Drosophila melanogaster Olfactory System: Comparison
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Drosophila melanogaster has provided a new dimension to the discipline of neuroscience. The research on olfactory and gustatory systems using fruit flies has grown rapidly during the last few years due to the strong genetic similarity that humans share with them.

  • Drosophila melanogaster
  • gustation
  • olfaction
  • gustatory receptors
  • olfactory receptors
  • insect repellents
  • ionotropic receptors

1. Introduction

Drosophila melanogaster has provided a new dimension to the discipline of neuroscience. The research on olfactory and gustatory systems using fruit flies has grown rapidly during the last few years due to the strong genetic similarity that humans share with them. This has proved instrumental in establishing D. melanogaster as an ideal model organism. Additionally, fruit flies offer additional advantages to researchers over humans or mammals. The flies can be easily cultured in laboratory conditions and are quite inexpensive to maintain. They produce a large number of eggs and have a relatively short life cycle that provides much-needed flexibility to the researchers. The flies can also be genetically modified [1] and the neurons easily detected in every individual fly [2]. The larval stages of the fly can be used for different experiments, since they are simple in structural organization and easy to handle as compared to adult flies.
Olfaction plays a vital role in the survival of D. melanogaster. The process commences with the binding of volatile odorant molecules to their specific receptors known as odorant receptors (Ors), which are expressed on the olfactory sensory neurons (OSNs). In the larval stages, each of the two dorsal organs (DO) have 21 OSNs [3][4], which contrarily, are contained in specialized sensory hairs known as sensilla, situated on the third antennal segments and maxillary palps in the adult flies. Earlier studies on olfaction in D. melanogaster used odorants in association with an appetitive or an aversive stimulus. The naïve D. melanogaster larvae showed vigorous chemotaxis towards many odorants, including ethyl acetate (EA) [5]. It was observed that the behavioral responses of larvae were diametrically opposite to shorter and longer chain acetates. The former (methyl to pentyl acetates) were attractive in nature, whereas the latter (hexyl to octyl acetates) triggered repulsion [6]. Besides this, the flies effectively avoided odorants which were paired with an electric shock in learning and memory experiments [7]. An age-dependent decline in olfactory response/memory was reported in D. melanogaster [8] and in those offspring born to aging flies [9]. These behavioral assays based on odorants have played a major role in discovering specific genes involved in the olfactory pathways [10][11] and the regions of the insect brain controlling them.
In gustation, there is a remarkable similarity of food choices and their detection that fruit flies share with mammals. This has given opportunities to researchers to conduct in-depth studies of taste perception. Both mammals and fruit flies consume carbohydrates as their major food source, and both avoid chemicals that are either toxic or taste bitter. The sensitivity and range of recognition of gustatory receptors (Grs) of D. melanogaster are similar to mammals. The Grs are mainly localized in the head and pharyngeal regions of the larvae [12], while in adult flies, they are dispersed on the mouthparts, leg tarsi, and around the female ovipositor. The wings of D. melanogaster also possess taste sensilla. The margins of the anterior wings respond to both appetitive and aversive stimuli due to increases in Ca2+ ions in the cytoplasm [13]. The Grs detecting food items are well characterized in D. melanogaster with a single Gr responding to fructose [14], but the case is different in bitter taste receptors. Several researchers have proposed bitter taste Grs to exhibit a multimeric organization comprising of one subunit tuned to a limited specificity, while others function as broadly required co-receptors [15][16][17][18][19][20]. The role of the intestinal gut of fruit flies in perceiving gustatory stimuli has also been reviewed. Due to the presence of Gr transcripts, the intestinal gut controls many biological functions such as ingestion, absorption of nutrients, and balancing body sugar levels [21].
The in-depth understanding of the chemosensory machinery of D. melanogaster has great practical applications, which may be implemented to design new methods of controlling disease-causing insect vectors and crop pests, and to gain a better understanding of how the batches of insect and pest repellents that are currently available in the market function. Insects are one of the major sources of the transmission of pathogens to humans and cattle, as well as the destruction of food crops [22]. Mosquitoes, ticks, sandflies, and mites are a few of the major insect vectors that spread life-threatening diseases to human beings, such as; malaria, dengue, West Nile fever, encephalitis, yellow fever, and Congo hemorrhagic disease [23]. In particular, mosquitoes are the biggest menace to the human population. Anopheles mosquitoes, i.e., An. Gambiae and An. Funestus, are involved in the transmission of the malarial parasite, Plasmodium sp., to their human hosts, triggering one million annual deaths [24][25]. The human filarial nematode Wuchereria bancrofti, and arboviruses spread through the bites of Culex mosquitoes [25] and Aedes aegypti (the yellow fever mosquito), account for many cases of dengue globally [25][26]. As regards crop pests, the facts are disturbing; for example, the spotted wing Drosophila suzukii, an invasive global insect pest, causes huge crop loss by destroying fresh, ripened small fruits and tree fruits at large scale [27][28][29][30].
To present remedies for such problems, the role of chemosensory mechanisms was evaluated in pest management using D. melanogaster as a model organism.

