Sensory Biology: Novel Peripheral Organization for Better Smell

Summary

Sensory systems have adopted various ways to enhance detection and discrimination. A recent study shows a novel spatial organization of sensory cells in the peripheral olfactory system in mice for better odor detection.

Our senses give rise to our perceptions of the outside world. Each sensory system, which starts with peripheral sensory receptor cells, is evolved for the detection and discrimination of a range of stimuli that is biologically relevant to fitness and survival. Sensory receptor cells transduce information about stimuli into electrical signals that are processed by the brain. Both the cellular properties of these peripheral sensors and their spatial organization in the corresponding sensory organ contribute to sensitivity, dynamic range, and acuity of the system. Olfactory sensory neurons are the sensors of the olfactory system. A new study by Challis et al. [1] now shows a novel spatial organization of olfactory sensory neurons in the peripheral olfactory system in mice where coordination of odorant deposition with sensory neuron morphology and responsiveness should lead to better odor detection.

In mammals olfactory sensory neurons are located in the olfactory epithelium that lines a portion of the nasal cavity. The nasal cavity has complex structures such as boney outgrowths that act to increase surface area and divert airflow for increased detection. The olfactory system is unique among sensory systems in the diversity and sheer number of stimuli it detects. To attain this feat, there are over one thousand unique types of olfactory sensory neurons, each determined by the odorant receptor it expresses [2, 3]. It is now well known that olfactory neurons expressing the same odorant receptor are distributed stochastically throughout a large regional zone of the olfactory epithelium. There are four such broad zones in rodents [4, 5] and two in a primates [6]. Given the stochastic distribution of each type of olfactory neuron, it is generally thought that the epithelium is functionally organized in a homogenous way such that any small portion of a given regional zone displays the full odorant receptor repertoire, thus the capacity to detect the entire odorant spectrum. As the olfactory epithelium is exposed to chemical and infectious assault through direct connection with the outside world, a homogeneous detection strategy would be beneficial in that it would serve to maintain sensory function after loss or damage to even large portions of the peripheral epithelium. However, air and odor flow through the nasal cavity is not uniform. Molecules of an odor can be differentially deposited in the epithelium due to the geometry of the nasal cavity, airflow rate (breath or sniff), and the chemical properties of odor molecules (hydrophobic or hydrophilic) [7, 8]. Thus, the populations of olfactory neurons in the nose are often differentially stimulated. To achieve homogeneous detection, one would expect that the olfactory system would develop more sensitive sensors in weakly stimulated areas to compensate for the weak stimulation. In contrast, Challis et al. report an opposition to the homogenous detection model in one region of the olfactory epithelium in the mouse, where more sensitive sensors are localized to strongly stimulated areas and less sensitive sensors are localized to weakly stimulated areas [1] (Figure 1).

Figure 1.

Figure 1A. Summary of the findings by Challis et al. [1]

Olfactory sensory neurons in the dorsal olfactory epithelium of the mouse display significant regional differences in ciliary length and number. Anterior neurons have longer cilia while those in the posterior have shorter cilia. Ciliary length correlates positively with the predicted odor stimulation level of the epithelial location and with the sensitivity of the sensory neuron. Response traces shown in the bottom are for eugenol stimulation of mOR-EG cells from Challis et al. [1].

Figure 1B. Sensitivity and dynamic range of detection

The spatial organization of olfactory sensory neurons with different sensitivities may enhance sensitivity and dynamic range of the olfactory system. In the dorsal olfactory epithelium (Top), cells with longer cilia are sensitive to low odorant levels but saturate early, while cells with shorter cilia respond only to higher odorant concentrations and saturate later. By having the most sensitive cells in most stimulated areas in the anterior of the dorsal epithelium, the system can achieve the best detection sensitivity. In parallel, broad dynamic range can be achieved by having less sensitive cells in weakly stimulated posterior areas. In other regions of the epithelium (Bottom), cells expressing the same receptor have similar ciliary lengths, thus similar sensitivity and dynamic range. Consequently, the dynamic range of the ensemble matches that of the individual cell.

Olfactory neurons detect odorants through odorant receptors expressed on multiple cilia that project into the mucus of the nasal cavity. These cilia are the site of olfactory transduction, where the detection of a chemical odor is converted into an electrical response. Although it has not been directly demonstrated, it is reasonable to assume that olfactory neurons with more and/or longer cilia are more sensitive than those with fewer and/or shorter cilia. To study the coding principle of the periphery olfactory organ, Challis et al. [1] used antibodies against specific odorant receptors to visualize the cilia of individual neurons in a whole-mount mouse olfactory epithelium preparation and found that neurons specifically in the dorsal epithelium displayed a significant difference in ciliary length along the anterior-posterior axis. They found that, within the dorsal epithelium, anterior neurons bear longer cilia, while posterior neurons bear shorter cilia and anterior neurons have an increased number of cilia compared to posterior neurons (Figure 1A). In contrast, neurons in the ventral epithelium did not display differences in cilia length or number. This finding revealed morphological differences between olfactory neurons of the same type (receptor) and anatomical organization of these neurons based on ciliary properties.

