Multiple Mechanisms of Nasal Chemoreception

描述(申请人提供)：哺乳动物的鼻腔内有不同的化学感觉上皮，包括主嗅觉上皮、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)。这些感受性上皮中的每一个都与不同化合物的检测有关，并引起不同的行为。传统上，犁鼻上皮被认为是检测信息素--同种异体释放的化学物质，在接受者身上引发生理或行为反应--而主要的嗅觉上皮被认为介导了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到潜在的有毒物质，这些物质可能会引起不良反应，如呼吸频率下降、打喷嚏或咳嗽。然而，最近的实验--包括我们在当前支持期发表的那些实验--表明，关于这些化学感觉系统作用的传统观点需要修正，因为主要的嗅觉上皮似乎也参与检测信息素和其他信号化学物质--参与动物交流的气味(Baxi等人，2006；Buck，2005；Lin等人，2007；Lin等人，2004)。本提案将研究主嗅觉系统化学接收的这一新的方面。我们将把重点放在我们的发现上，即磷脂酶C(PLC)途径中的一个效应器--瞬时受体通道M5(Trpm5)在主要嗅觉上皮中的一组嗅觉感觉神经元中表达，其轴突投射到信号化学反应性肾小球(Lin等人，2007)。我们提出了三个具体的目标：目的1.通过开放Trpm5通道来检测PLC通路是否参与了嗅觉传导，以响应气味引起的钙离子浓度的增加。目的2.验证出生后感觉输入到鼻部影响OSNs Trpm5表达的假设目的3.测试Trpm5 OSNs是否将有关信号化学物质的信息传递到MOB的限制性区域，该区域又投射到与生殖和防御行为相关的杏仁内侧区域。在人类中，嗅觉障碍在阿尔茨海默氏症(Doty，1991；Rawson，2000)、双相抑郁(Hahn等人，2005)和精神分裂症(Turetsky等人，2003)等疾病中遇到。这笔拨款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气味中心(RMTSC)的背景下进行的，RMTSC是一个致力于嗅觉和味觉的基础和临床相关研究的实体。Restrepo博士和Finger博士是RMTSC的联席董事。该中心内与临床相关的工作包括精神分裂症、唐氏综合症和脑部炎症。临床研究极大地受益于扎实的基础科学研究，正因为如此，我们预计我们目前的建议将加强RMTSC开展的临床相关工作。参考文献列表Doty，R.L.(1991)。神经退行性疾病中的嗅觉障碍。《健康和疾病中的嗅觉和味觉》，T.V.Getchell，R.L.Doty，L.M.Bartoshk和J.B.Snow，Jr.主编。(纽约：乌鸦出版社)，第735-752页。Hahn，C.G.，Gomez，G.，Restrepo，D.，Friedman，E.，Josiassen，R.，Pribitkin，E.A.，Lowry，L.D.，Gallop，R.J.，和Rawson，N.E.(2005年)。双相情感障碍患者嗅觉神经元细胞内钙信号的异常。上午好。J.精神病学162,616-618。罗森，N.E.(2000)。人类的嗅觉。在味觉和嗅觉的神经生物学中，T.E.Finger、W.L.Silver和D.Restrepo主编。(纽约：Wiley-Liss)，第257-284页。Turetsky，B.I.，Moberg，P.J.，Owzar，K.，Johnson，S.C.，Doty，R.L.和Gur，R.E.(2003)。精神分裂症患者嗅觉刺激加工的生理性损害。比奥尔。精神科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.