Mechanisms of Reciprocal Inhibition Development

描述（由申请人提供）：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，与肌肉拉伸的快速变化有关的反馈，通过本体感觉传入传递到脊髓，是特别重要的。虽然Ia传入与运动神经元（MNs）有一些单突触连接，但本体感觉对MN活动的直接影响是例外的；一般来说，本体感觉反馈到MNs是间接通过脊髓的神经元间回路。这些电路将感觉反馈与中枢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的重要性，很少知道这些电路是如何形成的。控制本体感觉输入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），其作用是防止在关节的拮抗屈肌和伸肌的共同收缩。这种感觉-运动回路包含一类中间神经元，甘氨酸能抑制中间神经元（IaIN）。这些中间神经元通过提供特定肌肉的传入神经的单突触输入接收有关肌肉伸展的感觉信息。RI的正常发育需要多个模块化电路的组装，以响应来自特定肌肉的Ia传入的激活，并抑制功能上适当的MN靶点。是什么发展机制引导了这个过程？在早期出生后动物中，活动诱导的RI回路调节表明，活动依赖机制可能参与了与功能适当的IaINs亚群建立感觉传入连接的可能性。本提案中提出的实验将通过在其发展的初始阶段调查传入连接与RI电路的状态来直接验证这一假设。我们将在小鼠中使用遗传策略测试在传入神经分离到IaINs亚群的过程中本体感觉传入神经活动的必要性和充分性。由IaINs介导的相互抑制的发展是正常运动发展的基础，而RI减少与异常的自主运动和运动有关。了解正常RI发育的进展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。

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.