Mechanisms of Synaptic Specificity in Visual Circuits

 描述(由申请人提供)：整合感觉信息对于检测显著刺激和适当反应的方向至关重要，这是一种必要的生存行为。感觉加工和整合的特定方面的中断是几种神经发育障碍的显著特征，强调了精确感觉回路形成的重要性。尽管如此，在整合中心建立这种突触特异性的机制仍然知之甚少，阻碍了有效治疗的发展。为了填补这一知识空白，我们将研究在上丘(SC)建立感觉回路的机制，上丘是整合多种感觉信息的关键中心。具体地说，我们将专注于SC中精确视觉连接的发育机制，它整合了正常发育期间初级视觉皮质(V1)的视网膜神经节细胞(RGC)和第五层(L5)神经元的输入，以及这些过程在神经发育障碍中是如何被破坏的。首先，我们将结合体内电生理学、尖端神经元追踪和分子分析，在一个独特的敲入小鼠模型中确定不同亚型的L5V1神经元整合到适当的子电路中的机制。其次，我们将在条件性基因敲除小鼠模型中结合体内电生理学和轴突追踪范式来剖析视觉空间地图对齐的机制。最后，我们将使用体内电生理学、轴突追踪和分子分析相结合的方法，在FXS小鼠模型中确定特定的神经感觉处理缺陷，以及哪些过程被破坏导致这些缺陷。综上所述，拟议的实验将阐明在发育和神经发育障碍的视觉中心建立精确连接和功能的新机制。我们的结果将为设计有效的治疗策略来治疗这些疾病提供必要的关键见解。

 DESCRIPTION (provided by applicant): Integrating sensory information is critical for detection of salient stimuli and direction of appropriate responses, a necessary survival behavior. Disruptions in specific aspects of sensory processing and integration are hallmark features of several neurodevelopmental disorders, underscoring the importance of precise sensory circuit formation. Despite this, the mechanisms by which such synaptic specificity is established in integrative centers remains poorly understood, precluding the development of effective therapies. To fill this gap in knowledge, we will investigate the mechanisms by which sensory circuits are established in the superior colliculus (SC), a critical center where multiple modalitis of sensory information are integrated. Specifically, we will focus on the developmental mechanisms of precise visual connections in the SC, which integrates input from retinal ganglion cells (RGCs) and Layer 5 (L5) neurons of the primary visual cortex (V1) during normal development and how these process are disrupted in neurodevelopmental disorders. First, we will use a combination of in vivo electrophysiology, cutting-edge neuronal tracing, and molecular analysis in a unique knock-in mouse model to determine the mechanisms by which distinct subtypes of L5 V1 neurons integrate into the appropriate subcircuit. Second, we will use a combination of in vivo electrophysiology and axon tracing paradigms in conditional knockout mouse models to dissect the mechanisms by which alignment of visual spatial maps is achieved. Finally, we will use a combination of in vivo electrophysiology, axon tracing and molecular analysis in a mouse model of FXS to determine the specific neural sensory processing deficits and which processes are disrupted to give rise to these deficits. Taken together, the proposed experiments will elucidate novel mechanisms by which precise connectivity and function are established in visual centers in development and neurodevelopmental disorders. Our results will provide critical insights necessary for the design of effective therapeutic strategies to treat these disorders.