Neurotrophin Regulation of Taste System Development

描述(申请人提供)：在发育过程中，味觉神经支配是一个严格调控的过程，在这个过程中，特定数量的初级味觉传入投射到口腔的离散区域。脑源性神经营养因子(BDNF)在胚胎发育过程中调节味觉神经支配的数量和位置。我们目前的研究旨在确定这些联系是否和/或如何对中枢味觉发育或味觉功能重要，以及BDNF是否调节出生后味觉系统的发育。这些研究结合了条件和诱导转基因小鼠的细胞计数、轨迹追踪、免疫组织化学、电生理学和行为测试：1)确定BDNF是否影响出生后膝状神经节和味蕾发育的变化；2)确定胚胎或出生后的BDNF对中枢终末区域组织是否重要；以及3)确定胚胎或出生后的BDNF对成人味觉功能是否重要。总而言之，这些研究验证了这样的假设：1)胚胎BDNF决定了支配味蕾的神经元的数量，味蕾在出生后会增大到符合这个数量的大小。2)中枢神经系统终末野的形成受脑源性神经营养因子和外周连接的特异性调节。3)味觉敏感度降低了，但味觉系统尽管进行了大范围的重组，仍能发挥作用。这些研究将确定早期的外周神经模式如何影响味觉系统的持续发展和功能。此外，我们将确定BDNF是否是出生后味觉发育所必需的。由于这些实验研究了神经营养因子对感觉神经支配的调节如何影响持续发育和成人功能，该项目对于这些强大的信号分子在神经元损伤后重建味觉功能的潜在治疗应用具有重要意义。 公共卫生相关性：味觉障碍可能会对一个人的健康和生活质量产生有害影响。根据NIDCD的数据，每年有超过20万人因包括味觉在内的化学感官问题而去看医生。许多味觉中断的潜在机制还没有被很好地理解。因此，人们非常重视对味蕾的基本了解。然而，支配味蕾的神经元很少受到关注，也是正常味觉功能所必需的。一些成人的味觉紊乱可能是由于调节味觉系统神经支配的因子(S)的改变所致，这既是发育过程中味觉系统神经支配的一部分，也是正常成人体内平衡的一部分。周围神经疾病相对常见，并经常伴有其他疾病。对在发育过程中促进神经支配并可能在成年后保持神经支配所需的因素的基本了解，可能会导致治疗方法，使其在失去味道后恢复。

DESCRIPTION (provided by applicant): During development, gustatory innervation is a tightly regulated process in which specific numbers of primary taste afferents project to discrete regions of the oral cavity. Brain-derived neurotrophic factor (BDNF) regulates both the number and location of gustatory innervation during embryonic development. Our current research is designed to determine if and/or how these connections are important for central gustatory development or taste function and whether BDNF regulates development of the postnatal taste system. The proposed studies combine cell counting, tract tracing, immunohistochemistry, electrophysiology, and behavioral testing in conditional and inducible transgenic mice to: 1) determine if BDNF influences postnatal changes in geniculate ganglion and taste bud development, 2) determine if embryonic or postnatal BDNF is important for central terminal field organization, and 3) determine if embryonic or postnatal BDNF is important for adult gustatory function. Together, these studies test the hypotheses that: 1) embryonic BDNF determines the number of neurons innervating a taste bud, and taste buds increase in size to meet that number postnatally. 2) CNS terminal field formation is regulated by BDNF and the specificity of peripheral connections. 3) Gustatory sensitivity is reduced but that the taste system still functions despite wide-scale reorganization. These studies will determine how early peripheral innervation patterns influence continued development and function of the taste system. In addition, we will determine whether BDNF is required for postnatal gustatory development. Because these experiments examine how neurotrophin regulation of sensory innervation influences continued development and adult function, this project has important implications for the potential therapeutic use of these powerful signaling molecules in re-establishing gustatory function following neuronal impairment. PUBLIC HEALTH RELEVANCE: Taste disorders can have detrimental effects on a person's health and quality of life. According to NIDCD, more than 200,000 people visit a doctor each year for problems with their chemical senses, including taste. The underlying mechanism of many gustatory disruptions is not well understood. As a result, much emphasis has been placed on a basic understanding of the taste bud. However, the neurons innervating taste buds receive little attention and are also required for normal gustatory function. Some adult gustatory disruptions may result from an alteration in factor(s) regulating gustatory system innervation both during development and as a part of normal adult homeostasis. Peripheral neuropathies are relatively common and frequently accompany other illnesses. A basic understanding of the factors that are required to promote innervation during development and possibly maintain it in adulthood may lead to therapeutic approaches that allow taste recovery following its loss.