2. Olfactory System—Components and Basic Organization

In D. melanogaster larvae, the olfactory system is mainly localized to the head region. The head portion of larvae has a couple of DOs expressing 21 OSNs in each [3][4] (Figure 1A). Contrarily, the adult fruit flies detect odorants through a pair of antennae and maxillary palps (Figure 1B). These appendages are positioned on the head region, enveloped with numerous sensory hairs called sensilla. The sensilla possess OSNs that are specialized in detecting odorants (Figure 2A). Each antenna has about 410 olfactory sensilla with nearly 1300 OSNs, whereas the number of olfactory sensilla is up to 60 in each maxillary palp with approximately 120 OSNs [31][32][33][34]. These sensory hairs exhibit differences in their morphology. A recent work on serial block-face scanning electron microscopy (SBEM) images of antennal tissues has further led to a systematic morphological and morphometric analysis of the identified olfactory sensilla in D. melanogaster. A plethora of new information, such as inner dendritic enlargement with enhanced mitochondrial content, the presence of extracellular vacuoles in the lumen of sensilla, empty sensilla with no OSNs, and two new unconventional types of basiconic sensory hairs, was discovered. The olfactory sensilla in fruit flies can be separated into four different groups [35] (Figure 2B), which are as follows:
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Figure 1. Components of the olfactory system: (A) Larva: With a much smaller and simplified architecture, the dorsal organ (DO), antennal nerve (AN), mushroom body (MB), larval antennal lobe (LAL), and ventral nerve cord (VG) constitute the larval olfactory system; (B) Adult: The antenna and maxillary palp (MP) along with the antennal lobe (AL), antennal nerve (AN), mushroom body (MB), and lateral horn (LH), complete the fly’s olfactory system (Modified from [36][37][38][39]).
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Figure 2. Schematic of (A) Sensillum: A sensillum consists of accessory cells, olfactory sensory neurons (OSNs), and pores for odorant molecules to enter; (B) Antenna: The antennae in D. melanogaster’s head are covered with sensory hairs called sensilla. These are of four types, namely trichoid (needle-shaped), basiconic (club-shaped), coeloconic (peg-shaped), and intermediate (shape between basiconic & trichoid) sensilla (Modified from [40]).
a. Basiconic sensilla: The sensory hairs at the proximomedial region of the antenna are club-shaped and are called basiconic sensilla. These sensilla are of 10 types, viz. ab1-ab10, are further grouped into three sub-classes, i.e., large, small, and thin. The large basiconic sensilla (ab1–ab3), ~12 µm in length, house two or four OSNs, whereas small basiconic sensilla (ab7–ab10), which are ~9 µm long, enclose two OSNs. The thin basiconic sensilla (ab4–ab6) are also ~12 µm in length but are thinner in shape. They encompass mostly two with a few cases of four OSNs per sensillum [31][41]. Additionally, there are also two novel types of basiconic sensilla; one is a large basiconic sensillum, abx(3), which encloses three OSNs, and the other is a small basiconic sensillum, abx(1), with a single OSN. Interestingly, one small basiconic sensillum with no OSN is also known to exist, which is designated as abx(0) [35]. The sensory hairs on the maxillary palp are all thin basiconic (pb1–pb3), each housing two OSNs [41]. The basiconic sensilla are single-walled.
b. Trichoid sensilla: The trichoid sensilla are pointed in shape and vary in length from 18–22 µm [31]. They occupy the lateral profile of the antenna, predominantly at the distal tip. These sensilla are of four types, namely at1-at4, and are classified as T1 (at1), T2 (at2), and T3 (at3 & at4) corresponding to the number of OSNs they house, i.e., one, two, and three, respectively [31][41]. However, Fluorescence-guided Single Sensillum Recording (FgSSR) analyses have re-categorized two trichoid sensilla, namely at2 and at3, as intermediate sensilla ai2 and ai3 [42]. Besides this, one trichoid sensillum belonging to the T1 subtype with no OSN has also been found in fruit flies and named T(0) [35]. The trichoid sensilla are also single-walled.
c. Intermediate sensilla: There are a few sensory hairs in the antenna exhibiting length and structure in between trichoid and basiconic sensilla. These are called intermediate sensilla. They are scattered among the trichoids on the frontal antennal surface, with their number varying from 10–20 on each antenna [31][41]. The intermediate sensilla are of two types, namely ai2 and ai3, housing two and three OSNs respectively [42]. They are single-walled.
d. Coeloconic sensilla: The coeloconic sensilla are the smallest of all the sensory hairs. They are short in size (~5 µm) and peg-shaped. Although they are dispersed with other groups of sensilla, the majority of them cover the posterior surface of the antenna. The number of OSNs in coeloconic sensilla varies between two to four neurons per coeloconic sensillum [31][41][43]. The ac3 sensillum houses two OSNs, ac2 and ac4, housing three OSNs each, whereas ac1 compartmentalizes four OSNs [35]. These sensory hairs are double-walled.
Further, in D. melanogaster, the antennal lobe (AL) functions as a deutocerebral neuropil showing functional similarities to the olfactory bulb of the vertebrate brain [44]. At larval stage, the antennal nerve (AN) connects 21 OSNs in DO to the larval antennal lobe (LAL). The LAL has about 30 subunits comparable to the glomerulus of an adult fly [4][45]. The sensory information from LAL then goes through several projections and local neurons (PNs & LNs) to be relayed to higher centers of the larval brain to initiate a behavioral response (Figure 3A). Similarly, in adult flies, OSNs located in the antenna relay sensory information to the AL, consisting of tightly packed neuropils called glomeruli. The number of glomeruli in D. melanogaster is 54 per AL, out of which 52 are innervated by chemosensory and 2 by thermosensory neurons [46][47]. At the glomeruli, the electric signals are further relayed to two specific classes of neurons, the PNs and LNs. The PNs housed in the AL project their axons to the protocerebrum [41] and from here on to the mushroom body (MB) and lateral horn (LH). Thus, the information from the PNs is transferred to these paired neural organs, which comprise higher centers of the fly’s brain [48][49], (Figure 3B).
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Figure 3. Olfactory signaling pathway of (A) Larva: At the larval stage, the odorant molecules are sensed by the dorsal organ (DO). The stimulus is then transferred to the larval antennal lobe (LAL) by the olfactory sensory neurons (OSNs) housed in the DO. From here onwards, through a grid of projection neurons (PNs) and local neurons (LNs) the electrical signal is projected to the larval brain to elicit a response; (B) Adult: In fruit flies, the olfactory signaling begins with the antennae and maxillary palps. The OSNs, with the help of odorant receptors (Ors), carry the olfactory cue to the antennal lobe (AL). From there on, through a network of PNs and LNs, the stimulus is transferred to the mushroom body (MB) and lateral horn (LH) to initiate a response (Modified from [34][50]).

