Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by motor impairment, but early-stages are dominated by non-motor symptoms such as olfactory dysfunction, anxiety, depression, and cognitive deficits, which are poorly replicated by currently studied animal models. In animal models of PD, stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the substantia nigra induces dopaminergic neurodegeneration, which consequently produces motor deficits; but inadequately representing early non-motor features. Emerging evidence suggests that transient receptor potential melastatin 3 (TRPM3)-associated neuroinflammation may contribute to early PD progression and non-motor symptoms. However, its role in early-stage PD, particularly in non-invasive models, remains unclear. Therefore, this study aimed to develop a novel non-invasive early-stage PD model and investigate TRPM3-associated neuroinflammation. Early-stage PD-like symptoms were induced in rats by intranasal 6-OHDA (5 mg/nostril) for 7 consecutive days and evaluated using the buried food, odor identification, open field, and elevated plus maze tests. Tyrosine hydroxylase (TH) immunoreactivity was quantified in the olfactory bulb, ventral striatum, and posterior ventral tegmental area (pVTA). TRPM3 immunoreactivity, neuroplastic changes in the pVTA and interleukin-1β (IL-1β) in the ventral striatum and pVTA were also assessed. 6-OHDA produced behavioral deficits, reduced TH immunoreactivity, increased TRPM3, elevated IL-1β, and impaired pVTA neuroplasticity. Intraperitoneal (i.p.) treatment of TRPM3 inhibitor primidone (2.5, 5, and 10 mg/kg) significantly reversed these alterations, and standard pramipexole (3 mg/kg, i.p.) also reduced behavioral deficits. Overall, the intranasal 6-OHDA model reproduces key features of early-stage PD, including non-motor deficits, dopaminergic dysfunction, TRPM3-associated neuroinflammation, and impaired neuroplasticity, providing a simple and clinically relevant platform for therapeutic evaluation.

BackgroundOlfactory dysfunction is a common disorder linked to adverse health outcomes and is more prevalent in men than in women. Sex steroid hormones have been proposed to underlie these sex differences, but population-based evidence remains limited.ObjectiveTo examine the associations of serum free testosterone and estradiol with olfactory dysfunction in US adults and to explore sex and age differences.MethodsWe analyzed data from 2750 participants (1373 men and 1377 women) aged ≥40 years in the 2013-2014 National Health and Nutrition Examination Survey. Olfactory function was assessed using the 8-item Pocket Smell Test. Dysfunction was defined as a score ≤5. Serum sex hormones were measured by mass spectrometry, and free testosterone was calculated from total testosterone, sex hormone-binding globulin, and albumin. Survey-weighted multivariable logistic and linear regression models evaluated associations between hormone quartiles and olfactory dysfunction or test scores, adjusting for sociodemographic factors, lifestyle, comorbidities, and olfaction-related medical history.ResultsThe weighted prevalence of olfactory dysfunction was 16.49% in men and 10.58% in women. Among men, higher free testosterone was associated with lower odds of olfactory dysfunction (adjusted odds ratio for highest vs lowest quartile, 0.47; 95% CI, 0.26-0.83; P for trend = .004), particularly in those older than 50 years. No significant associations were observed for free testosterone or estradiol in women.ConclusionHigher free testosterone levels are associated with a lower prevalence of olfactory dysfunction in men, whereas no clear hormone-olfaction associations were detected in women. Circulating testosterone may contribute to sex differences in olfactory performance.

The nasal epithelium is a complex tissue composed of both respiratory and olfactory tissue, and is constantly exposed to environmental insults, including toxins and pathogens. The main olfactory epithelium (MOE) serves as the critical site for olfaction, or sense of smell. Dysfunction at this critical barrier tissue can result in partial or total loss of olfactory function, resulting in significant impact to quality of life. The MOE is heterogeneous, comprised of many cell types including olfactory sensory neurons, support cells, and immune cells. It is not well understood how these diverse cell types in the MOE interact to regulate this tissue during homeostasis, and during times of injury and inflammation. We investigated how environmental olfactory exposures impact cell type specific transcriptional responses in the mouse MOE. We performed single-cell RNA sequencing (scRNA-seq) of the MOE following controlled environmental exposure to both well-known odorants and allergens. We identified major cell types and subtypes within the MOE, and identified transcriptional changes in response to the olfactory exposures. We identified transcriptional changes in OSNs, sustentacular cells, and resident immune cells to each condition. This indicated that environmental olfactory exposures drive changes to multiple cell types in the MOE. To our knowledge, this is the first study to identify effects of environmental olfactory exposures on cell-type specific transcription at homeostasis. These findings highlight the potential importance of multi-cellular interactions and communication in regulation of the olfactory epithelium.

People with Lewy body disease exhibit heterogeneous clinical symptoms, diverse patterns of neurodegeneration on imaging and variable Lewy body pathology at post-mortem. The brain-first versus body-first (BvB) model provides a unifying framework that may account for much of this variability. According to the BvB model, Lewy pathology originates either in autonomic nerves of the gut or other peripheral neurons (body first) or in the olfactory bulb with subsequent spread to the limbic system (brain first). Both subtypes are thought to begin largely outside the CNS, possibly triggered by exogenous factors such as infectious agents or toxins. The model is supported by several observations. First, some individuals develop autonomic dysfunction and sleep disorders years before diagnosis, whereas other individuals experience these symptoms only after diagnosis. Second, in people with prodromal sleep disorders, cardiac sympathetic denervation precedes nigrostriatal degeneration by approximately a decade, whereas in individuals without sleep disorders, these systems degenerate in the opposite sequence. Third, post-mortem studies often reveal bottom-up or top-down gradients of Lewy pathology, consistent with body-first versus olfactory-first origins. This Review provides a critical appraisal of the BvB model, highlighting supporting evidence and current limitations. The article also considers implications for diagnostics, therapy and prevention, and outlines key avenues for future research.

