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  • dizocilpine A c and CD are

    2023-01-28

    A2c and CD73 are expressed in a small population of OSNs with pear-shaped morphology. In spite of the expression of molecular markers of ciliated OSNs such as Golf, ACIII, and OMP [1, 17], these OSNs have an extremely short dendrite and are located in the superficial layer of OE. In addition to the ciliated and microvillous OSNs, zebrafish possess two minor types of OSNs, crypt cells and Kappe cells, both of which are located in the superficial layer [13, 22]. However, the crypt and Kappe cells innervate two distinct mediodorsal glomeruli in the OB, mdG2 and mdG5, respectively [13, 23], which are different from lG2 innervated by the A2c-expressing OSNs. In addition, V1R4 is expressed in the crypt cells [24], but not in the A2c-positive pear-shaped OSNs (Figure 4A). Based on these results, we propose designation of this fifth type of unique OSNs as the “pear OSNs.” The A2c receptor recognizes only adenosine, but not ATP, related nucleotides or other nucleosides, whereas the lG2 glomerulus is activated by adenosine, AMP, ADP, and ATP. Our results indicate that ATP is enzymatically dephosphorylated and converted to adenosine by two GPI-anchoring ecto-nucletotidases, TNAP and CD73. TNAP in non-neuronal cells located close to the inlet of nose pit catalyzes the serial conversion of ATP to ADP, AMP, and adenosine, while CD73 co-expressed in A2c-positive pear OSNs dephosphorylates AMP to adenosine. How does ATP in the water environment efficiently reach the nose pit, enter into the nostril, and undergo subsequent enzymatic conversion to adenosine for activation of the A2c receptor? Recently, an interesting paper was published on the motile cilia-mediated directional flow in the zebrafish nose, which dizocilpine allows quick exchange of the content of the nasal mucus to facilitate the detection of odorants in stagnant environment [25]. We speculate that such a ciliary beating-based mechanism may be important for generating directional flow of ATP and its metabolites in the nose as well as effectively displacing mucus for highly sensitive responsiveness of the A2c receptor in vivo. The zebrafish OB contains nine glomerular clusters that are spatially segregated and invariant across individuals. The lateral cluster consists of dorsally located five identifiable glomeruli (lG1–lG5), ventrally located one identifiable glomerulus (lG6), and smaller, indistinguishable, multiple glomeruli (lGx) [1, 18]. The present study revealed that adenosine and related nucleotides activate a single large glomerulus lG2 that is innervated by the pear OSNs. In contrast, dizocilpine activate multiple lGx in a combinatorial manner, which are innervated by microvillous OSNs [7, 10]. Despite the fact that adenosine and amino acids bind different types of olfactory receptors (A2c and V2Rs) [26, 27] expressed in distinct types of OSNs (pear and microvillous), those axons innervate the nearby glomeruli in the lateral OB. Thus, it is likely that these lateral glomeruli, lG2 and lGx, might be responsible for relaying the information of food-associated olfactory cues synergistically. We hypothesize that topographically organized glomerular domains in the OB may play roles as functional units collecting ethologically relevant odorant or pheromone information and sending it to higher olfactory centers to evoke specific output responses. Beyond the OB, three brain regions (Vs, PTN, and Hd) are commonly activated by ATP and alanine. In contrast, Dp and a small population of neurons in the ventral-most Hv tend to be activated by ATP, but not alanine, suggesting a possibility of ATP-specific behavioral or physiological responses that we could not observe in the present study. The Dp and Vs are equivalent to the mammalian piriform cortex [28] and central amygdala [29, 30, 31], which receive direct inputs from the OB in fish [32, 33, 34] and whose functions may be related to olfactory perception and emotion, respectively [28, 29, 31]. In addition, it has been recently reported that the central amygdala in mice mediates predatory hunting [35]. Thus, it is likely that the fish Vs may play a similar role in food searching upon activation by the olfactory stimuli. The PTN is a diencephalic nucleus that also receives massive inputs directly from the OB in zebrafish [34]. It is controversial which brain region in mammals corresponds to the fish PTN [36, 37]. In sea lamprey, however, the PTN functions as a relay station transforming olfactory inputs into motor outputs [38]. Although mammalian homologs of the fish Hd and Hv cannot be precisely assigned at present, it is evident that the hypothalamic nuclei play a central role in feeding behavior [39, 40, 41, 42]. Because the ventral Hv in zebrafish contains several types of neurons expressing feeding-related neuropeptides such as agouti-related peptide (AgRP) and proopiomelanocortin (POMC) [40], we speculate that the ventral Hv activated by ATP might correspond to the arcuate nucleus, a feeding center, in mammals. Taken together, the activation of these brain regions by food-derived odorants leads to olfactory perception, emotion, motivation, and locomotion, all of which collectively and synergistically orchestrate the feeding behavior.