Multielectrode recordings of cockroach antennal lobe neurons in response to temporal dynamics of odor concentrations.

The initial representation of the instantaneous temporal information about food odor concentration in the primary olfactory center, the antennal lobe, was examined by simultaneously recording the activity of antagonistic ON and OFF neurons with 4-channel tetrodes. During presentation of pulse-like concentration changes, ON neurons encode the rapid concentration increase at pulse onset and the pulse duration, and OFF neurons the rapid concentration decrease at pulse offset and the duration of the pulse interval. A group of ON neurons establish a concentration-invariant representation of odor pulses. The responses of ON and OFF neurons to oscillating changes in odor concentration are determined by the rate of change in dependence on the duration of the oscillation period. By adjusting sensitivity for fluctuating concentrations, these neurons improve the representation of the rate of the changing concentration. In other ON and OFF neurons, the response to changing concentrations is invariant to large variations in the rate of change due to variations in the oscillation period, facilitating odor identification in the antennal-lobe. The independent processing of odor identity and the temporal dynamics of odor concentration may speed up processing time and improve behavioral performance associated with plume tracking, especially when the air is not moving.

Olfactory sensory experience regulates gliomagenesis via neuronal IGF1.

Animals constantly receive various sensory stimuli, such as odours, sounds, light and touch, from the surrounding environment. These sensory inputs are essential for animals to search for food and avoid predators, but they also affect their physiological status, and may cause diseases such as cancer. Malignant gliomas-the most lethal form of brain tumour1-are known to intimately communicate with neurons at the cellular level2,3. However, it remains unclear whether external sensory stimuli can directly affect the development of malignant glioma under normal living conditions. Here we show that olfaction can directly regulate gliomagenesis. In an autochthonous mouse model that recapitulates adult gliomagenesis4-6 originating in oligodendrocyte precursor cells (OPCs), gliomas preferentially emerge in the olfactory bulb-the first relay of brain olfactory circuitry. Manipulating the activity of olfactory receptor neurons (ORNs) affects the development of glioma. Mechanistically, olfaction excites mitral and tufted (M/T) cells, which receive sensory information from ORNs and release insulin-like growth factor 1 (IGF1) in an activity-dependent manner. Specific knockout of Igf1 in M/T cells suppresses gliomagenesis. In addition, knocking out the IGF1 receptor in pre-cancerous mutant OPCs abolishes the ORN-activity-dependent mitogenic effects. Our findings establish a link between sensory experience and gliomagenesis through their corresponding sensory neuronal circuits.

Integrated age-related immunohistological changes occur in human olfactory epithelium and olfactory bulb.

Olfactory epithelium (OE) is capable of lifelong regeneration due to presence of basal progenitor cells that respond to injury or neuronal loss with increased activity. However, this capability diminishes with advancing age and a decrease in odor perception in older individuals is well established. To characterize changes associated with age in the peripheral olfactory system, an in-depth analysis of the OE and its neuronal projections onto the olfactory bulb (OB) as a function of age was performed. Human olfactory tissue autopsy samples from 36 subjects with an average age of 74.1 years were analyzed. Established cell type-specific antibodies were used to identify OE component cells in whole mucosal sheets and epithelial sections as well as glomeruli and periglomerular structures in OB sections. With age, a reduction in OE area occurs across the mucosa progressing in a posterior-dorsal direction. Deterioration of the olfactory system is accompanied with diminution of neuron-containing OE, mature olfactory sensory neurons (OSNs) and OB innervation. On an individual level, the neuronal density within the epithelium appears to predict synapse density within the OB. The innervation of the OB is uneven with higher density at the ventral half that decreases with age as opposed to stable innervation at the dorsal half. Respiratory metaplasia, submucosal cysts, and neuromata, were commonly identified in aged OE. The finding of respiratory metaplasia and aneuronal epithelium with reduction in global basal cells suggests a progression of stem cell quiescence as an underlying pathophysiology of age-related smell loss in humans. KEY POINTS: A gradual loss of olfactory sensory neurons with age in human olfactory epithelium is also reflected in a reduction in glomeruli within the olfactory bulb. This gradual loss of neurons and synaptic connections with age occurs in a specific, spatially inhomogeneous manner. Decreasing mitotically active olfactory epithelium basal cells may contribute to age-related neuronal decline and smell loss in humans.