2.1. Olfactory Sensory Neurons (OSNs)

The OSNs form the most important aspect of olfactory detection in D. melanogaster. Their numbers exhibit great variations between the larval and adult stages of the fly. In larvae there are 21 OSNs per DO, whereas the adult fruit flies house much greater number of neurons. Each antenna displays ~1300 OSNs, whereas the actual number is 120 in each maxillary palp. An individual OSN typically embodies a single Or, although a few multiple receptor OSNs are also present in D. melanogaster [44][51]. The OSNs expressing identical receptor gene/genes then project to a specific glomerulus [52][53], where they synapse onto PNs and LNs [54] for further processing of the olfactory cues. A few studies have suggested that the number of OSNs converging into glomeruli varies between 52–53 OSNs per glomerulus [55]. However, each glomeruli has its own unique neuronal composition and glomerular volume, which is a result of varying numbers of OSNs and uniglomerular PNs received by different sets of glomeruli [56]. Additionally, an increased number of glomeruli per antennal lobe has been reported in DD. melanogaster. melanogaster. The number is now 58, out of which 51 are olfactory [57] and 7, i.e., VP1d, VP1l, VP1m [58], VP2, VP3 [59], and VP4 [60][61][62] are thermo/hygrosensory in nature. They house a total of ~2600 antennal lobe sensory neurons (ALSNs) including OSNs and thermo/hygrosensory neurons (T/HSNs) [63].

2.2. Odorant Receptors (Ors)

The odorant receptors (Ors) in D. melanogaster are membrane-associated proteins by nature. They are encoded and expressed by Or genes [64][65]. The seven transmembrane domains possessed by these proteins are quite distinct and have no homology to the vertebrate GPCRs or Ors [66][67][68]. There are 60 Or genes in D. melanogaster, which encode 62 Ors by the process of alternative splicing (Table 1) [69][70][71]. However, studies using transgenic reporter techniques have changed the scenario to a considerable effect. These studies have revealed that the count of genes exclusive for antennal Ors is 40, whereas 7 genes translate receptors specific to maxillary palps [34][41][52]. The remaining Or genes are involved in the encoding of larval Ors and are not detectably expressed in adult fruit flies. There are 25 larval Ors, of which 13 are specifically expressed in larvae [70][72][73]. Additionally, Ors exhibit a unique feature. The receptors expressed in the antennae and maxillary palps of D. melanogaster are exclusive to them and are not expressed in each other, as established by several algorithmic studies. These studies have identified a dyad element that promotes the expression of maxillary-palp-specific Ors and a motif that represses their expression in the antennae [74]. One more restrictive feature of Ors is that the expression of Or genes in morphologically distinct sensilla follows a set pattern [75]. The study of this pattern has revealed a strong correlation between the developmental pathways of the sensilla and the types of Ors they express [32].
Table 1. Odorant receptors (Ors) in Drosophila melanogaster.
Olfactory Sensory Neuron Odorant Receptor Glomerulus
- Or1a * -
ai3 Or2a DA4m
Ir21a Ir7c Ir56d Ir20a Ir11a Ir20a Ir7c Ir7b Ir7c ab4A Or7a DL5
Ir25a Ir11a Ir76b Ir25a Ir20a Ir25a Ir11a Ir7c Ir10a ab8B Or9a VM3
Ir31a Ir25a   Ir56a Ir25a Ir76b Ir20a Ir10a Ir11a ab1D Or10a DL1
Ir40a Ir47a   Ir60b Ir56a Ir100a Ir25a Ir25a Ir20a ab6A Or13a DC2
    Ir76b
Ir41a Ir56a   Ir60c Ir76b   Ir47a Ir52a Ir25a ai3A Or19a DC1
  Ir56c   Ir48c     Ir85a
Ir64a Ir56b   Ir60d Ir94a   Ir52a Ir52b Ir56a ai3A Or19b DC1
  Ir60c   Ir51b
Ir68a Ir56d       
Ir67c Ir94b   Ir52b Ir52c Ir76b ab3A Or22a DM2
  Ir76b   Ir60b      
Ir75a Ir60c   Ir76b Ir94c   Ir52c Ir56a   ab3A Or22b DM2
  Ir94e   Ir60d      
Ir75b Ir60d   Ir94a Ir94h   Ir52d Ir56d   - Or22c * -
  Ir94h   Ir60e
Ir75c Ir76b   Ir94e     Ir56a Ir60c   ai2B Or23a DA3
Ir75d Ir94b   Ir94f     Ir56d Ir76b   - Or24a * -
Ir76a Ir94e   Ir94h     Ir60c Ir94e   - Or30a * -
     
