Department of Internal Medicine, Section on Gerontology and Geriatric Medicine. Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Acta Physiol (Oxf). 2022 Nov;236(3):e13887. doi: 10.1111/apha.13887. Epub 2022 Sep 15.
Brainstem noradrenergic neuron clusters form a node integrating efferents projecting to distinct areas such as those regulating cognition and skeletal muscle structure and function, and receive dissimilar afferents through established circuits to coordinate organismal responses to internal and environmental challenges. Genetic lineage tracing shows the remarkable heterogeneity of brainstem noradrenergic neurons, which may explain their varied functions. They project to the locus coeruleus, the primary source of noradrenaline in the brain, which supports learning and cognition. They also project to pre-ganglionic neurons, which lie within the spinal cord and form synapses onto post-ganglionic neurons. The synapse between descending brainstem noradrenergic neurons and pre-ganglionic spinal neurons, and these in turn with post-ganglionic noradrenergic neurons located at the paravertebral sympathetic ganglia, support an anatomical hierarchy that regulates skeletal muscle innervation, neuromuscular transmission, and muscle trophism. Whether any noradrenergic neuron subpopulation is more susceptible to damaged protein deposit and death with ageing and neurodegeneration is a relevant question that answer will help us to detect neurodegeneration at an early stage, establish prognosis, and anticipate disease progression. Loss of muscle mass and strength with ageing, termed sarcopenia, may predict impaired cognition with ageing and neurodegeneration and establish an early time to start interventions aimed at reducing central noradrenergic neurons hyperactivity. Complex multidisciplinary approaches, including genetic tracing, specific circuit labelling, optogenetics and chemogenetics, electrophysiology, and single-cell transcriptomics and proteomics, are required to test this hypothesis pre-clinical.
脑干去甲肾上腺素能神经元簇形成一个节点，整合投射到不同区域的传出神经，如调节认知和骨骼肌结构和功能的区域，并且通过已建立的回路接收不同的传入神经，以协调机体对内环境和环境挑战的反应。遗传谱系追踪显示，脑干去甲肾上腺素能神经元具有显著的异质性，这可能解释了它们的不同功能。它们投射到蓝斑，这是大脑中去甲肾上腺素的主要来源，支持学习和认知。它们还投射到节前神经元，这些神经元位于脊髓内，并与节后神经元形成突触。下行脑干去甲肾上腺素能神经元与脊髓节前神经元之间的突触，以及这些神经元与位于椎旁交感神经节的节后去甲肾上腺素能神经元之间的突触，支持调节骨骼肌神经支配、神经肌肉传递和肌肉营养的解剖学层次结构。随着年龄的增长和神经退行性变，任何去甲肾上腺素能神经元亚群是否更容易受到受损蛋白质沉积和死亡的影响，这是一个相关的问题，答案将帮助我们在早期检测神经退行性变，建立预后，并预测疾病进展。随着年龄的增长，肌肉质量和力量的丧失，称为肌肉减少症，可能预示着与年龄相关的认知能力下降和神经退行性变，并确定开始旨在减少中枢去甲肾上腺素能神经元过度活跃的干预措施的早期时间。需要采用复杂的多学科方法，包括遗传追踪、特定回路标记、光遗传学和化学遗传学、电生理学以及单细胞转录组学和蛋白质组学，来在临床前阶段检验这一假设。