Heterogeneous distribution of mature olfactory sensory neurons in human olfactory epithelium.

BACKGROUND: The olfactory cleft (OC) comprising the olfactory epithelium (OE) is the most important anatomical location for olfactory function. Endoscopic sinus surgery (ESS) is used to treat diseases related to the OC and improve olfactory dysfunction. However, iatrogenic OE injury occasionally occurs. Comprehensive knowledge of the olfactory region is required to avoid damage to the OE during endoscopic procedures. METHODS: Immunohistochemistry was performed on olfactory mucosa obtained from the unaffected side of olfactory neuroblastoma surgical specimens. The OE was defined as the epithelium containing mature olfactory sensory neurons (OSNs). The distribution and cell kinetics of the OE were examined. RESULTS: The OE was selectively localized to the anterior two-thirds of the superior turbinate (ST) and in the nasal septum (NS) just opposite to the ST; the OE was not detected within the mucosa of the superior meatus. The density of mature OSNs was high at the ethmoid tegmen but gradually decreased with distance from the ethmoid tegmen. The extent of cell death and proliferation was relatively even across the OE. Analysis of airflow profiles revealed that resection of inferior ST does not decrease airflow to the OC. CONCLUSION: The results indicate that the distribution and degree of differentiation of mature OSNs are heterogenous throughout the OE. Epithelial resection of the anterior or superior ST has the potential to damage olfactory function. Resection of the inferior or posterior ST or widening of the superior meatus is a safer alternative that does not damage mature OSNs or alter airflow to the OC.

An Ancient Adenosine Receptor Gains Olfactory Function in Bony Vertebrates.

Nucleotides are an important class of odorants for aquatic vertebrates such as frogs and fishes, but also have manifold signaling roles in other cellular processes. Recently, an adenosine receptor believed to belong to the adora2 clade has been identified as an olfactory receptor in zebrafish. Here, we set out to elucidate the evolutionary history of both this gene and its olfactory function. We have performed a thorough phylogenetic study in vertebrates, chordates and their sister group, ambulacraria, and show that the origin of the zebrafish olfactory receptor gene can be traced back to the most recent common ancestor of all three groups as a segregate sister clade (adorb) to the adora gene family. Eel, carp, and clawed frog all express adorb in a sparse and distributed pattern within their olfactory epithelium very similar to the pattern observed for zebrafish that is, consistent with a function as olfactory receptor. In sharp contrast, lamprey adorb-expressing cells are absent from the sensory region of the lamprey nose, but form a contiguous domain directly adjacent to the sensory region. Double-labeling experiments confirmed the expression of lamprey adorb in nonneuronal cells and are consistent with an expression in neuronal progenitor cells. Thus, adorb may have undergone a switch of function in the jawed lineage of vertebrates towards a role as olfactory receptor.

The cyclic AMP signaling pathway in the rodent main olfactory system.

Odor perception begins with the detection of odorant molecules by the main olfactory epithelium located in the nasal cavity. Odorant molecules bind to and activate a large family of G-protein-coupled odorant receptors and trigger a cAMP-mediated transduction cascade that converts the chemical stimulus into an electrical signal transmitted to the brain. Morever, odorant receptors and cAMP signaling plays a relevant role in olfactory sensory neuron development and axonal targeting to the olfactory bulb. This review will first explore the physiological response of olfactory sensory neurons to odorants and then analyze the different components of cAMP signaling and their different roles in odorant detection and olfactory sensory neuron development.