      Ir94b    
. The remaining four Irs, i.e., Ir8a, Ir25a, Ir76b, and Ir93a are present and function as co-receptors in different amalgamations [9391][9492]. This paired functioning of Irs with co-receptors suggests that they work in tandem, resulting in ion channels responding to volatile odorant molecules [9492][9593]. Additionally, the identification of the co-receptor extra loop (CREL), a conserved sequence of the Ir co-receptor ligand-binding domain (LBD) has brought an array of new insights. It has helped in understanding the assembly and stoichiometry of Ir complexes and their intracellular transport in a much-improved way [9694]. Besides olfaction, the Irs are also involved in the perception of gustatory stimuli. A group of approximately 35 Irs, the Ir20a clade is translated in all of the taste organs of the fly co-expressed with bitter or sweet Grs [9795]. This is explained in detail later, in the gustatory section of the review.
Table 3. Ionotropic receptors (Irs) in Drosophila melanogaster (adult).
Antenna LTB LTP LSO VCSO DCSO Legs Wings Abdomen
 
 
 
 
 
  Ir67b      
      Ir67c      
      Ir76b      
Ir76b     Ir100a     Ir67a     ab4B Or33a DA2
      Ir92a       ab2B, ab5B Or33b DM5, DM3
      Ir94a pb2A Or33c VC1
  ac3B Or35a VC3
      Ir94g       pb1A Or42a VM7d
      Ir100a ab1A Or42b DM1
ai3 Or43a DA4l
ab8A Or43b VM2
- Or45a * -
- Or45b * -
pb2B
Outline of larval repertoire of ionotropic receptors (Irs). (Adapted from [91]). DO—Dorsal organ, TO—Terminal organ, VO—Ventral organ, DPO—Dorsal pharyngeal organ, DPS—Dorsal pharyngeal sensilla, VPS—Ventral pharyngeal sensilla, PPS—Posterior pharyngeal sensilla.
The Irs confer odorant responses much like the Ors, but more in-depth studies need to be conducted in this direction. The number of Ir genes in the D. melanogaster genome is 61, in addition to 2 putative pseudogenes. Among these, 17 genes encode the antennal Irs, while the rest of them are translated and scattered all over the fly’s body (both in the larval and adult stages); the latter are called divergent Irs. Amid the antenna, out of 13 Irs, the majority of them sense olfactory cues from amines, aldehydes and evaporative acids, and few Irs are hygrosensory or thermosensory in nature [60][8583][9189][9290]
Ir8a Ir7a Ir25a Ir10a Ir7a Ir10a Ir7a Ir7a Ir7a
Ir84a
 
 
 
 
 
Or46a
VA71
Ir76b
ab5B
Or47a
DM3
at4A Or47b VA1v
ab10B Or49a DL4
ab6B Or49b VA5
ab4B Or56a DA2
- Or59a * -
ab2A Or59b DM4
pb3A Or59c VM7v
- Or63a * -
at4B Or65a DL3
at4B Or65b DL3
   
Ir92a         at4B Or65c DL3
ab10A Or67a DM6
ab9 Or67b VA3
ab7B Or67c VC4
at1A Or67d DA1
ab9 Or69a D
pb1B Or71a VC2
- Or74a * -
ab5A Or82a VA6
- Or83a * -
ab, ai, at, pb, ac3 Or83b/Orco DA, DC, DL, DM, VA, VC, VM
ai2A Or83c DC3
ab2B Or85a DM5
ab3B Or85b VM5d
- Or85c * -
pb3B Or85d VA4
pb2A Or85e VC1
ab10B Or85f DL4
at4C Or88a VA1d
ab1B Or92a VA2
- Or94a * -
- Or94b * -
ab7A Or98a VM5v
ab6 Or98b VM5d
Outline of odorant receptors (Ors), their OSN classes, and targeted glomeruli. Larval specific Ors are marked with asterisk *. (Adapted from [76][77]).
It is well-established that a solo Or gene is translated in each OSN [41][7876][7977]. However, a few studies have revealed interesting facts about Or gene expression. Each D. melanogaster OSN expressing an Or also expresses a co-receptor named as Orco/Or83b [65][8078]. This co-receptor is essential to the appropriate ciliary routing and functioning of every single Or [65][8179]. The flies devoid of Orco exhibit defective behavioral and electrophysiological responses to a number of odorants [67]. Besides this, four populations of OSNs co-express two conventional Ors (Or33a/Or56a, Or33b/Or47a, Or33b/Or85a and Or33c/Or85e) and a fifth one co-expresses one Or and one Gr (Or10a/Gr10a) along with the co-receptor Orco leading to a modulated ligand response profile [51][52]. A couple of recent works using cryo-electron microscopy have further given an insight into the functioning of Or/Orco heteromeric complexes. Butterwick et al., through structural analyses, has found that an Orco homomer consists of four subunits organized in a symmetrical fashion around a central pore. Each Orco subunit is further composed of seven transmembrane helical segments (S1–S7), out of which S7a (the cytoplasmic section) forms the crux of the anchor domain, whereas S7b (the transmembrane section) contours the central pore. The pore is narrowest at the extracellular end of S7b due to the presence of hydrophobic residues Leu473 and Val469. When a ligand binds to the Or/Orco heteromeric complex, the hydrophobic aperture is expanded. This central ion-conduction pathway then veers into the four lateral channels (6-Å long) that open to the cytosol, providing an uninterrupted pathway for the transfer of ions [8280]. On a similar note, Marmol et al. has deciphered that the odorant receptor MhOr5 in Machilis hrabei exhibits identical quadrivial structural organization and functions similarly to Orco. Here, the binding of the ligand also dilates the S7b helices to gate the ion conduction pathway. In nutshell, these structural understandings of the Or and Orco have shed a light on the promiscuous nature of these receptors, allowing insects to have a versatile chemical recognition system [8381].