To make sense of this organization pattern, Challis et al. [1] simulated adsorption of an odorant that activates a subset of olfactory neurons along the dorsal epithelium to compare the ciliary length pattern with the pattern of stimulation across the nasal epithelium. They found a positive correlation between ciliary length and odorant absorption in the dorsal epithelium, meaning that cells with longest cilia were located in areas that were predicted to have the highest odor absorption (Figure 1A). The authors further measured the responses of olfactory neurons with different cilia lengths in the dorsal epithelium using single-cell patch-clamp recordings in intact olfactory epithelium. The ex vivo recording approach avoided cell dissociation, which can disrupt cilia and mucus [9]. The results of the electrophysiology revealed that olfactory sensory neurons bearing longer cilia possessed higher response sensitivity while olfactory neurons bearing shorter cilia possessed lower sensitivity but were less easily to saturate (Figure 1A).

Prior to the findings reported by Challis et al. [1], several groups had reported separately about regional differences in cilia length, cellular responsiveness, and odorant adsorption. Differences in ciliary length and number have been observed but not explained, often being dismissed as the product of tissue damage or the difference between immature and mature neurons [10, 11]. The phenomenon of variable response levels in different regions of olfactory epithelium has been reported previously but was attributed to differential odorant adsorption [7, 12]. Similarly, single-cell analyses of olfactory sensory neurons expressing the same receptor have described differences in responsiveness between individual neurons [9, 13], but the mechanism underlying response heterogeneity has remained an open question. The study by Challis et al. [1] is the first systematic analysis to show that olfactory neurons expressing the same receptor display differences in ciliary length, access to stimulation, and responsiveness, thus providing evidence for an additional mechanism to increase odor detection in the peripheral olfactory system that complements the anatomical and organizational aspects of the system.

From a systems point of view, the cilia length pattern described by Challis et al. [1] may increase the sensitivity of the peripheral olfactory organ and allow for detection of very low levels of odors while maintaining discrimination of high levels of odors. In the dorsal olfactory epithelium, cells with longest cilia are very sensitive to low levels of odorant but can saturate early, while cells with shortest cilia respond only to higher odorant concentrations and are less likely to saturate. By positioning the most sensitive cells in the most strongly stimulated anterior areas, the system can achieve the best detection sensitivity, while a broad dynamic range can be achieved by positioning less sensitive cells in weakly stimulated posterior areas. In this way, the diverse sensitivity of olfactory neurons expressing the same odorant receptor and their spatial organization in the olfactory epithelium can potentially enhance both the sensitivity and dynamic range of the olfactory system (Figure 1B).

Interestingly, the ciliary length gradient described by the authors is not ubiquitous across the entire olfactory epithelium, but is limited to a distinct region of the dorsal nasal passage, suggesting that there may be a unique function for this region of the olfactory epithelium. Coincidentally, this area is predicted to be the site of adsorption of hydrophilic odor molecules [7] and is reminiscent of a regional zone of the olfactory epithelium that is populated by neurons expressing Class I odorant receptors, which are evolutionarily similar to odorant receptors of fish [14]. Future studies analyzing the odorant receptors expressed in this region and their ligands may provide functional justification for the presence of a mechanism to increase sensitivity and dynamic range in this specific region of the epithelium.

The relevance of the findings of Challis et al. [1] to human olfaction is currently unclear. The proportion of the nasal epithelium that is olfactory epithelium is much smaller in humans than in mouse, and odorant absorption across the human olfactory epithelium differs from that observed in rodents [15]. Additionally, olfaction is particularly important in rodents for survival and reproduction, thus any modification to increase sensitivity or dynamic range in the olfactory system would be advantageous. As some primates have evolved a unique strategy for increasing visual acuity through the fovea, the ciliary length pattern strategy described by Challis et al. [1] may be an evolutionary adaptation specific to mice and other animals that are more reliant on olfaction. Still, there is some descriptive evidence of differences in ciliary length of olfactory sensory neurons in humans [10]. Future studies analyzing ciliary length in other species will determine whether divergent ciliary length in differentially stimulated areas of the epithelium is a general strategy for enhancing detection in the olfactory periphery.

The study of Challis et al. [1] also adds to our understanding of the functional consequences of regulating cilia length and morphology. Cilia function in development and physiology through roles in cell sensing, signaling, and movement. From paramecia to mammalian photoreceptors, evolution has lead to a great diversity of cilia sizes and morphologies that reflect the diversity in ciliary functions. Understanding the specific function of cilia in different cells has been receiving increased attention due, in part, to the realization that most cells produce cilia and the discovery that various human diseases are caused by disruptions in cilia formation and/or function [16, 17]. This has lead to an increased effort focused on elucidating the signals important for creating diverse cilia shapes and sizes. How is the regional ciliary length pattern of the olfactory epithelium established and maintained? Challis et al. [1] have ruled out a role for neuronal activity, either induced or spontaneous, through a slew of genetic and experimental approaches to disrupt olfactory neuron activation. The authors provided evidence that the type III adenylyl cyclase (ACIII), a key olfactory transduction component in the olfactory cilia, was permissive for the establishment or maintenance of the ciliary length pattern, as ACIII gene knockout resulted in shortened yet uniform ciliary length across the dorsal epithelium. Whether or how ACIII may play an instructive role remains to be determined. Future studies are needed in order to understand the mechanisms controlling the ciliary length and the length pattern in the olfactory periphery and elsewhere.

Sensory systems have adopted a variety of mechanisms to achieve a common goal: to enhance detection and discrimination. The findings by Challis et al. [1] provide evidence of a novel organization model of peripheral sensory neurons within the olfactory system, where the most sensitive sensors are localized to the most strongly stimulated areas to ensure the best detection of certain odorants. The discovery adds an important, previously overlooked, aspect to our understanding of olfactory coding.