COVID-19 and chronic fatigue syndrome: Is the worst yet to come?

There has been concern about possible long-term sequelae resembling myalgic encephalomyelitis/chronic fatigue syndrome in COVID-19 patients. Clarifying the mechanisms underlying such a "post-COVID-19 fatigue syndrome" is essential for the development of preventive and early treatment methods for this syndrome. In the present paper, by integrating insights pertaining to the glymphatic system and the nasal cerebrospinal fluid outflow pathway with findings in patients with chronic fatigue syndrome, idiopathic intracranial hypertension, and COVID-19, I provide a coherent conceptual framework for understanding the pathophysiology of post-COVID-19 fatigue syndrome. According to this hypothesis, this syndrome may result from damage to olfactory sensory neurons, causing reduced outflow of cerebrospinal fluid through the cribriform plate, and further leading to congestion of the glymphatic system with subsequent toxic build-up within the central nervous system. I further postulate that patients with post-COVID-19 fatigue syndrome may benefit from cerebrospinal fluid drainage by restoring glymphatic transport and waste removal from the brain. Obviously, further research is required to provide further evidence for the presence of this post-viral syndrome, and to provide additional insight regarding the relative contribution of the glymphatic-lymphatic system to it. Other mechanisms may also be involved. If confirmed, the glymphatic-lymphatic system could represent a target in combating post-COVID-19 fatigue syndrome. Moreover, further research in this area could also provide new insights into the understanding of chronic fatigue syndrome.

The evolutionary origins of the vertebrate olfactory system.

Vertebrates develop an olfactory system that detects odorants and pheromones through their interaction with specialized cell surface receptors on olfactory sensory neurons. During development, the olfactory system forms from the olfactory placodes, specialized areas of the anterior ectoderm that share cellular and molecular properties with placodes involved in the development of other cranial senses. The early-diverging chordate lineages amphioxus, tunicates, lampreys and hagfishes give insight into how this system evolved. Here, we review olfactory system development and cell types in these lineages alongside chemosensory receptor gene evolution, integrating these data into a description of how the vertebrate olfactory system evolved. Some olfactory system cell types predate the vertebrates, as do some of the mechanisms specifying placodes, and it is likely these two were already connected in the common ancestor of vertebrates and tunicates. In stem vertebrates, this evolved into an organ system integrating additional tissues and morphogenetic processes defining distinct olfactory and adenohypophyseal components, followed by splitting of the ancestral placode to produce the characteristic paired olfactory organs of most modern vertebrates.

Olfactory marker protein directly buffers cAMP to avoid depolarization-induced silencing of olfactory receptor neurons.

Olfactory receptor neurons (ORNs) use odour-induced intracellular cAMP surge to gate cyclic nucleotide-gated nonselective cation (CNG) channels in cilia. Prolonged exposure to cAMP causes calmodulin-dependent feedback-adaptation of CNG channels and attenuates neural responses. On the other hand, the odour-source searching behaviour requires ORNs to be sensitive to odours when approaching targets. How ORNs accommodate these conflicting aspects of cAMP responses remains unknown. Here, we discover that olfactory marker protein (OMP) is a major cAMP buffer that maintains the sensitivity of ORNs. Upon the application of sensory stimuli, OMP directly captured and swiftly reduced freely available cAMP, which transiently uncoupled downstream CNG channel activity and prevented persistent depolarization. Under repetitive stimulation, OMP-/- ORNs were immediately silenced after burst firing due to sustained depolarization and inactivated firing machinery. Consequently, OMP-/- mice showed serious impairment in odour-source searching tasks. Therefore, cAMP buffering by OMP maintains the resilient firing of ORNs.

Olfactory receptor gene abundance in invasive breast carcinoma.