2.3. Ionotropic Receptors (Irs)

Besides Ors, an additional group of receptors, called ionotropic receptors (Irs), is also involved in olfaction in D. melanogaster. Structural analyses have revealed their similarities to the ionotropic glutamate receptors (iGluRs) with a homology of less than 34% [8482][8583]. They also share the ion-channel-like characteristic of iGluRs, though the binding site for glutamate is not present [8684][8785]. The chemosensory apparatus of the larval stage is mainly distributed to the head region, encompassing the dorsal organ (DO), terminal organ (TO), ventral organ (VO), dorsal pharyngeal organ (DPO), dorsal pharyngeal sensilla (DPS), ventral pharyngeal sensilla (VPS), and posterior pharyngeal sensilla (PPS), all existing in pairs [45][8886][8987][9088]. All of the above organs express Irs. A few Irs are also present in the body area that forms the complete larval repertoire together with the receptors of the head region (Table 2) [9189]. Contrarily, the distribution of Irs in adult flies is quite diverse (Table 3). In the head region, they are dispersed in the antenna, labral sense organ (LSO), dorsal cibarial sense organ (DCSO), ventral cibarial sense organ (VCSO), and the labellum. The Irs are also expressed in the wings and legs of the fruit fly [9189].
Table 2. Ionotropic receptors (Irs) in Drosophila melanogaster (larva).
DO TO VO DPO/DPS VPS PPS Abdomen
Ir21a Ir7a Ir7g Ir7a Ir7b Ir25a Ir7d
Ir25a Ir7b Ir25a Ir7f Ir7g Ir76b Ir7g
Ir68a Ir7d Ir67a Ir7g Ir25a Ir92a Ir10a
Ir92a Ir7e Ir76b Ir11a Ir76b Ir94g Ir25a
Ir93a Ir7g   Ir25a   Ir100a Ir68b
  Ir25a   Ir48b
 
Ir94e
 
 
Ir93a           Ir94h

Outline of distribution of ionotropic receptors (Irs) in adult flies. (Adapted from [91][97]). LTB—Labellar taste bristles, LTP—Labellar taste pegs, LSO—Labral sense organ, VCSO—Ventral cibarial sense organ, DCSO—Dorsal cibarial sense organ.

2.4. Odorant Binding Proteins (Obps)

Encoded by a clan of 52 genes, the Obps are found in abundance in D. melanogaster [9290]. They are a group of highly divergent pint-sized proteins of 13–28 kDa secreted in the olfactory sensillar lymph [9896][9997]. The Obps ease the transportation of hydrophobic odorants such as a few food odorants, pheromones, etc. to the Ors [96][98][10099][101]. The Obp76a, also known as LUSH, is essential for the detection of the pheromone cis-vaccenyl acetate (cVA) by Or67d in trichoid sensilla [102100]. However, various studies have shown that even in the absence of Obp76a, D. melanogaster can detect cVA, refuting its essentiality [101][102]. Another study involving Obp28a, one of the most abundant Obps in fruit flies, showed that it was not involved in the transportation of odorants [103]. Contrary to these findings, recent work has established that Obp28a is essential for the detection of the floral odorant β-ionone by fruit flies [104]. Thus, these findings of the functioning of different Obps suggest that a much larger picture of the exact role and mechanism of their operation remains to be deciphered.

3. Olfactory Signaling Pathway—Interpreting Olfaction in Drosophila melanogaster

3.1. Larva

The larvae and adults of D. melanogaster share a general outline of the olfactory system, though in larvae, it is smaller and simplified. The presence of a reduced number of OSNs in larvae suggests a diminished primary olfactory repertoire as compared to adult flies [105]. The 21 OSNs in the DO are connected to the LAL by the AN. The LAL conother ssists of approximately 30 subunits showing resemblance to the adult glomerulus, though smaller in number and size [4][45]. In the LAL, the OSNs interact with 21 udy involvinniglomerular PNs, 14 multiglomerular PNs, 14 GABAergic and cholinergic LNs, 4 neuromodulatory neurons, 6 subesophageal zone (SEZ) neurons, and 1 descending neuron. The olfactory signals are thus transmitted to higher centers of the larval brain to elicit different behavioral responses [106][107].

