Mechanisms of Reciprocal Inhibition Development

描述(申请人提供)：关于肢体位置的感觉反馈对于正常运动和适应运动过程中的外部扰动至关重要。在这方面，与肌肉伸展的快速变化有关的反馈，由本体感觉Ia感觉传入传递到脊髓，尤其重要。虽然Ia传入与运动神经元(MN)建立了一些单突触联系，但本体感觉对MN活动的直接影响是例外的；一般来说，对MN的本体感觉反馈是通过脊髓神经元间回路间接的。这些电路将感觉反馈与中央产生的活动模式结合起来，以调节MN反应。尽管这些更复杂的电路在塑造电机输出方面很重要，但人们对这些电路是如何形成的知之甚少。控制本体感觉输入建立到神经元间回路的发育机制，甚至那些包含单一中间神经元类别的机制，实际上是未知的。一个简单的感觉-运动回路负责相互抑制(RI)，这是为了防止关节处拮抗性屈肌和伸肌的共同收缩。这种感觉-运动回路包含一类单一的中间神经元，即甘氨酸能Ia抑制中间神经元(IAIN)。这些中间神经元通过提供特定肌肉的Ia传入的单突触输入，接收有关肌肉伸展的感觉信息。RI的正常发展需要组装多个模块电路，以响应特定肌肉产生的Ia传入神经的激活，并抑制功能上合适的MN靶点。是什么发展机制指导了这一过程？在出生后早期的动物中，活动诱导的RI回路调节表明，活动依赖的机制可能参与了与IaIN的功能适当亚群建立Ia感觉传入联系的可能性。这项建议中提出的实验将通过调查在其发展的初始阶段与RI电路的传入连接的状态来直接检验这一假说。我们将利用遗传策略在小鼠体内测试本体感受性传入活动在传入分离到IaINs亚群的过程中的必要性和充分性。IaINs介导的相互抑制是正常运动发育的基础，RI降低与异常自主运动和运动有关。了解正常RI的发展过程和机制将为理解疾病和损伤状态下异常运动行为的表达提供重要的背景和视角。 公共卫生相关性：拮抗肌的相互抑制由脊髓神经元控制，并受感觉反馈的影响。它对正常的运动至关重要，但人们对它是如何发展的知之甚少。本项目研究正常的相互抑制发展的机制，以更好地了解其在脑瘫等儿童运动障碍中的作用。

DESCRIPTION (provided by applicant): Sensory feedback regarding limb position is critical for normal locomotion and adaptation to external perturbations during movement. Feedback relating to rapid changes in muscle stretch, conveyed to the spinal cord by proprioceptive Ia sensory afferents, is especially important in this regard. While Ia afferents make some monosynaptic connections with motor neurons (MNs), direct proprioceptive influence on MN activity is exceptional; in general, proprioceptive feedback to MNs is indirect via interneuronal circuits of the spinal cord. These circuits integrate sensory feedback with centrally generated patterns of activity to modulate MN responses. Despite the importance of these more complex circuits in shaping motor output, very little is known about how these circuits are formed. Developmental mechanisms that control the establishment of proprioceptive input to interneuronal circuits, even those containing a single interneuron class, are virtually unknown. One simple sensory-motor circuit is responsible for reciprocal inhibition (RI), which acts to prevent co- contraction of antagonist flexor and extensor muscles at a joint. This sensory-motor circuit contains a single class of interneuron, the glycinergic Ia inhibitory interneuron (IaIN). These interneurons receive sensory information about muscle stretch through monosynaptic inputs from Ia afferents supplying specific muscles. Normal development of RI requires assembly of multiple, modular circuits responding to activation of Ia afferents arising from specific muscles and inhibiting functionally appropriate MN targets. What developmental mechanisms guide this process? Activity-induced RI circuit modulation in early postnatal animals suggests the possibility that activity-dependent mechanisms may be involved in the establishment of Ia sensory afferent connections with functionally appropriate subsets of IaINs. Experiments presented in this proposal will directly test this hypothesis by investigating the status of afferent connectivity with RI circuits at the initial stages of its development. We will test the necessity and sufficiency of proprioceptive afferent activity in the process of afferent segregation onto subsets of IaINs using genetic strategies in mice. Development of reciprocal inhibition mediated by IaINs is fundamental to the development of normal locomotion, and reduced RI is associated with abnormal voluntary movement and locomotion. Understanding the progression and mechanisms of normal RI development will provide an important context and perspective for understanding the expression of abnormal motor behaviors in disease and injury states. PUBLIC HEALTH RELEVANCE: Reciprocal inhibition of antagonist muscles is controlled by spinal neurons and is influenced by sensory feedback. It is critical for normal movement, but very little is known about how it develops. This project investigates the mechanisms of normal reciprocal inhibition development to better understand its function in childhood movement disorders such as cerebral palsy.