Expression of olfactory receptors (ORs) has been reported in many human tissues outside the nasal epithelium. ORs have been validated as biomarkers in prostate cancer. In breast cancer, however, the expression and role of OR genes remain understudied. We examined the significance of OR transcript abundance in a large invasive breast carcinoma population and identified two OR genes, OR2W3 and OR2B6 to be potentially correlated to breast cancer progression. 960 breast invasive tumors and 56 human breast cancer cell lines were assessed for OR gene expression and 21 OR genes were highly abundant among 198 cases. Our transcriptome analysis discovered three significantly abundant OR genes among three sub-populations of invasive breast carcinoma patients. OR2W3 was correlated with invasion genes and basal-like subtype whereas OR2B6 was correlated with proliferation genes and luminal A subtype. Analyzing the OR gene upregulation among breast cancer cell lines showed that OR2B6 and OR2W3 were abundant similar to invasive breast tumors. Our study suggests that specific OR genes may be correlated with breast cancer characteristics, making ORs potential new diagnostic, and/or treatment markers. This study suggests future directions for the exploration of a role for ORs in the mechanisms of breast cancer proliferation and progression.

Caloric restriction reduces basal cell proliferation and results in the deterioration of neuroepithelial regeneration following olfactotoxic mucosal damage in mouse olfactory mucosa.

The effects of caloric restriction (CR) on cell dynamics and gene expression in the mouse olfactory neuroepithelium are evaluated. Eight-week-old male C57BL/6 mice were fed either control pellets (104 kcal/week) or CR pellets (67 kcal/week). The cytoarchitecture of the olfactory neuroepithelium in the uninjured condition and its regeneration after injury by an olfactotoxic chemical, methimazole, were compared between mice fed with the control and CR diets. In the uninjured condition, there were significantly fewer olfactory marker protein (OMP)-positive olfactory receptor neurons and Ki67-positive proliferating basal cells at 3 months in the CR group than in the control group. The number of Ki67-positive basal cells increased after methimazole-induced mucosal injury in both the control and the CR groups, but the increase was less robust in the CR group. The recovery of the neuroepithelium at 2 months after methimazole administration was less complete in the CR group than in the control group. These histological changes were region-specific. The decrease in the OMP-positive neurons was prominent in the anterior region of the olfactory mucosa. Gene expression analysis using a DNA microarray and quantitative real-time polymerase chain reaction demonstrated that the expression levels of two inflammatory cytokines, interleukin-6 and chemokine ligand 1, were elevated in the olfactory mucosa of the CR group compared with the control group. These findings suggest that CR may be disadvantageous to the maintenance of the olfactory neuroepithelium, especially when it is injured.

Olfactory sensory neurons mediate ultrarapid antiviral immune responses in a TrkA-dependent manner.

The nervous system regulates host immunity in complex ways. Vertebrate olfactory sensory neurons (OSNs) are located in direct contact with pathogens; however, OSNs' ability to detect danger and initiate immune responses is unclear. We report that nasal delivery of rhabdoviruses induces apoptosis in crypt OSNs via the interaction of the OSN TrkA receptor with the viral glycoprotein in teleost fish. This signal results in electrical activation of neurons and very rapid proinflammatory responses in the olfactory organ (OO), but dampened inflammation in the olfactory bulb (OB). CD8α+ cells infiltrate the OO within minutes of nasal viral delivery, and TrkA blocking, but not caspase-3 blocking, abrogates this response. Infiltrating CD8α+ cells were TCRαß T cells with a nonconventional phenotype that originated from the microvasculature surrounding the OB and not the periphery. Nasal delivery of viral glycoprotein (G protein) recapitulated the immune responses observed with the whole virus, and antibody blocking of viral G protein abrogated these responses. Ablation of crypt neurons in zebrafish resulted in increased susceptibility to rhabdoviruses. These results indicate a function for OSNs as a first layer of pathogen detection in vertebrates and as orchestrators of nasal-CNS antiviral immune responses.

Loss of BMI1 in mature olfactory sensory neurons leads to increased olfactory basal cell proliferation.