3.2. Adult Fly

The antennae and maxillary palps are key to olfaction in adult fruit flies. They house several OSNs that are primarily involved in sensing odorants in D. melanogaster [108]. Studies have revealed that an Or behaves differently to different odorants. It can be excited by some odorants and inhibited by others [109]. Such a response shows the temporally complex nature of odorant signaling. Barring a few cases where the OSNs express either multiple Ors—such as ab5 sensilla, where Or33b and Or47a, are expressed together [51]—or receptors of the gustatory family [110][111], the majority of the 1300 OSNs in the D. melanogaster genome expresses one Or per neuron from the total of 61 Ors [36]. An additional Or, Or83b/Orco functioning as a co-receptor is also expressed in each neuron. It acts in concert with conventional Ors to recognize different odorants [65].
The point of emphasis is this: how do OSNs further process the olfactory stimuli they sense? The answer lies within the antennal lobe. Each of the 52 glomeruli it houses receives projections from the OSNs embodying the same Or [41][46][49][52][60]. From here on, the stimuli are relayed on to a network comprising projection neurons (PNs), inhibitory local neurons (iLNs), and excitatory local neurons (eLNs). The PNs are involved in transmitting olfactory information to higher centers of the fruit fly’s brain, i.e., MBs and LHs, whereas iLNs and eLNs establish lateral connections among different glomeruli [112]. What is interesting at this point is the systemization of the PNs into two different neural tracts. They are the:
a. Inner antennocerebral tract (iACT): the calyx neuropil of the MB, along with the LH, forms synaptic connections with the PNs of the iACT [113].
b. Medial antennocerebral tract (mACT): The PNs of the mACT bypass the MB calyx and go straight to the LH [114]. A few cases have revealed that part of the PNs of the mACT sends its extensions into multiple glomeruli, which trigger an inhibitory response.
This is how olfactory stimuli are perceived by the OSNs and relayed to the higher centers of the brain for further processing, to initiate varying behavioral responses in adult fruit flies.

4. Molecular Basis of Olfactory Signaling—Decoding the Game of Smell

In D. melanogaster, the Or targeting a specific odorant (OrX) forms a heteromeric complex with the universal co-receptor Orco [115]. The mode of action of this complex is synonymous with the functioning of a ligand-activated cation channel [116][117]. On the other hand, the Irs are known to form heteromeric complexes with up to three different subunits. They consist of a variable, odorant-specific Ir (IrX), and one or two broadly expressed co-receptors out of Ir8a, Ir25a, and Ir76b [91][92]. The Irs exhibit a distinct similarity with iGluRs in having a transmembrane done omain, a ligand-binding domain (LBD), and an aperture region [118]. Various models have been extensively studied focusing the moson the functioning of the above-mentioned olfactory receptors in D. melanogaster. These models include the amolecular signaling pathways involved in the sensing of food odorants, pheromones, and CO2, respectively. To have a much better undant erstanding of the cited models, let us divulge the details of these signaling cascades.

4.1. General Odorant Sensing

The odorant-binding proteins (Obps) in frcarry odorant molecules to the OrX-Orco heteromeric complex. The binding of the ligand and receptor leads to the activation of an ion channel [119]. This channel is a non-specific cation channel permeable to Ca2+ and other positively charged ions (Na+, K+). The permeability leads to an influx of catit fliesons changing the membrane potential of the OSNs, leading to their depolarization and repolarization in a subsequent manner [116]. Thus, the olfactory shoignal (electrical activity) is transmitted along the OSNs to the PNs and then to higher centers of D. melanogaster’s brain. This type of signaling is known as ionotropic signaling (Figure 4). In parallel, there are several reports that point toward that is the involvement of G-proteins in odorant detection. It was not infound that the olfactory acumen of flies was altered by mutations targeting the cAMP signaling cascade [120]. The Ors expressed in HEK293 cells, when stimulated by an odorant, resulted in an enhanced cAMP production [121]. A decreased level olf cAMP was also reported to alter the proper detection of odorants by flies [122], whereas odorant stimulation led to an increase in cAMP production [123]. In addition, the role of Gαq [124], Gαo [125], and Gαs in the transmission of odorant stimuli further characterized the involvement of phospholipid in tand cAMP second messengers in olfactory signaling [126]. Still, the involvementrans of G-proteins in odorant detection is still debatable now [127] and is most likely to modulate the functioning of ion channels in one or another way.
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Figure 4. Schematic of ionotropic signaling in general odorant sensing: It involves opening a non-specific cation channel, owing to the binding of odorant molecules to the OrX-Orco heteromeric complex. This leads to a change in the membrane potential and depolarization of the olfactory sensory neurons (OSNs). (Modified from [128]).

4.2. Signaling in Pheromone-Sensing Ors (Prs)

The pherortation of omone molecules attached to the pheromone-binding proteins (PBPs) are fixed to the PrX-Orco heteromeric complex. The SNMP1, i.e., sensory neuron membrane protein 1 most likely associates with the complex and mediates the transfer of pheromones to PrX (pheromone specific Or protein) [129]. The pheromone-receptor complex then activates an ionotropic channel (PrX-Orco channel), leading to an influx of cations (Ca2+, Na+, K+) and subsequent depolarizantstion of the pheromone sensory neurons (PSNs) [105130]. This results in the transmission of the olfactory signal (Figure 5).
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Figure 5. Schematic of ionotropic signaling in pheromone-sensing Ors (Prs): Binding of pheromone molecules to the specific PrX-SNMP1 heteromeric complex results in the activation of an ionotropic channel. This leads to an influx of cations and subsequent depolarization of the pheromone sensory neurons (PSNs). (Modified from [128]).

