Neural circuit mechanisms of sensorimotor disability in cancer treatment.
Neural circuit mechanisms of sensorimotor disability in cancer treatment.
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DOI：
10.1073/pnas.2100428118
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发表时间：
2021-12-21
影响因子：
11.1
通讯作者：
Cope TC
中科院分区：
文献类型：
--
作者：
Housley SN;Nardelli P;Rotterman TM;Cope TC
严重和持续的残疾往往会破坏癌症治疗所带来的挽救生命的好处。疼痛和疲劳，以及感觉、运动和认知障碍，是世界上大多数癌症治疗中使用的铂类抗癌药物的主要副作用。由于研究集中于感觉神经元的外周变性，而低估了中枢神经系统内神经过程的可能参与，这些残疾在临床上仍然没有得到缓解，并且在经验上无法解释。目前的研究结果表明，信息处理的基本特性在中枢神经系统中存在功能缺陷。我们得出结论，癌症治疗引起的长期感觉运动和可能的其他残疾是由周围和中枢神经系统复合的独立神经缺陷引起的。癌症幸存者将感觉运动障碍列为化疗最令人痛苦的长期后果之一。步态、平衡和熟练运动障碍通常被认为是周围感觉神经元的化学毒性损伤，而没有考虑将感觉信息转化为运动的神经回路所起的决定性作用。这种疏忽妨碍了充分的、机制的理解，并导致缺乏有效的治疗方法来逆转化疗引起的残疾。我们通过结合电生理学、行为学和建模来研究慢性奥沙利铂（化疗）诱导的神经病变（cOIN）大鼠模型的脊髓感觉运动回路的体内运作，纠正了这一遗漏。研究了本体感觉信息编码过程中的关键序列事件及其在运动神经元中转化为突触电位的电路过程。在cOIN大鼠中，多个类别的本体感觉神经元表达有缺陷的放电，从而降低了肌肉对拉伸机械反应的准确感觉表征。由于脊髓内存在缺陷的机制，本体感觉信号转化为突触电位的准确性进一步下降。这些顺序的、外周的和中枢的缺陷叠加在一起，驱动感觉运动回路进入功能性崩溃，这是预测本体感觉引导的运动行为显著错误的结果，在我们的大鼠模型中得到了证实，并在cOIN患者中得到了报道。我们得出结论，癌症治疗引起的感觉运动障碍是由感觉运动回路外周和中枢元素中独立缺陷的联合表达引起的。
Severe and persistent disability often undermines the life-saving benefits of cancer treatment. Pain and fatigue, together with sensory, motor, and cognitive disorders, are chief among the constellation of side effects that occur with the platinum-based anticancer agents used in a majority of cancer treatments worldwide. These disabilities remain clinically unmitigated and empirically unexplained as research concentrates on peripheral degeneration of sensory neurons while understating the possible involvement of neural processes within the central nervous system. The present findings demonstrate functional defects in the fundamental properties of information processing localized within the central nervous system. We conclude that long-lasting sensorimotor and possibly other disabilities induced by cancer treatment result from independent neural defects compounded across both peripheral and central nervous systems. Cancer survivors rank sensorimotor disability among the most distressing, long-term consequences of chemotherapy. Disorders in gait, balance, and skilled movements are commonly assigned to chemotoxic damage of peripheral sensory neurons without consideration of the deterministic role played by the neural circuits that translate sensory information into movement. This oversight precludes sufficient, mechanistic understanding and contributes to the absence of effective treatment for reversing chemotherapy-induced disability. We rectified this omission through the use of a combination of electrophysiology, behavior, and modeling to study the operation of a spinal sensorimotor circuit in vivo in a rat model of chronic, oxaliplatin (chemotherapy)–induced neuropathy (cOIN). Key sequential events were studied in the encoding of propriosensory information and its circuit translation into the synaptic potentials produced in motoneurons. In cOIN rats, multiple classes of propriosensory neurons expressed defective firing that reduced accurate sensory representation of muscle mechanical responses to stretch. Accuracy degraded further in the translation of propriosensory signals into synaptic potentials as a result of defective mechanisms residing inside the spinal cord. These sequential, peripheral, and central defects compounded to drive the sensorimotor circuit into a functional collapse that was consequential in predicting the significant errors in propriosensory-guided movement behaviors demonstrated here in our rat model and reported for people with cOIN. We conclude that sensorimotor disability induced by cancer treatment emerges from the joint expression of independent defects occurring in both peripheral and central elements of sensorimotor circuits.
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影响因子：
4.6
作者：
Boehmerle W;Huehnchen P;Peruzzaro S;Balkaya M;Endres M
通讯作者：
Endres M
影响因子：
4
作者：
Côté MP;Murray LM;Knikou M
通讯作者：
Knikou M
影响因子：
5.8
作者：
Avan, Abolfazl;Postma, Tjeerd J.;Peters, Godefridus J.
通讯作者：
Peters, Godefridus J.
DOI：
10.1073/pnas.1419045111
发表时间：
2014-11-25
影响因子：
11.1
作者：
Akay, Turgay;Tourtellotte, Warren G.;Jessell, Thomas M.
通讯作者：
Jessell, Thomas M.
影响因子：
2.5
作者：
DREW, T;ROSSIGNOL, S
通讯作者：
ROSSIGNOL, S