BACKGROUND: Damage to olfactory sensory neurons (OSNs), situated within the neuroepithelium of the olfactory cleft, may be associated with anosmia. Although their direct contact with the nasal airspace make OSNs vulnerable to injury and death, multiple mechanisms maintain epithelium integrity and olfactory function. We hypothesized that BMI1, a polycomb protein found to be enriched in OSNs, may function in neuroprotection. Here, we explored BMI1 function in a mouse model. METHODS: Utilizing a mouse genetic approach to delete Bmi1 selectively in mature OSNs, we investigated changes in OE homeostasis by performing immunohistochemical, biochemical, and functional assays. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunostaining, and electro-olfactograms were used to compare gene expression, cell composition, and olfactory function in OSN-specific BMI1 knockout mice (n = 3 to 5) and controls. Chromatin studies were also performed to identify protein-DNA interactions between BMI1 and its target genes (n = 3). RESULTS: OSN-specific BMI1 knockout led to increased neuron death and basal cell activation. Chromatin studies suggested a mechanism of increased neurodegeneration due to de-repression of a pro-apoptosis gene, p19ARF. Despite the increased turnover, we found that olfactory neuroepithelium thickness and olfactory function remained intact. Our studies also revealed the presence of additional polycomb group proteins that may compensate for the loss of BMI1 in mature OSNs. CONCLUSION: The olfactory neuroepithelium employs multiple mechanisms to maintain epithelial homeostasis. Our findings provide evidence that in a mouse model of BMI1 deletion, the overall integrity and function of the olfactory neuroepithelium are not compromised, despite increased neuronal turnover, reflecting a remarkable reparative capacity to sustain a critical sensory system.

Electrical properties of cells from human olfactory epithelium.

OBJECTIVE: The electrical properties of olfactory cells (OCs) are typically examined using animals such as newts, mice, and frogs, with few studies on human OCs. This study investigated the electrical properties of human cells from olfactory epithelium (hCOEs) obtained from subjects of olfactory epithelium showing no clinical symptoms during endoscopic sinus surgery. METHODS: hCOEs were isolated by collagenase treatment for whole-cell patch clamp recording. The identity of the cells was confirmed by immunohistochemistry with an antibody against olfactory maker protein. Under the voltage clamp with the whole-cell recording configuration, the voltage-gated currents of isolated hCOEs were recorded when the membrane potential was depolarized from a holding potential of -100 mV in a stepwise manner between -90 mV and + 40 mV. RESULTS: Only one of 14 hCOE samples expressed a transient inward current at the depolarizing voltage step that was activated by depolarization beyond -40 mV and reached a peak at -30 mV. Delayed and sustained outward currents (444 ± 106 pA at + 40 mV pulse; n = 20) were suppressed by tetraethyl ammonium (n = 3), which is consistent with the properties of newt OCs. CONCLUSIONS: Most hCOEs did not exhibit the transient inward current observed in animal models. These findings provide insight into the physiological basis of the unique aspects of human olfactory signal transduction.

BBS4 is required for intraflagellar transport coordination and basal body number in mammalian olfactory cilia.

Bardet-Beidl syndrome (BBS) manifests from genetic mutations encoding for one or more BBS proteins. BBS4 loss impacts olfactory ciliation and odor detection, yet the cellular mechanisms remain unclear. Here, we report that Bbs4-/- mice exhibit shorter and fewer olfactory sensory neuron (OSN) cilia despite retaining odorant receptor localization. Within Bbs4-/- OSN cilia, we observed asynchronous rates of IFT-A/B particle movements, indicating miscoordination in IFT complex trafficking. Within the OSN dendritic knob, the basal bodies are dynamic, with incorporation of ectopically expressed centrin-2 and γ-tubulin occurring after nascent ciliogenesis. Importantly, BBS4 loss results in the reduction of basal body numbers separate from cilia loss. Adenoviral expression of BBS4 restored OSN cilia lengths and was sufficient to re-establish odor detection, but failed to rescue ciliary and basal body numbers. Our results yield a model for the plurality of BBS4 functions in OSNs that includes intraciliary and periciliary roles that can explain the loss of cilia and penetrance of ciliopathy phenotypes in olfactory neurons.