4.3. Signaling in the Sensing of CO2

The CO2 triggers a strong and inborn evading olfactory behavior in D. melanogaster [131][132]. Its sensing at a concentration of less than ~2% is mediated by the class of OSNs (ab1C) co-expressing Gr21a and Gr63a [131][133][134][135], whereas detection at a higher concentration of more than 5% involves acid-mediating Ir64a and Ir8a [90][136]. A few reports propose that at lower concentrations, the G-proteins might be involved in the detection of CO2 by fruit flies. The Gαq and Gγ30A were found to play a role in the signaling of CO2 in D. melanogaster [127]. Another work hinted that the CO2 receptors Gr21a and Gr63a might activate the TRPC channels through Gαq and PLC21C [137]. However, this is not an established view and more work needs to be conducted in this direction to further validate the involvement of G-proteins in CO2 signaling. At higher levels of CO2, Ir64a and Ir8a act in tandem to decipher a dip in the pH of the sensory lymph to trigger an avoidance behavior [90][136]. Besides this, a different study has put forward the participation of PNs innervating the V-glomerulus (PNvs) in managing the avoidance response of fruit flies to low and high CO2 concentrations. It was shown that the PNv-1pathway is activated at lower concentrations of CO2 (0.5%), whereas higher levels of CO2 (2%) stimulate PNv-1, PNv-2, and GABAergic PNv-3 pathways [138]. Another interesting finding involving the sensing of CO2 by D. melanogaster has come to the light. It has been found that fruit flies, while walking, perceive CO2 as an aversive stimulus, whereas the same stimulus while flying becomes attractive. This in-flight attraction to CO2 involves different components working in tandem, i.e., Ir64a, Orco, and octopamine signaling [139]. However, recent work has Cput forward the fact that fruit flies perceive CO2 as an attractant in both walkintrary to these g and flying conditions when they are in an activated stage of searching for food. This modus operandi is facilitated by the functioning of a distinct chemosensory pathway involving Ir25a [140].
In nutshell, these models highlight the functindingsoning of insect olfactory receptors as heteromeric ligand-gated ion channels. Novel research decoding the structure of Orco has further substantiated the involvement of ion conduction pathways in the perception of olfactory stimuli by insects [80].

