**Acknowledgements**

*Sino-Nasal and Olfactory System Disorders*

in hippocampus and cortex [100].

drugs in treating depression [101].

of SST based therapeutic approaches.

**8. Discussion and conclusions**

elevated pro-inflammatory cytokines and increased levels of BDNF and serotonin

Depression with psychomotor agitation (PMA) is a putative psychiatric disorder associated with substance dependence, specifically, opioids. It remains unaffected by drug induced major depressive episodes indicating complex interplay of therapeutic

The AON, a key area of the olfactory system, shows accumulation of characteristic neuropathological markers such as hyperphosphorylated tau, α-synuclein and β-amyloid proteins at the earliest stages of AD in a Somatostatin (SST) expressing subpopulation of interneurons. In the limbic system, the same accumulation is evident in same subpopulation of interneurons [102]. However, SST is unequally involved in two predominant neurodegenerative disorders with a very strong

involvement in AD pathology but quite weaker participation in PD. In early stages of AD, SST is reduced in olfactory areas whereas it is preserved in non-demented PD cases [102]. Further analysis of SST related olfactory deficiencies will pave the way

Olfactory dysfunctions unrelated to blocked nasal passages are present in a significant percentage of Covid-19 patients [103–105]. Altered expression of SARS-CoV-2 entry genes in supporting cells of the olfactory epithelium has been proposed

The mammalian olfactory bulb has been termed the "brain inside the brain", due to the presence of sensory inputs, neuronal lamination and contribution of new neural elements throughout the lifetime [108]. It plays a pivotal role in olfactory processing [8, 109]. In addition to AD, PD, MCI and depressive disorders, inadequate and/or improper olfactory function together with impaired olfactory processing exist in many other neurodegenerative and neuropsychiatric disorders. For instance, in the case of multiple sclerosis (MS), prevalence of olfactory dysfunction ranges from 20 to 45% of the MS population. However, the mechanism of loss of olfaction remains unknown, except for decreased olfactory bulb and brain volume [110, 111]. In patients with a diagnosis of a behavioral FTD variant, OI and odor discrimination did not show any difference from control cases, but there was a significant difference in the odor association test. It has been attributed to impaired olfactory processing [112]. Within the healthy population, impulsive tendencies exhibit some link to olfactory defects [113]. Narcolepsy is associated with hypocretin deficiency of the limbic system. Despite genetic predisposition, it has been postulated to increase by environmental substances that may access the olfactory

as a mechanism underlying COVID-19-associated anosmia [106, 107].

bulb, triggering neuroinflammation and induce neurodegeneration [114].

Single cell transcriptome analysis during mouse olfactory neurogenesis in early development reveals that expression of olfactory receptor (OR) genes becomes progressively restricted to one gene per neuron in each mature neuron instead of several receptor genes that express in immature neurons [115, 116]. Expression of a single OR allele in olfactory sensory neurons is the outcome of coalescence of multiple intergenic enhancers to a multi-chromosomal hub that allows the expression of a single OR allele while the remaining OR genes converge into few heterochromatic compartments leading to effective transcriptional silencing [117]. Age associated chromosomal breakage and DNA damage lead to an increase in markers of genome instability [118] and requires many layers of regulatory functions such as inducing senescence [48], reducing accumulation of DNA damage and enhancing DNA repair pathways [119]. Genome protection from DNA damage to minimize

**104**

This work was supported in part by grants from the National Science Foundation (NSF IOS-1355034) and the **Charles and Mary** Latham Trust Fund.
