Mechanisms of mechanosensory transduction in Merkel cells

 描述(申请人提供)：触觉对我们的生存至关重要，因为它对于像拿起叉子这样简单的目的和像与新生儿建立联系这样复杂的目的都是必不可少的。尽管它对完成基本任务很重要，但将皮肤上的力转化为神经信号的分子和细胞机制却知之甚少。这项研究的长期目标是阐明皮肤中的感受器如何将触摸刺激转化为神经信号，向我们的大脑告知有关物理世界的信息。我们使用保守的辨别性触摸感受器Merkel细胞-轴突复合体作为模型来研究这些过程。默克尔细胞是上皮源性的靶细胞，接触向中枢神经系统发送信息的感觉神经元的末端。刺激这些Merkel细胞-轴突复合体会产生缓慢适应的I型反应，这对检测边缘和曲率等对象特征很重要。我们之前的研究表明，默克尔细胞直接感受机械力，并将这一信息传达给潜在的感觉神经元。支配这一过程的分子是完全未知的。在默克尔细胞中已经发现了许多参与突触传递和神经递质的分子，但试图确定体内的信号机制却产生了相互矛盾的结果。因此，这项研究的目的是确定默克尔细胞向神经系统传递触觉信息的机制。我们将通过使用转基因小鼠、光遗传学、体外和体外生理学以及行为研究的创新组合来实现这一目标。我们的中心假设是，默克尔细胞在帐篷敏感的圈套依赖的化学突触上释放神经递质，以刺激触觉传入的放电。在目标1中，我们将确定Merkel细胞是否使用帐篷敏感的圈套介导的囊泡释放。目标2将确定兴奋Merkel细胞传入神经元的神经递质或神经调节通路。这些研究将产生对外周触觉的基本见解 机制，这对于提高对支配躯体感觉编码的原则的基本知识至关重要。

 DESCRIPTION (provided by applicant): The sense of touch is vital for our survival, as it is essential for purposes as simple as picking up a fork and as complex as bonding with a newborn. Despite its importance for accomplishing basic tasks, the molecular and cellular mechanisms that convert a force on the skin into a neural signal are poorly understood. The long term goal of this research is to elucidate how receptors in the skin convert a touch stimulus into a neural signal to inform our brains about the physical world. We use Merkel cell-neurite complexes, which are conserved discriminative touch receptors, as a model to study these processes. Merkel cells are epithelial derived target cells that contact the endings of sensory neurons that send information to the central nervous system. Stimulating these Merkel cell-neurite complexes generates slowly adapting type I responses, which are important for detecting object features such as edges and curvature. Our previous studies revealed that Merkel cells directly sense mechanical force and convey this information to the underlying sensory neurons. The molecules that govern this process are completely unknown. Numerous molecules involved in synaptic transmission and neurotransmitters have been identified in Merkel cells, yet attempts to identify signaling mechanisms in vivo have yielded contradictory results. Thus, the objective of this research is to identify mechanisms by which Merkel cells convey tactile information to the nervous system. We will accomplish this goal by using an innovative combination of transgenic mice, optogenetics, in vitro and ex vivo physiology, and behavioral studies. Our central hypothesis is that Merkel cells release neurotransmitters at TeNT-sensitive SNARE-dependent chemical synapses to excite firing in tactile afferents. In Aim 1, we will determine whether Merkel cells employ TeNT-sensitive SNARE-mediated vesicular release. Aim 2 will identify the neurotransmitter or neuromodulatory pathways that excite Merkel-cell afferent neurons. These studies will yield fundamental insights into peripheral tactile mechanisms, which is essential to advance basic knowledge of principles that govern encoding of somatic senses.