**7. Conclusion and future direction**

*Sino-Nasal and Olfactory System Disorders*

stimulate potassium (K<sup>+</sup>

**86**

*of the salivary gland.*

**Figure 6.**

*The tripartite communication of three tissues [olfactory tissue (OLF), central nervous system (CNS)/brain, and salivary gland (SG)] for successful feeding. The left picture showed the flow of signal from odor response to salivary action, which is indicated by the downward arrows. The right picture is the detailed representation of the left one. Primarily, odorants bind with their cognate receptors, present on the dendritic membrane of the olfactory receptor neurons (ORNs). Odor binding initiates the downstream signal transduction procedure, which includes the synthesis of either the second messengers (cAMP, IP3) or change in the membrane ion* 

serotonin from the neurons into the hemolymph which acts as a neurohormone and alters the cytosolic calcium (Ca2+) and adenosine cyclic monophosphate (cAMP) concentration within the secretory cells of the salivary gland [107]. The increased calcium level consequently facilitates the movement of chloride (Cl<sup>−</sup>) ions from the hemolymph side into the lumen of the gland. On the contrary, cAMP was found to

The simultaneous induction of two different pathways leads to the activation of either phospholipase C (PLC)/inositol 1,4,5-trisphosphate (IP3)/diacylglycerol/ Ca2+ signaling pathway or cyclic AMP/adenylyl cyclase signaling cascade which

) transport towards the luminal side of the salivary gland.

*membrane potential and consequently generates the action potential. This action potential rapidly moves through the axons towards the CNS (indicated as red arrow). The antennal lobe (AL) is the primary site for odor perception in mosquitoes. The axons of the ORNs expressing the same receptors which bind to a particular odor molecule merge in a single AL (indicated by orange and blue rods). From the AL, the odor signal then transmitted to higher brain centers [mushroom body (MB), and lateral horn (LH)] through projection neurons (PNs). Along with the neuromodulator-mediated regulation, nerve innervation (originating from the higher brain region) also regulates salivation of the salivary gland in insects (indicated by red zigzag lines over the salivary gland). One of the biogenic amines, the 5-hydroxy tryptamine (5-HT), and its cognate receptor (highlighted in sky blue circle and purple rods) facilitate salivation. But this receptor-mediated downstream signal transduction events and the resultant change in salivary gland membrane potential is not known in the case of mosquitoes (highlighted in red circle). The involvement of other biogenic amine receptors (BAR) and neuropeptide receptors (NPR) in saliva regulation is also yet to be explored. DL, distant lobe; ML, medial lobe* 

*, Ca+*

*, and K+*

*) and facilitates the change in* 

*channel conformation which then allows the flow of ions (Na+*

Evolution and adaptation to blood-feeding behavior in adult female mosquitoes provided a natural mechanism for their reproductive success. Here, we propose a system biology approach which defines the harmonious actions of the olfactory, the brain, and salivary glands, regulating the complex feeding behavior of mosquitoes. However, deciphering the molecular basis on how mosquitoes meet and manage the conflicting demands of sugar feeding vs. blood-feeding and how olfactory conditioning of salivation commenced may lead to the identification of crucial molecular targets including different neurohormones, biogenic amines, neuropeptides, and their receptors for genetic manipulation. Functional genomics and the advancement of electrophysiological techniques illuminate our understanding of mosquitoes' sensory systems. Although it is challenging to identify the species-specific potential olfactory factors that play a pivotal role in mosquitoes' host-seeking and blood-feeding behavior, it will be very effective for the development of novel approaches to control different mosquito populations. The efficacy of emerging genetic tools such as CRISPR/Cas9, a gene drive technology in mosquitoes, can facilitate the molecular understanding of neuronal mechanism of olfactory selection and differential learning and memory formation across different mosquito species which can be manipulated for more effective disruption of host-seeking behavior. Furthermore, unraveling the microbiome-gut-brain-axis communication mechanism during metabolic switch in mosquitoes may enlighten the innovative idea of microbiome-mediated alteration of mosquitoes' olfactory perception.