Stimulus dynamics-dependent information transfer of olfactory and vomeronasal sensory neurons in mice.

The parallel processing of chemical signals by the main olfactory system and the vomeronasal system has been known to control animal behavior. The physiological significance of peripheral parallel pathways consisting of olfactory sensory neurons and vomeronasal sensory neurons is not well understood. Here, we show complementary characteristics of the information transfer of the olfactory sensory neurons and vomeronasal sensory neurons. A difference in excitability between the sensory neurons was revealed by patch-clamp experiments. The olfactory and vomeronasal sensory neurons showed phasic and tonic firing, respectively. Intrinsic channel kinetics determining firing patterns was demonstrated by a Hodgkin-Huxley-style computation. Our estimation of the information carried by action potentials during one cycle of sinusoidal stimulation with variable durations revealed distinct characteristics of information transfer between the sensory neurons. Phasic firing of the olfactory sensory neurons was suitable to carry information about rapid changes in a shorter cycle (<200 ms). In contrast, tonic firing of the vomeronasal sensory neurons was able to convey information about smaller stimuli changing slowly with longer cycles (>500 ms). Thus, the parallel pathways of the two types of sensory neurons can convey information about a wide range of dynamic stimuli. A combination of complementary characteristics of olfactory information transfer may enhance the synergy of the interaction between the main olfactory system and the vomeronasal system.

Loss of odor-induced c-Fos expression of juxtaglomerular activity following maintenance of mice on fatty diets.

Diet-induced obesity (DIO) decreases the number of OMP+ olfactory sensory neurons (OSN) in the olfactory epithelium by 25% and reduces correlate axonal projections to the olfactory bulb (OB). Whether surviving OSNs have equivalent odor responsivity is largely unknown. Herein, we utilized c-fos immediate-early gene expression to map neuronal activity and determine whether mice weaned to control (CF), moderately-high fat (MHF), or high-fat (HF) diet for a period of 6 months had changes in odor activation. Diet-challenged M72-IRES-tau-GFP mice were exposed to either a preferred M72 (Olfr160) ligand, isopropyl tiglate, or clean air in a custom-made Bell-jar infusion chamber using an alternating odor exposure pattern generated by a picosprizer™. Mice maintained on fatty diets weighed significantly more and cleared glucose less efficiently as determined by an intraperitoneal glucose tolerance test (IPGTT). The number of juxtaglomerular cells (JGs) decreased following maintenance of the mice on the MHF diet for cells surrounding the medial but not lateral M72 glomerulus within a 4 cell-column distance. The percentage of c-fos + JGs surrounding the lateral M72 glomerulus decreased in fat-challenged mice whereas those surrounding the medial glomerulus were not affected by diet. Altogether, these results show an asymmetry in the responsiveness of the 'mirror image' glomerular map for the M72 receptor that shows greater sensitivity of the lateral vs. medial glomerulus upon exposure to fatty diet.

Spatial Determination of Neuronal Diversification in the Olfactory Epithelium.

