Multiple Mechanisms of Nasal Chemoreception

描述（由申请人提供）：哺乳动物的鼻腔容纳不同的化学感觉上皮，包括主要的嗅觉上皮、犁鼻上皮和三叉神经支配的呼吸上皮（所谓的“非感觉”上皮）（Finger等人，2000年）。这些接受性上皮细胞中的每一个都涉及不同化合物的检测，并引起不同的行为。传统上，犁鼻上皮被认为是检测信息素-由同种释放的化学物质，引起受体的生理或行为反应-而主要的嗅觉上皮被认为是介导对一般气味的有意识感知。此外，三叉神经系统被认为可以检测潜在的有害物质，这些物质可以引起厌恶反应，例如呼吸频率降低，打喷嚏或咳嗽。然而，最近的实验-包括我们在当前的支持期内发表的那些-表明，关于这些化学感觉系统的作用的传统观点需要修改，因为主要的嗅觉上皮似乎也参与检测信息素和其他化学信息素-参与动物交流的气味（Baxi等人，2006; Buck，2005; Lin等人，2007; Lin等人，2004年）。这一新的方面的化学感受的主要嗅觉系统将在此建议进行研究。我们将把我们的建议集中在我们的发现上，即瞬时受体通道M5（TRPM 5），磷脂酶C（PLC）途径中的效应物，在主要嗅觉上皮中的嗅觉感觉神经元的子集中表达，其轴突投射到化学信息素反应性肾小球（Lin et al.，2007年）。我们提出三个具体目标：目标1。测试PLC通路是否通过打开TRPM 5通道参与嗅觉转导，以响应气味引起的钙增加。目标2.检验出生后对鼻子的感觉输入影响OSN中TRPM 5表达的假设。测试TRPM 5 OSN是否将有关化学信息素的信息传递到MOB的限制区域，这些区域反过来投射到内侧杏仁核-一个与生殖和防御行为相关的区域。 在人类中，嗅觉障碍在诸如阿尔茨海默氏症（Doty，1991;罗森，2000）、双相抑郁症（Hahn等人，2005）和精神分裂症（Turetsky等人，2003年）。该基金将研究嗅觉感觉神经元中嗅觉传导的基本机制以及嗅觉系统的中枢投射。这项基础科学研究是在落基山味觉和味觉中心（RMTSC）的背景下进行的，该中心致力于嗅觉和味觉的基础和临床相关研究。雷斯特雷波博士和芬格博士是RMTSC的共同主任。该中心的临床相关工作包括精神分裂症、唐斯综合征和脑部炎症。临床研究从坚实的基础科学研究中受益匪浅，因此，我们希望我们目前的提案能够加强RMTSC开展的临床相关工作。参考文献列表Doty，R.L.（1991年）。神经退行性疾病中的嗅觉功能障碍。在健康和疾病中的味觉和味觉，T. V. Gettero，R.L.多蒂，L.M. Bartoshuk和J.B.小斯诺，eds. (New约克：Raven Press），pp. 735-752. Hahn，C.G.，Gomez，G.，Restrepo，D.，Friedman，E.，Josiassen河，Pribitkin，E.A.，洛瑞有限责任公司盖洛普，R. J.，和罗森，N.E.（2005）。双相情感障碍患者嗅神经元胞内钙信号异常。Am. J. Psychiatry 162，616-618.罗森，N.E.（2000年）。人类的嗅觉在味觉和嗅觉的神经生物学中，T.E.芬格，W.L.银和D. Restrepo，eds. (New约克：Wiley-Liss），pp. 257-284. Turetsky，B.I.，Moberg，P.J.，Owzar，K.，约翰逊，南卡罗来纳州，多蒂，R.L.，和Gur，R.E.（2003年）的报告。精神分裂症患者嗅觉刺激加工的生理损害。Biol. Psychiatry 53，403-411.

Description (provided by applicant): The nasal cavity in mammals houses distinct chemosensory epithelia including the main olfactory epithelium, the vomeronasal epithelium and the trigeminally innervated respiratory epithelium (so-called "non- sensory" epithelium) (Finger et al., 2000). Each of these receptive epithelia is implicated in detection of diverse compounds and evokes different behaviors. Traditionally, the vomeronasal epithelium was thought to detect pheromones - chemicals released by a conspecific that elicit a physiological or behavioral response in the recipient - while the main olfactory epithelium was thought to mediate conscious perception of general odorants. In addition, the trigeminal system is thought to detect potentially noxious substances, which can elicit aversive responses such as a decrease in respiratory rate, sneezing or coughing. However, recent experiments - including those published by us in the current period of support - indicate that the traditional view on the role of these chemosensory systems needs to be revised because the main olfactory epithelium also appears to be involved in detecting pheromones and other semiochemicals - odors involved in animal communication (Baxi et al., 2006; Buck, 2005; Lin et al., 2007; Lin et al., 2004). This novel aspect of chemoreception by the main olfactory system will be studied in this proposal. We will focus our proposal on our finding that the transient receptor channel M5 (TRPM5), an effector in the phospholipase C (PLC) pathway, is expressed in a subset of olfactory sensory neurons in the main olfactory epithelium whose axons project to semiochemical-responsive glomeruli (Lin et al., 2007). We propose three specific aims: Aim 1. Test whether the PLC pathway participates in olfactory transduction by opening the TRPM5 channel in response to the increase in calcium elicited by odors. Aim 2. Test the hypothesis that sensory input to the nose during the postnatal period affects TRPM5 expression in OSNs Aim 3. Test whether TRPM5 OSNs transmit information about semiochemicals to restricted areas of the MOB which project in turn to the medial amygdala - an area associated with reproductive and defensive behaviors. In humans, disorders of the sense of smell are encountered in diseases such as Alzheimer's (Doty, 1991;Rawson, 2000), bipolar depression (Hahn et al., 2005) and schizophrenia (Turetsky et al., 2003). This grant will study the basic mechanisms of olfactory transduction in olfactory sensory neurons as well as central projections of the olfactory system. This basic science study is performed within the context of the Rocky Mountain Taste and Smell Center (RMTSC), an entity dedicated to basic and clinically-relevant research on olfaction and taste. Drs. Restrepo and Finger are Co-Directors of the RMTSC. Clinically relevant work within the center includes work on schizophrenia, Downs syndrome and brain inflammation. The clinical studies benefit greatly from solid basic science research, and because of this we expect our current proposal to strengthen the clinically relevant work carried out by the RMTSC. Reference List Doty,R.L. (1991). Olfactory dysfunction in neurodegenerative diseases. In Smell and taste in health and disease, T.V. Getchell, R.L. Doty, L.M. Bartoshuk, and J.B. Snow, Jr., eds. (New York: Raven Press), pp. 735-752. Hahn,C.G., Gomez,G., Restrepo,D., Friedman,E., Josiassen,R., Pribitkin,E.A., Lowry,L.D., Gallop,R.J., and Rawson,N.E. (2005). Aberrant intracellular calcium signaling in olfactory neurons from patients with bipolar disorder. Am. J. Psychiatry 162, 616-618. Rawson,N.E. (2000). Human olfaction. In The neurobiology of taste and smell, T.E. Finger, W.L. Silver, and D. Restrepo, eds. (New York: Wiley-Liss), pp. 257-284. Turetsky,B.I., Moberg,P.J., Owzar,K., Johnson,S.C., Doty,R.L., and Gur,R.E. (2003). Physiologic impairment of olfactory stimulus processing in schizophrenia. Biol. Psychiatry 53, 403-411.