Open research questions in Olfactory and Sensory Function Studies

What the literature leaves open

• Olfactory habituation at the bulbar level involves NMDA receptor-dependent synaptic adaptation, but the upstream sensory mechanisms—specifically how odorant receptor desensitization, odorant metabolism, or receptor trafficking interact with bulbar habituation circuits—have not been characterized. The relationship between peripheral odorant receptor dynamics and central habituation remains unexplored.

  Rapid odorant metabolism organizes identity- and timing-based odor representations by olfactory bulb inputs and outputs · 2026 · DOI

• The structural basis of odorant receptor selectivity has been elucidated for individual human receptors and insect heteromeric complexes, but no systematic framework exists for predicting how sequence variations across the ~400 human odorant receptors determine ligand specificity and antagonism. Prior structural studies examine one or two receptors in isolation without addressing cross-receptor generalization.

  Allosteric Gating Mechanism Regulates Odorant Selectivity and Antagonism in Odorant Receptors · 2026 · DOI

• While odorant metabolism generates secondary odorants that reshape odor representations, the molecular mechanisms by which odorant-metabolizing enzymes modulate olfactory receptor activation and selectivity remain uncharacterized. Existing work documents that metabolism occurs and affects timing-based coding, but does not explain how primary and secondary metabolites differentially engage specific odorant receptors or allosteric gating mechanisms.

  Rapid odorant metabolism organizes identity- and timing-based odor representations by olfactory bulb inputs and outputs · 2026 · DOI

• Future research should focus on clarify- ing optimal dosing strategies, treatment timing, and patient selection, as well as determining whether PRP offers an additive benefit when combined with established interven- tions such as olfactory training.

  Navigating the efficacy, safety and outcome of intranasal platelet-rich plasma for persistent olfactory loss: a systematic review and meta-analysis · 2026 · DOI

• Few trials were fully randomized or blinded, and patient populations (post-COVID, post-viral non- COVID, post-traumatic) were mixed without consistent subgroup reporting, which reduces certainty and external validity.

  Navigating the efficacy, safety and outcome of intranasal platelet-rich plasma for persistent olfactory loss: a systematic review and meta-analysis · 2026 · DOI

• Objective This scoping review investigated how OT/AT can be used to reduce depressive symptoms, summarized intervention characteristics reported in the literature, and pointed out gaps in the literature.

  Olfactory Training and Aromatherapy for Treating Depressive Symptomatology: A Scoping Review · 2026 · DOI

• The predicted spectra show concordance between receptor discriminative capacity and expression level, and highlight the understudied OR52 family as a potential contributor to primary odor recognition.

  Receptor-Anchored Olfaction Representation through Perception-Consistent Metric Learning · 2026 · DOI

• While activity processing, plasticity and behavioral relevance of the PC have been extensively studied, evidence on the functional properties of the olfactory amygdala is scarce.

  Experience-dependent critical period for synaptic plasticity in the rat olfactory amygdala · 2026 · DOI

• Further investigative research is needed to define the role for regenerative therapies, such as PRP, in treating anosmia associated with neurodegenerative disorders. One of the authors (ZMP) is also investigating endoscopic electrical stimulation to the olfactory epithelium, with potential for regeneration in both the peripheral and central nervous system. Promoting recovery of olfactory pathways in both peripheral and central structures could have relevance to not only smell but also related cognitive functions such as memory and concentration, processes that may help slow neurodegeneration. Controlled studies are necessary to determine efficacy and therapeutic regimens, such as optimal delivery and how many PRP injections may be needed to achieve sustained neuroregeneration and reduced neuroinflammation. Experience in other medical fields suggests that treatment appears safe and well-tolerated, offering a personalized therapeutic option. However, well-designed clinical trials involving both otolaryngologists and neurologists are needed to assess its efficacy for anosmia and potential applicability to clinical treatment of neurodegenerative disorders.

  Regenerating smell in neurodegenerative disease –translating theory into therapy · 2026 · DOI

• Despite the promising analytical performance of the developed method, certain limitations must be acknowledged. First, the clinical cohort included a relatively small sample size, which serves as a preliminary proof-of-concept rather than a definitive clinical study. Consequently, these findings should be interpreted as suggestive of a potential biochemical association between nasal cyclic nucleotides and olfactory loss. Second, the cross-sectional nature of the current study provides a snapshot of biomarker levels but lacks the external validation required to establish these molecules as primary diagnostic markers. Future research involving larger, multi-center longitudinal cohorts and independent validation sets is essential to confirm the clinical reliability and diagnostic utility of the proposed methodology in routine practice.

  Simultaneous spectrofluorimetric determination of nasal cyclic nucleotides as biochemical markers in post-COVID-19 olfactory dysfunction using supramolecular-enhanced derivative spectroscopy · 2026 · DOI