Neurogenesis, a critical process implicated in diverse brain disorders, is greatly diminished in the adult human brain, complicating direct investigations into its mechanistic role in disease. In the olfactory epithelium (OE), olfactory sensory neurons (OSNs) maintain homeostasis via continual neurogenesis throughout life, providing a niche to investigate neurogenesis in vivo. However, the molecular mechanisms underlying this process and its similarities to brain neurogenesis remain largely unknown. Here, we performed single-nucleus RNA-seq on specimens of human OE from 6 living adult donors, yielding high-quality transcriptomes representing 145,720 cells. Integrating with two independent OE single-cell transcriptomics datasets, different developmental stages of OSNs were identified, including neural precursor cells (globose basal cells, GBCs), as well as immature and mature OSNs. We inferred trajectories and assessed the transcriptional and regulatory dynamics of OSN development. Genes and transcription factors (TFs) involved in regulating neuronal differentiation and neurogenesis were highly expressed in GBCs and early immature OSNs, but were downregulated in mature neurons. OSNs and cortical excitatory neurons exhibited convergence during early developmental stages, including dynamically expressed genes, TFs, biological processes, and polygenic enrichment for psychiatric disorders. In addition, expression trajectory alignment between OSNs and cortical excitatory neurons (CENs) revealed that OSNs could partially track the expression dynamics of autism spectrum disorder (ASD) risk genes in CENs. Overall, cells in the neuronal lineage of the OE represent a potential proxy to study gene programs involved in neurogenesis in the human brain, providing an accessible model for investigating neurodevelopmental dysfunction in psychiatric disorders.

Ectopic olfactory receptors (ORs) are G protein-coupled chemosensors expressed outside the olfactory epithelium, where they may couple local chemical inputs to cell-specific signaling. The oral cavity is continuously exposed to food-derived compounds, microbial metabolites, volatile organic compounds, and inflammation-associated metabolites, yet the molecular roles of oral ORs remain incompletely defined. This review critically synthesizes current evidence for OR expression and signaling in oral tissues and associated cell populations, with emphasis on ligand-receptor-signaling relationships and disease relevance. Functional OR signaling has been demonstrated in mammalian taste cells, while emerging transcriptomic studies in oral mucosa and transcriptomic/localization studies in the periodontal ligament indicate OR-related programs during tissue-specific or repair-associated states. Candidate metabolic axes, including short-chain fatty acids and lactate linked to OR51E1/OR51E2/Olfr78-related pathways in non-oral models, provide testable mechanistic hypotheses for microbiome-host communication in periodontitis and oral cancer; however, direct causal validation in oral disease models remains limited. We propose an evidence-tiered framework integrating spatial expression mapping, metabolomics-guided deorphanization, receptor perturbation, and longitudinal oral-fluid profiling. Oral ORs should currently be regarded as candidate molecular modulators and components of multimodal biomarker strategies rather than validated standalone diagnostic or therapeutic targets.

Hypoxic-ischemic injury is a major cause of olfactory dysfunction, yet the cellular and morphological mechanisms underlying this sensory loss remain poorly understood. Here, we investigated the structural, cellular, and functional effects of acute hypoxic exposure on the olfactory system of adult zebrafish (Danio rerio) of both sexes, a model organism with remarkable neuroregenerative capacity. Fish were subjected to 15 minutes of acute severe hypoxia (0.8 mg/L dissolved oxygen) and assessed at 1- and 5-days post-hypoxia (dph). We evaluated olfactory function by means of cadaverine-evoked aversive behavioral assays. Structural and morphological integrity and inflammation of the olfactory epithelium (OE) and olfactory bulb (OB) were characterized using immunohistochemistry, histological stainings, and a 2,3,5-triphenyltetrazolium chloride (TTC) colorimetric assay. Acute hypoxic exposure impaired olfactory-mediated behaviors without affecting locomotion or exploratory behavior. In the peripheral OE, hypoxia caused neurodegeneration, disruption of the nasal mucus layer, and robust leukocytic infiltration. We observed reduced mitochondrial dehydrogenase activity in the olfactory bulb (OB) along with reactive astrogliosis. Olfactory function recovered by 5 days, coinciding with full restoration of OE morphology, and supported by a strong proliferative response. These findings reveal a coordinated degenerative and regenerative response to hypoxia across the olfactory axis, with implications for understanding hypoxia-induced sensory loss and neural repair.Significance Statement This work addresses an important gap in knowledge regarding the mechanisms linking hypoxic insult and olfactory dysfunction. By using adult zebrafish, an extraordinarily regenerative vertebrate, it also provides insight into neuronal repair and regenerative processes supporting olfactory recovery. The novelty of our study resides in that, to our knowledge, there are no studies that provide a comprehensive characterization of the effects of hypoxia in the olfactory system across molecular, histological, and functional levels. These findings advance our understanding of hypoxia-induced sensory neurodegeneration and regeneration, and highlight the zebrafish olfactory system as a powerful model for investigating neural repair mechanisms relevant to hypoxic-ischemic brain injury.