Neurons in the murine olfactory epithelium (OE) differ by the olfactory receptor they express as well as other molecular phenotypes that are regionally restricted. These patterns can be precisely regenerated following epithelial injury, suggesting that spatial cues within the tissue can direct neuronal diversification. Nonetheless, the permanency and mechanism of this spatial patterning remain subject to debate. Via transplantation of stem and progenitor cells from dorsal OE into ventral OE, we demonstrate that, in mice of both sexes, nonautonomous spatial cues can direct the spatially circumscribed differentiation of olfactory sensory neurons. The vast majority of dorsal transplant-derived neurons express the ventral marker OCAM (NCAM2) and lose expression of NQO1 to match their new location. Single-cell analysis also demonstrates that OSNs adopt a fate defined by their new position following progenitor cell transplant, such that a ventral olfactory receptor is expressed after stem and progenitor cell engraftment. Thus, spatially constrained differentiation of olfactory sensory neurons is plastic, and any bias toward an epigenetic memory of place can be overcome.SIGNIFICANCE STATEMENT Spatially restricted differentiation of olfactory sensory neurons is both key to normal olfactory function and a challenging example of biological specificity. That the stem cells of the olfactory epithelium reproduce the organization of the olfactory periphery to a very close approximation during lesion-induced regeneration begs the question of whether stem cell-autonomous genomic architecture or environmental cues are responsible. The plasticity demonstrated after transfer to a novel location suggests that cues external to the transplanted stem and progenitor cells confer neuronal identity. Thus, a necessary prerequisite is satisfied for using engraftment of olfactory stem and progenitor cells as a cellular therapeutic intervention to reinvigorate neurogenesis whose exhaustion contributes to the waning of olfaction with age.

Therapeutic potential of ectopic olfactory and taste receptors.

Olfactory and taste receptors are expressed primarily in the nasal olfactory epithelium and gustatory taste bud cells, where they transmit real-time sensory signals to the brain. However, they are also expressed in multiple extra-nasal and extra-oral tissues, being implicated in diverse biological processes including sperm chemotaxis, muscle regeneration, bronchoconstriction and bronchodilatation, inflammation, appetite regulation and energy metabolism. Elucidation of the physiological roles of these ectopic receptors is revealing potential therapeutic and diagnostic applications in conditions including wounds, hair loss, asthma, obesity and cancers. This Review outlines current understanding of the diverse functions of ectopic olfactory and taste receptors and assesses their potential to be therapeutically exploited.

Peripheral Gene Therapeutic Rescue of an Olfactory Ciliopathy Restores Sensory Input, Axonal Pathfinding, and Odor-Guided Behavior.

Cilia of olfactory sensory neurons (OSNs) are the primary site of odor binding; hence, their loss results in anosmia, a clinical manifestation of pleiotropic ciliopathies for which there are no curative therapies. We used OSN-specific Ift88 knock-out mice (Ift88osnKO) of both sexes to examine the mechanisms of ciliopathy-induced olfactory dysfunction and the potential for gene replacement to rescue odorant detection, restore olfactory circuitry, and restore odor-guided behaviors. Loss of OSN cilia in Ift88osnKO mice resulted in substantially reduced odor detection and odor-driven synaptic activity in the olfactory bulb (OB). Defects in OSN axon targeting to the OB were also observed in parallel with aberrant odor-guided behavior. Intranasal gene delivery of wild-type IFT88 to Ift88osnKO mice rescued OSN ciliation and peripheral olfactory function. Importantly, this recovery of sensory input in a limited number of mature OSNs was sufficient to restore axonal targeting in the OB of juvenile mice, and with delayed onset in adult mice. In addition, restoration of sensory input re-established course odor-guided behaviors. These findings highlight the spare capacity of the olfactory epithelium and the plasticity of primary synaptic input into the central olfactory system. The restoration of peripheral and central neuronal function supports the potential for treatment of ciliopathy-related anosmia using gene therapy.SIGNIFICANCE STATEMENT Ciliopathies, for which there are no curative therapies, are genetic disorders that alter cilia morphology and/or function in numerous tissue types, including the olfactory system, leading to sensory dysfunction. We show that in vivo intranasal gene delivery restores peripheral olfactory function in a ciliopathy mouse model, including axonal targeting in the juvenile and adult olfactory bulb. Gene therapy also demonstrated restoration of olfactory perception by rescuing odor-guided behaviors. Understanding the therapeutic window and viability for gene therapy to restore odor detection and perception may facilitate translation of therapies to ciliopathy patients with olfactory dysfunctions.