Olfactory transduction is the process by which olfactory sensory neurons (OSNs) transform odor information into neuronal electrical signals. Over the past two and a half decades, extensive investigations have led to the elucidation of a core transduction pathway in vertebrate OSNs. However, the processes that regulate transduction to allow for proper sensitivity and response kinetics are not well understood. Calcium is a key olfactory transduction regulator. Calcium enters the sensory cilium through the olfactory cyclic nucleotide-gated (CNG) channel during the odor response, amplifies OSN depolarization, and also negatively regulating several olfactory transduction components. This negative regulation governs OSN adaptation--a phenomenon manifested as reduced sensitivity upon sustained or repeated stimulation. In this proposal, we propose to take advantage of multiple genetically modified mouse strains that we generated to: 1) investigate the integration of multiple Ca2+-dependent feedback mechanisms in OSN adaptation (Aim 1);and 2) investigate the role of negative regulatory mechanisms, which function in termination and adaptation, in setting OSN sensitivity at rest (Aim 2). Electrophysiological analysis, at the level of intact olfactory epithelium and the isolated single cell level, will be conducted on mice carrying double or triple mutations for calcium-dependent feedback mechanisms (Aim 1) as well as on mice that lack a calcium-dependent feedback mechanism and also lack efficient calcium extrusion (Aim 2). The long-term goal of this proposal is to elucidate the molecular mechanisms underlying olfaction. The proposed investigation will lead to a better understanding of how OSNs encode the intensity and temporal features of odor stimulations by regulating sensitivity and response kinetics. The knowledge gained from the proposed research will enhance our understanding of normal olfactory function and olfactory dysfunctions.
The sense of smell is important for locating food, mates, avoiding danger, and enhancing the quality of life. Despite the fact that many of the molecular components that allow us to smell are known, the mechanisms governing the sensitivity and response speed are not well understood. The proposed research will enhance our understanding of the basic responses of the olfactory system, which will give us insight into the genetic and physiological causes of smell disorders.
|Dong, Frederick N; Amiri-Yekta, Amir; Martinez, Guillaume et al. (2018) Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse. Am J Hum Genet 102:636-648|
|Chen, Chih-Ming; Orefice, Lauren L; Chiu, Shu-Ling et al. (2017) Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice. Proc Natl Acad Sci U S A 114:E619-E628|
|Chew, Kylie S; Renna, Jordan M; McNeill, David S et al. (2017) A subset of ipRGCs regulates both maturation of the circadian clock and segregation of retinogeniculate projections in mice. Elife 6:|
|Gigante, Crystal M; Dibattista, Michele; Dong, Frederick N et al. (2017) Lamin B1 is required for mature neuron-specific gene expression during olfactory sensory neuron differentiation. Nat Commun 8:15098|
|Chew, Kylie S; Fernandez, Diego C; Hattar, Samer et al. (2017) Anatomical and Behavioral Investigation of C1ql3 in the Mouse Suprachiasmatic Nucleus. J Biol Rhythms 32:222-236|
|Vinberg, Frans; Wang, Tian; De Maria, Alicia et al. (2017) The Na+/Ca2+, K+ exchanger NCKX4 is required for efficient cone-mediated vision. Elife 6:|
|Ferguson, Christopher H; Zhao, Haiqing (2017) Simultaneous Loss of NCKX4 and CNG Channel Desensitization Impairs Olfactory Sensitivity. J Neurosci 37:110-119|
|Talaga, Anna K; Dong, Frederick N; Reisert, Johannes et al. (2017) Cilia- and Flagella-Associated Protein 69 Regulates Olfactory Transduction Kinetics in Mice. J Neurosci 37:5699-5710|
|Ye, Hong; Wang, Xiaofang; Sussman, Caroline R et al. (2016) Modulation of Polycystic Kidney Disease Severity by Phosphodiesterase 1 and 3 Subfamilies. J Am Soc Nephrol 27:1312-20|
|Cai, Yujun; Nagel, David J; Zhou, Qian et al. (2015) Role of cAMP-phosphodiesterase 1C signaling in regulating growth factor receptor stability, vascular smooth muscle cell growth, migration, and neointimal hyperplasia. Circ Res 116:1120-32|
Showing the most recent 10 out of 21 publications