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运动期间的正常运动和适应外部扰动至关重要。在这方面，与通过本体感受Ia感觉传入传递到脊髓的肌肉拉伸的快速变化相关的反馈尤其重要。虽然Ia传入与运动神经元（MN）进行一些单突触连接，但对MN活动的直接本体感受影响是例外的;一般而言，对MN的本体感受反馈是通过脊髓的神经元间回路间接的。这些回路将感觉反馈与中枢产生的活动模式相结合，以调节MN反应。尽管这些更复杂的电路在形成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。控制本体感受输入到中间神经元回路的建立的发育机制，即使是包含单个中间神经元类别的那些，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），其用于防止关节处的拮抗屈肌和伸肌的共同收缩。这种感觉-运动回路包含单一类别的中间神经元，即甘氨酸能Ia抑制性中间神经元（IaIN）。这些中间神经元通过供应特定肌肉的Ia传入神经的单突触输入接收关于肌肉拉伸的感觉信息。 RI的正常发展需要组装多个模块化回路，这些回路响应于来自特定肌肉的Ia传入的激活并抑制功能上适当的MN靶点。什么样的发展机制指导这一进程？活动诱导的RI电路调制在出生后早期的动物表明，活动依赖性机制可能参与建立Ia感觉传入连接与功能适当的IaINs的子集。在这个建议中提出的实验将直接测试这一假设，通过调查的状态传入连接RI电路在其发展的初始阶段。我们将测试的必要性和充分性的本体感受传入活动的过程中的传入隔离到亚群的IaIN使用遗传策略在小鼠中。 由IaINs介导的相互抑制的发展是正常运动发展的基础，RI降低与异常自主运动和运动相关。了解正常RI发展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.