Odorant-Dependent Generation of Nitric Oxide in Mammalian Olfactory Sensory Neurons

The gaseous signalling molecule nitric oxide (NO) is involved in various physiological processes including regulation of blood pressure, immunocytotoxicity and neurotransmission. In the mammalian olfactory bulb (OB), NO plays a role in the formation of olfactory memory evoked by pheromones as well as conventional odorants. While NO generated by the neuronal isoform of NO synthase (nNOS) regulates neurogenesis in the olfactory epithelium, NO has not been implicated in olfactory signal transduction. We now show the expression and function of the endothelial isoform of NO synthase (eNOS) in mature olfactory sensory neurons (OSNs) of adult mice. Using NO-sensitive micro electrodes, we show that stimulation liberates NO from isolated wild-type OSNs, but not from OSNs of eNOS deficient mice. Integrated electrophysiological recordings (electro-olfactograms or EOGs) from the olfactory epithelium of these mice show that NO plays a significant role in modulating adaptation. Evidence for the presence of eNOS in mature mammalian OSNs and its involvement in odorant adaptation implicates NO as an important new element involved in olfactory signal transduction. As a diffusible messenger, NO could also have additional functions related to cross adaptation, regeneration, and maintenance of MOE homeostasis

Molecular mechanisms of signal transduction in chemosensory neurons of mice

Die Rolle von NO im intakten olfaktorischen System von adulten Nagetieren wird noch immer kontrovers diskutiert. In der vorliegenden Studie waren wir in der Lage mRNA und Proteinexpression der endothelialen Isoform von Stickstoffmonoxid-Synthase (eNOS) in olfaktorische Rezeptorneuronen (OSNs) von adulten Mäusen zu zeigen. Des Weiteren konnten wir zeigen, dass isolierte Rezeptorneurone in der Lage sind NO stimulusabhängig freizusetzen. Wir untersuchten auch potentielle Funktionen von NO im Riechepithel von Wild Typ- und eNOS-defizienten Mäusen, konnten jedoch keine Effekte auf die Proliferation von Basalzellen des olfaktorischen Epithels feststellen. Stattdessen zeigten eNOS-defiziente Mäuse eine signifikant veränderte Adaptationskinetik duftinduzierter Signale. Zusammengefasst deuten unsere Ergebnisse darauf hin, dass eNOS für aktivitätsabhängige NO-Ausschüttung in den OSN verantwortlich ist und an der Modulation von Adaptationsprozessen beteiligt ist.The gaseous signalling molecule nitric oxide (NO) is involved in many different biological processes. However, the role of NO in the intact OE of adult rodents is still controversially discussed. In the present study we were able to demonstrate for the first time mRNA and protein expression of endothelial isoform of NO synthase (eNOS) in olfactory sensory neurons (OSNs) of adult mice. Furthermore we found that NO is released by individual OSNs in a stimulus dependent manner. Studying potential functions of eNOS in the OE of wild type and eNOS-deficient mice we found no effect on basal cell proliferation. In contrast to that EOG recordings from wild type compared to eNOS-deficient mice showed significantly altered desensitization kinetics of odorant-induced signals. In summary our results strongly suggest that eNOS is the enzyme responsible for activitydependent NO production in the OSN, pointing to a possible function for eNOS derived NO in adaptation

Cortical multisensory integration—a special role of the agranular insular cortex?

Sirtuin1 deficiency or reduced activity comprises one of the hallmarks of diseases as diverse as chronic cardiovascular, renal, and metabolic, some malignancies, and infections, as well as aging-associated diseases. In a mouse model of endothelium-limited defect in sirtuin 1 deacetylase activity, we found a dramatic reduction in the volume of endothelial glycocalyx. This was associated with the surge in the levels of one of key scaffolding heparan sulfate proteoglycans of endothelial glycocalyx, syndecan-4, and specifically, its extracellular domain (ectodomain). We found that the defect in endothelial sirtuin 1 deacetylase activity is associated with (a) elevated basal and stimulated levels of superoxide generation (via the FoxO1 over-acetylation mechanism) and (b) increased nuclear translocation of NF-kB (via p65 over-acetylation mechanism). These findings laid the foundation for the proposed novel function of sirtuin 1, namely, the maintenance of endothelial glycocalyx, particularly manifest in conditions associated with sirtuin 1 depletion. In the forthcoming review, we summarize the emerging conceptual framework of the enhanced glycocalyx degradation in the states of defective endothelial sirtuin 1 function, thus explaining a broad footprint of the syndrome of endothelial dysfunction, from impaired flow-induced nitric oxide production, deterrent leukocytes infiltration, increased endothelial permeability, coagulation, and pro-inflammatory changes to development of microvascular rarefaction and progression of an underlying disease

Extrinsic neuromodulation in the rodent olfactory bulb

Evolutionarily, olfaction is one of the oldest senses and pivotal for an individual's health and survival. The olfactory bulb (OB), as the first olfactory relay station in the brain, is known to heavily process sensory information. To adapt to an animal's needs, OB activity can be influenced by many factors either from within (intrinsic neuromodulation) or outside (extrinsic neuromodulation) the OB which include neurotransmitters, neuromodulators, hormones, and neuropeptides. Extrinsic sources seem to be of special importance as the OB receives massive efferent input from numerous brain centers even outweighing the sensory input from the nose. Here, we review neuromodulatory processes in the rodent OB from such extrinsic sources. We will discuss extrinsic neuromodulation according to points of origin, receptors involved, affected circuits, and changes in behavior. In the end, we give a brief outlook on potential future directions in research on neuromodulation in the OB