Sense of Smell: Structural, Functional, Mechanistic Advancements and Challenges in Human Olfactory Research.

Olfaction, the sense of smell detects and discriminate odors as well as social cues which influence our innate responses. The olfactory system in human beings is found to be weak as compared to other animals; however, it seems to be very precise. It can detect and discriminate millions of chemical moieties (odorants) even in minuscule quantities. The process initiates with the binding of odorants to specialized olfactory receptors, encoded by a large family of Olfactory Receptor (OR) genes belonging to the G-protein-coupled receptor superfamily. Stimulation of ORs converts the chemical information encoded in the odorants, into respective neuronal action-potentials which causes depolarization of olfactory sensory neurons. The olfactory bulb relays this signal to different parts of the brain for processing. Odors are encrypted using a combinatorial approach to detect a variety of chemicals and encode their unique identity. The discovery of functional OR genes and proteins provided an important information to decipher the genomic, structural and functional basis of olfaction. ORs constitute 17 gene families, out of which 4 families were reported to contain more than hundred members each. The olfactory machinery is not limited to GPCRs; a number of non- GPCRs is also employed to detect chemosensory stimuli. The article provides detailed information about such olfaction machinery, structures, transduction mechanism, theories of odor perception, and challenges in the olfaction research. It covers the structural, functional and computational studies carried out in the olfaction research in the recent past.

Diverse populations of local interneurons integrate into the Drosophila adult olfactory circuit.

Drosophila olfactory local interneurons (LNs) in the antennal lobe are highly diverse and variable. How and when distinct types of LNs emerge, differentiate, and integrate into the olfactory circuit is unknown. Through systematic developmental analyses, we found that LNs are recruited to the adult olfactory circuit in three groups. Group 1 LNs are residual larval LNs. Group 2 are adult-specific LNs that emerge before cognate sensory and projection neurons establish synaptic specificity, and Group 3 LNs emerge after synaptic specificity is established. Group 1 larval LNs are selectively reintegrated into the adult circuit through pruning and re-extension of processes to distinct regions of the antennal lobe, while others die during metamorphosis. Precise temporal control of this pruning and cell death shapes the global organization of the adult antennal lobe. Our findings provide a road map to understand how LNs develop and contribute to constructing the olfactory circuit.

Two Parallel Olfactory Pathways for Processing General Odors in a Cockroach.

In animals, sensory processing via parallel pathways, including the olfactory system, is a common design. However, the mechanisms that parallel pathways use to encode highly complex and dynamic odor signals remain unclear. In the current study, we examined the anatomical and physiological features of parallel olfactory pathways in an evolutionally basal insect, the cockroach Periplaneta americana. In this insect, the entire system for processing general odors, from olfactory sensory neurons to higher brain centers, is anatomically segregated into two parallel pathways. Two separate populations of secondary olfactory neurons, type1 and type2 projection neurons (PNs), with dendrites in distinct glomerular groups relay olfactory signals to segregated areas of higher brain centers. We conducted intracellular recordings, revealing olfactory properties and temporal patterns of both types of PNs. Generally, type1 PNs exhibit higher odor-specificities to nine tested odorants than type2 PNs. Cluster analyses revealed that odor-evoked responses were temporally complex and varied in type1 PNs, while type2 PNs exhibited phasic on-responses with either early or late latencies to an effective odor. The late responses are 30-40 ms later than the early responses. Simultaneous intracellular recordings from two different PNs revealed that a given odor activated both types of PNs with different temporal patterns, and latencies of early and late responses in type2 PNs might be precisely controlled. Our results suggest that the cockroach is equipped with two anatomically and physiologically segregated parallel olfactory pathways, which might employ different neural strategies to encode odor information.

Variation in olfactory neuron repertoires is genetically controlled and environmentally modulated.

The mouse olfactory sensory neuron (OSN) repertoire is composed of 10 million cells and each expresses one olfactory receptor (OR) gene from a pool of over 1000. Thus, the nose is sub-stratified into more than a thousand OSN subtypes. Here, we employ and validate an RNA-sequencing-based method to quantify the abundance of all OSN subtypes in parallel, and investigate the genetic and environmental factors that contribute to neuronal diversity. We find that the OSN subtype distribution is stereotyped in genetically identical mice, but varies extensively between different strains. Further, we identify cis-acting genetic variation as the greatest component influencing OSN composition and demonstrate independence from OR function. However, we show that olfactory stimulation with particular odorants results in modulation of dozens of OSN subtypes in a subtle but reproducible, specific and time-dependent manner. Together, these mechanisms generate a highly individualized olfactory sensory system by promoting neuronal diversity.

Mechanisms controlling diversification of olfactory sensory neuron classes.

Animals survive in harsh and fluctuating environments using sensory neurons to detect and respond to changes in their surroundings. Olfactory sensory neurons are essential for detecting food, identifying danger, and sensing pheromones. The ability to sense a large repertoire of different types of odors is crucial to distinguish between different situations, and is achieved through neuronal diversity within the olfactory system. Here, we review the developmental mechanisms used to establish diversity of olfactory sensory neurons in various model organisms, including Caenorhabditis elegans, Drosophila, and vertebrate models. Understanding and comparing how different olfactory neurons develop within the nervous system of different animals can provide insight into how the olfactory system is shaped in humans.

Early Odorant Exposure Increases the Number of Mitral and Tufted Cells Associated with a Single Glomerulus.

The highly specific organization of the olfactory bulb (OB) is well known, but the impact of early odorant experience on its circuit structure is unclear. Olfactory sensory neurons (OSNs) project axons from the olfactory epithelium to the OB, where they form spherical neuropil structures called glomeruli. These glomeruli and the postsynaptic targets of OSNs, including mitral and tufted cells (M/TCs) and juxtaglomerular cells, form glomerular modules, which represent the basic odor-coding units of the OB. Here, we labeled M/TCs within a single glomerular module of the mouse OB and show that odorant exposure that starts prenatally and continues through postnatal day 25 has a major impact on the structure of the glomerular module. We confirm that exposure increases the volume of the activated glomeruli and show that exposure increases M/TC number by >40% in a glomerulus-specific fashion. Given the role of M/TCs in OB output and in lateral inhibition, increasing the number of M/TCs connected to a single glomerulus may also increase the influence of that glomerulus on the OB network and on OB output. Our results show that early odorant exposure has a profound effect on OB connectivity and thus may affect odorant processing significantly. SIGNIFICANCE STATEMENT: Experience shapes neural circuits in a variety of ways, most commonly by changing the strength of activated connections. Relatively little is known about how experience changes circuitry in the olfactory system. Here, we show that for a genetically identified glomerulus in the mouse olfactory bulb, early odorant exposure increases the number of associated mitral and tufted cells by 40% and 100%, respectively. Understanding the structural changes induced by early odorant experience can provide insight into how bulbar organization gives rise to efficient processing. We find that odorant experience increases the number of projection neurons associated with a single glomerulus significantly, a dramatic and long-lasting structural change that may have important functional implications.