2025.01.20.633641. doi: 10.1101/2025.01.20.633641.
The ability to amplify motor neuron (MN) output is essential for generating high intensity motor actions. This is critical for breathing that must be rapidly adjusted to accommodate changing metabolic demands. While brainstem circuits generate the breathing rhythm, the pathways that directly augment respiratory MN output are not well understood. Here, we mapped first-order inputs to phrenic motor neurons (PMNs), a key respiratory MN population that initiates diaphragm contraction to drive breathing. We identified a predominant spinal input from a distinct subset of genetically-defined V0 cholinergic interneurons. We found that these interneurons receive phasic excitation from brainstem respiratory centers, augment phrenic output through M2 muscarinic receptors, and are highly activated under a hypercapnia challenge. Specifically silencing cholinergic interneuron neurotransmission impairs the breathing response to hypercapnia. Collectively, our findings identify a novel spinal pathway that amplifies breathing, presenting a potential target for promoting recovery of breathing following spinal cord injury.
放大运动神经元（MN）输出的能力对于产生高强度运动动作至关重要。这对于呼吸来说至关重要，因为呼吸必须迅速调整以适应不断变化的代谢需求。虽然脑干回路产生呼吸节律，但直接增强呼吸MN输出的途径尚不清楚。在这里，我们绘制了膈运动神经元（PMNs）的一级输入图谱，PMNs是启动膈肌收缩以驱动呼吸的关键呼吸MN群体。我们确定了来自基因定义的V0胆碱能中间神经元的一个独特子集的主要脊髓输入。我们发现这些中间神经元从脑干呼吸中枢接受相位性兴奋，通过M2毒蕈碱受体增强膈输出，并且在高碳酸血症挑战下高度激活。特异性沉默胆碱能中间神经元神经传递会损害对高碳酸血症的呼吸反应。总的来说，我们的发现确定了一条放大呼吸的新型脊髓途径，为促进脊髓损伤后呼吸恢复提供了一个潜在靶点。
