Federica Genovese

Neuropeptide receptors provide a signalling pathway for trigeminal modulation of olfactory transduction

The mammalian olfactory epithelium contains olfactory receptor neurons and trigeminal sensory endings. The former mediate odor detection, the latter the detection of irritants. The two apparently parallel chemosensory systems are in reality interdependent in various well‐documented ways. Psychophysical studies have shown that virtually all odorants can act as irritants, and that most irritants have an odor. Thus, the sensory perception of odorants and irritants is based on simultaneous input from the two systems. Moreover, functional interactions between the olfactory system and the trigeminal system exist on both peripheral and central levels. Here we examine the impact of trigeminal stimulation on the odor response of olfactory receptor neurons. Using an odorant with low trigeminal potency (phenylethyl alcohol) and a non‐odorous irritant (CO2), we have explored this interaction in psychophysical experiments with human subjects and in electroolfactogram (EOG) recordings from rats. We have demonstrated that simultaneous activation of the trigeminal system attenuates the perception of odor intensity and distorts the EOG response. On the molecular level, we have identified a route for this cross‐modal interaction. The neuropeptide calcitonin‐gene related peptide (CGRP), which is released from trigeminal sensory fibres upon irritant stimulation, inhibits the odor response of olfactory receptor neurons. CGRP receptors expressed by these neurons mediate this neuromodulatory effect. This study demonstrates a site of trigeminal–olfactory interaction in the periphery. It reveals a pathway for trigeminal impact on olfactory signal processing that influences odor perception.

Properties of an optogenetic model for olfactory stimulation.

In olfactory research it is difficult to deliver stimuli with defined intensity and duration to olfactory sensory neurons. Expression of channelrhodopsin 2 (ChR2) in olfactory sensory neurons provides a means to activate these neurons with light flashes. Appropriate mouse models are available. The present study explores the suitability of an established olfactory marker protein (OMP)/ChR2–yellow fluorescent protein (YFP) mouse model for ex vivo experimentation. Expression of ChR2 in sensory neurons of the main olfactory epithelium, the septal organ and vomeronasal organ is characterized. Expression pattern of ChR2 in olfactory receptor neurons and the properties of light responses indicate that light stimulation does not impact on signal transduction in the chemosensory cilia. Light‐induced electro‐olfactograms are characterized with light flashes of different intensities, durations and frequencies. The impact of light‐induced afferent stimulation on the olfactory bulb is examined with respect to response amplitude, polarity and low‐pass filtering.

Possible role of calcitonin gene‐related peptide in trigeminal modulation of glomerular microcircuits of the rodent olfactory bulb

Chemosensation in the mammalian nose comprises detection of odorants, irritants and pheromones. While the traditional view assigned one distinct sub‐system to each stimulus type, recent research has produced a more complex picture. Odorants are not only detected by olfactory sensory neurons but also by the trigeminal system. Irritants, in turn, may have a distinct odor, and some pheromones are detected by the olfactory epithelium. Moreover, it is well‐established that irritants change odor perception and vice versa. A wealth of psychophysical evidence on olfactory‐trigeminal interactions in humans contrasts with a paucity of structural insight. In particular, it is unclear whether the two systems communicate just by sharing stimuli, or whether neuronal connections mediate cross‐modal signaling. One connection could exist in the olfactory bulb which performs the primary processing of olfactory signals and receives trigeminal innervation. In the present study, neuroanatomical tracing of the mouse ethmoid nerve illustrates how peptidergic fibers enter the glomerular layer of the olfactory bulb, where local microcircuits process and filter the afferent signal. Biochemical assays reveal release of calcitonin gene‐related peptide from olfactory bulb slices and attenuation of cAMP signaling by the neuropeptide. In the non‐stimulated tissue, the neuropeptide specifically inhibited the basal activity of calbindin‐expressing periglomerular interneurons, but did not affect the basal activity of neurons expressing calretinin, parvalbumin, or tyrosine hydroxylase, nor the activity of astrocytes. This study represents a first step toward understanding trigeminal neuromodulation of olfactory‐bulb microcircuits and provides a working hypothesis for trigeminal inhibition of olfactory signal processing.

Cardiac magnetic resonance using late gadolinium enhancement and atrial T1 mapping predicts poor outcome in patients with atrial fibrillation after catheter ablation therapy

To determine the pre-procedural value of different fibrotic biomarkers and comprehensive cardiac magnetic resonance (CMR) for the prediction of poor response to ablation therapy in patients with atrial fibrillation (AF). Left atrial (LA) late gadolinium enhancement (LGE) and native LA T1 relaxation times were assessed using CMR. Plasma levels of relaxin, myeloperoxidase and serum levels of matrix metalloproteinase (MMP)-mediated cardiac specific titin fragmentation and MMP-mediated type IV collagen degradation were obtained. Poor outcome was defined by the recurrence of AF during 1-year follow-up. 61 patients were included in final analysis. Twenty (32.8%) patients had recurrence of AF. Patients with a recurrence of AF had a higher percentage of LA LGE (26.7 ± 12.5% vs. 17.0 ± 7.7%; P < 0.001), higher LA T1 relaxation times (856.7 ± 112.2 ms vs. 746.8 ± 91.0 ms; P < 0.001) and higher plasma levels of relaxin (0.69 ± 1.34 pg/ml vs. 0.37 ± 0.88 pg/ml; P = 0.035). In the multivariate Cox regression analysis, poor ablation outcome was best predicted by advanced LGE stage (hazard ratio (HR):5.487; P = 0.001) and T1 relaxation times (HR:1.007; P = 0.001). Pre-procedural CMR is a valuable tool for prediction of poor response to catheter ablation therapy in patients with AF. It offers various imaging techniques for outcome prediction and might be valuable for a better patient selection prior to ablation therapy.