5. Olfaction-Based Repellency—The Established and New Players on the Horizon

The process of olfaction is indispensable to the survival of insects. It allows them to detect food, precent obable mates, and the signs of danger so as to avoid them. Likewise, the disease-transmitting insect vectors also use their sense of smell to trace and feed on their human hosts [141][142][143][144]. Additionally, crop infesting insects such as Drosophila suzukii, a major global fruit pest, use olfactory detection of higher CO2 emission to target ripening fruits [145]. This results in a humongous amount of agricultural loss globally, accounting for millions of dollars [145][146][147]. Consequently, targeting and modulating the olfactory system has become a prominent choice for researchers to control the menace of insects and develop better alternatives for combating insect pests.
Insect repellents are still the first line of defense against disease-causing insect vectors. The major ingredient used in these current batches of repellents is N, N-diethyl-m-toluamide (DEET), which triggers an airborne repugnancy among insects [144][148][149]. As a result, DEET is wildly used to ward off blood-sucking has esmosquitoes to limit the transmission of pathogens among humans [148][150]. To understand the molecular machinery blishedehind this olfaction-based repellency caused by DEET, many researchers have opted for D. melanogaster as a model organism. In one of the reseat Obprch works, it was observed that fruit flies with intact antennae avoided DEET-treated food vials. Conversely, flies devoid of both of the antennae, with their maxillary palps unharmed, did not show any repellency to DEET. Thus, it was concluded that the DEET repellency is olfaction driven as antennae house OSNs. To confirm the findings, Or83b/Orco mutant fruit flies were used, as Orco is an indispensable co-receptor required for the proper functioning of Ors [65][67]. The results were consistent, as wild-type flies avoided DEET-treated food vials while Orco mutants were insensitive to DEET. Further in-depth analysis revealed that the reduced acuity of food odorant was related to the electrophysiological inhibition of Or828a/Orco housed in the ab5A sensillum and Or47a/Orco in ab5B sensillum. In summary, it was concluded that DEET reduces the perception of food aroma in fruit flies by inhibiting the odorant-induced activation of a subset of Or/Orco complexes to varying degrees [150]. Similarly, using Orco mutant mosquitoes exhibited that they were not repelled by volatile DEET, indicating the need for an intact Or pathway for DEET repellency [149].
A different work using D. melanogaster also exhibited involvement of the olfactory system in the functioning of DEET. The study revealed that Or42a was involved in the DEET repellency. The receptor was also sensitive to two other major repellents—picaridin and Ir3535—hinting towards is ets generic nature [25]. However, a recent analysisential for the detec with fruit flies has unveiled that, although higher concentrations of DEET were detected by the Orco based olfactory system, there was no specific OSN involved in this process. The deletion of Or42a and Or2a neurons showed no difference in DEET avoidance, pointing towards the involvement of multiple OSNs in the repugnancy of DEET [151]. Altogether, ion of the floral ot can be inferred that the repugnant behavior of insects towards DEET involves their olfactory system. Still, there are several conflicting models involved in DEET olfactory repellency. DEET is found to work by masking odorants. One such example is the reduced attraction of Aedes aegypti mosquitoes to humans by masking the smell of lactic acid [152]. DEET is also known to cause a dip in the rant elease of 1-octen-3-ol, disrupting the host-seeking mechanism of insects by changing the chemical profile of the host’s skin odorants [153][154]. Another hypothesis of the functioning of DEET is that it acts as a confusant. It is likely to alter the regular activation pattern of the glomeruli of insects, thereby blocking the host’s attractiveness. Besides this, as per the smell and avoid model, DEET activates aversive GRNs in insects that override the neural activity of GRNs sensing attractive cues coming from the host. This allow insects to preferably avoid their hosts [155]. In addition to DEET, pyrethrum is also an extremely popular insect repellent that has been used by humans for a long time to control arthropod pests. It is extracted from the dry flowers of the plant Tanacetum cinerariifolium. However, the molecular mode of functioning of this repellent was still a question that needed to be answered. Currently, it has been revealed that there is the involvement of Or7a, Or42b, Or59b, and Or98a in avoidance behavior towards pyrethrum. The first three receptors mentioned above are activated by pyrethrins which are the key insecticidal constituents of pyrethrum, whereas Or98a is stimulated by E-β-farnesene (EBF), a mionone by fnor constituent. It was observed that genetically knocking out Or7a, Or59b, and Or98a obliterated the repellency of fruit flies to pyrethrum, pointing towards their involvement in avoidance behavior [106156].
DEET is a highly efficient insect repellent, with its fair share of problems. First, it needs to be applied on a recurrent basis in increased concentrations making it quite expensive for the people in areas infested with vector-borne diseases [148]. In Thus, these finaddition, a reduced repugnancy by DEET is observed in mosquitoes owing to its repeated exposure. Therefore, there have been efforts from the research community to design and develop better alternatives to DEET, to deal with the menace of insect vectors and pests. A few of the prominent examples are as follows:
a. Geosmin: Trans-1,10-dimethyl-trangs of ts-9-decalol, commonly known as Geosmin is a compound with an earthy smell produced by a few specific groups of bacteria, fungi, and cyanobacteria. Using D. melanogaster as a model organism, it was revealed that at extreme fly low concentrations, Geosmin triggered repellency. Further in-depth analysis exhibited that this aversive behavior was triggered by Or56a housed in the ab4B OSNs [154][157]. Geosmin is also known to induce a dip inctioning o the attraction of fruit flies towards vinegar compounds [157][158]. Thus, the ability of Geosmin to indiffeuce aversion and modulation of inborn attraction makes it a very desirable candidate for a strong repellent.
b. OX1w: In insects, each OSN expressint Og an Or also expresses a co-receptor named Orco [65][78]. This co-receptor is indispensable to the ps roper ciliary routing and functioning of every single Or [65][79]. In D. melanogaster, the attraction towards ethyl acetate (EA) is mediated by the Or42b/Orco heteromeric complex [159]. A group of researchers workingges on fruit fly larvae found that the air-borne application of the Orco antagonist, OX1w, eliminated their chemotactic movement towards EA [144]. Thus, inhibiting that a me functioning of Orco by designing more potent Orco antagonists can be a potential method to control insect vectors and pests.
c. Coffee furanone: 2-methyltetrahydrofuran-3-one, also known as ch largoffee furanone is a natural volatile compound, found to have repellent/attractant properties. A recent work using D. melanogaster showed that the application of coffee furanone triggered an aversive behavior picture in fruit flies. An in-depth analysis brought to light the functions of this compound, as activating the variable OrX subunit of the exact role anOrX/Orco heteromeric complex is necessary for odorant detection. What makes coffee furanone special is its promiscuous nature, as it is known to stimulate nearly 80% of the OSNs in the antennae of D. melanogaster and various other insect mechanism ospecies. In addition, coffee furanone is a common flavoring agent used in food and is considered safe for humans. Consequently, all of these features of coffee furanone brands it a highly desirable candidate to serve as a repellent or attractant to combat insect vectors or crop pests [119].
d. Essential oils: Since it has already been shown that insects use their olfactory their operation remainsystem to detect food and hosts, the use of plant-based essential oils to repel them has immense potential to be developed into high-quality repellents. Several essential oils such as camphor, peppermint oil, norcamphor, nerol, menthyl acetate, menthone, (-)-menthol, etc. have been found to elicit repellency in D. melanogaster and D. suzukii, which are serious to be decipheredglobal crop pests. It was observed that aversion to essential oils was reduced in Orco mutant fruit flies, pointing towards their olfactory mode of functioning. Thus, further in-depth study of the molecular mechanism of the operation of essential oils will be helpful in the long run to ward off the ever-increasing menace of the insects [160] (Figure 6).
Insects 13 00142 g006 550
Figure 6. Schematic of molecular players involved in the olfaction-based avoidance of insect repellents: Using D. melanogaster as a model organism it has been observed that the functioning of DEET, pyrethrum, and a slew of new potent alternatives is based on the targeting of either OrX or Orco subunit of the OrX/Orco heteromeric complexes.

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