• (1); our Developmental bypass branch: psychophysical testing limitations however, disability, neurodevelopmental We endorse Trecca et al.’s recognition that psychophysical testing may be limited by age, attention span, or comprehension (1). In children with congenital or syndromic conditions and associated these constraints may be not merely probabilistic but effectively absolute. Children with CS, for instance, frequently present with intellectual disability and developmental delay, prolonged tube feeding, or uncorrected bilateral choanal atresia, each of which can render standard psychophysical assessment [such as UPSIT (7) or Sniffin’ Sticks (8)] impractical. Rather than framing these as mere caveats, we propose a formal ‘developmental bypass’ criterion: clinicians should move directly to adjunctive assessment - without attempting psychophysical testing - when a child (a) has a non-verbal developmental age below approximately four years, (b) cannot reliably follow a two-step verbal command, (c) has uncorrected bilateral choanal atresia precluding nasal airflow, or (d) is receiving prolonged enteral feeding with no established oral intake. These criteria are offered as practical starting points for clinical discussion, not as validated thresholds. Even when supplemented by “self” or “parent” evaluation, as discussed by the authors (1), the literature has shown a lack of agreement between parental assessment and psychophysical olfactory testing. For example, Chalouhi et al. in 2005 found that only 6 of 13 children with CS had parental agreement with paediatric adapted Biolfa psychophysical olfactory testing (9). Another study of communication and language development in CS found that objective severity of the condition did not correlate with parental perceptions of their child’s impairment (10). Parents may calibrate their assessments against their own expectations or lived experience rather than against normative olfactory function, limiting the reliability of proxy-report as a standalone measure (2). Proxy-report nevertheless remains a useful complement to objective methods and should not be abandoned; its limitations simply reinforce the case for the adjunctive pathway outlined below. or exclude identify structural malformations For children routed through the developmental bypass, MRI of the olfactory cleft, anterior skull base, and olfactory bulbs and tracts serves as an important adjunctive investigation, primarily to and developmental anomalies relevant to clinical management (1). We agree with Trecca et al. that MRI findings must be integrated with, rather for, clinical and functional data. As a cautionary note, Weiss et al. demonstrated rare cases of normal olfaction despite apparent olfactory bulb agenesis on MRI (11); although such cases are exceptional and do not diminish MRI utility, they do counsel against inferring functional status from morphology alone. than substituted is not this branch, feasible due that, based on testing factors—a group This has implications beyond CS alone. The diagnostic pathway currently does not include a dedicated branch for children in whom to standard psychophysical neurodevelopmental the Payandeh et al. scoping review, may account for at least 40% of congenital paediatric OD cases (5). We propose that a dedicated developmental bypass branch be added to the algorithm for this subgroup. Within the pathway should direct clinicians toward: (i) a heightened index of suspicion at history and examination; (ii) adjunctive MRI in selected cases to characterise structural anomalies; (iii) proxy-report interpreted in full awareness of its documented limitations; and (iv) OERPs, which offer objective, non-volitional assessment of olfactory pathway function and are particularly well-suited to children who cannot participate in standard testing. Critically, this branch should function as a developmental bridge: as children mature cognitively, or appropriate psychophysical tools become available, the pathway should direct clinicians back toward psychophysical assessment.

  Commentary: Clinical evaluation of pediatric olfactory disorders: a review from etiology to management · 2026 · DOI

• Inter-individual differences in odorant receptor variants and their functional consequences for olfactory sensitivity have been identified in single receptors, but no comprehensive mapping exists of how natural OR52 variants or variants across the broader human odorant receptor repertoire affect population-level odor perception thresholds and discrimination abilities.

  Olfactory Sensitivity in Mammalian Species · 2016 · DOI

• Whether or how ACIII may play an instructive role remains to be determined. Future studies are needed in order to understand the mechanisms controlling the ciliary length and the length pattern in the olfactory periphery and elsewhere.

  Sensory Biology: Novel Peripheral Organization for Better Smell · 2015 · DOI

• Dopaminergic and noradrenergic neuromodulation of olfactory bulb processing have been shown to affect odor discrimination and learning, yet the circuit-level mechanisms by which these modulatory systems interact with odorant receptor-driven sensory input to shape perceptual representations remain unresolved. No study integrates receptor-level odorant encoding with bulbar neuromodulation.

  Association of an odor with an activation of olfactory bulb noradrenergic β-receptors or locus coeruleus stimulation is sufficient to produce learned approach responses to that odor in neonatal rats. · 2000 · DOI

• The results showed that pups exposed to odor paired with beta-receptor activation limited to the olfactory bulb (isoproterenol, 50 microM) displayed a conditioned approach response on subsequent exposure to that odor.

  Association of an odor with an activation of olfactory bulb noradrenergic β-receptors or locus coeruleus stimulation is sufficient to produce learned approach responses to that odor in neonatal rats. · 2000 · DOI

• Therefore the meat odours were not well defined by any single stimulus used in these studies. Not well understood, but otherwise correctly described as of animal or floral and herbal origin. Not well understood; otherwise correctly interpreted as unpleasant cabbage, burnt potatoes, second-rate boarding houses, etc. 4 (5/20) Not well defined by the stimuli used in these investigations. 3 (9/20) Not well defined by the stimuli used in this experiment. 8 (6/15) 0-5 (4/15) Not well defined by any single stimulus used. HARPER AND OTHERS Well defined by y-butyrolactone for the inexperienced group, especially in view of the low variance involved: inadequately defined for the experienced group by this stimulus.

  ODOUR QUALITIES: A GLOSSARY OF USAGE · 1968 · DOI

• Odorant receptors (ORs) belong to class A G protein coupled receptors that detect diverse small molecules, yet the steps that link odorant association to receptor mediated selectivity remains incompletely defined.

  Allosteric Gating Mechanism Regulates Odorant Selectivity and Antagonism in Odorant Receptors · 2026 · DOI

• However, the specific roles of the olfactory bulb and cortical outputs in wider interactions with other interconnected regions throughout the brain remain unclear due to the lack of suitable in vivo techniques.

  Olfactory cortical outputs recruit and shape distinct brain-wide spatiotemporal networks · 2026 · DOI

• These intricacies need to be explored by further research as this may help us approach some gastrointestinal infections in a way that addresses the root cause.

  VARIABILITY IN THE INNATE BEHAVIOR OF DISGUST: A BRIEF REVIEW · 2023 · DOI

• However, whether sociodemographic factors and olfactory ability predict educational achievements has not been directly compared in the context of culinary vocational education, which formed the aim of the current study.

  What Makes a Qualified Chef? Olfactory and Sociodemographic Predictors of Vocational Exam Results in Culinary School Students · 2023 · DOI

• The right hemisphere has traditionally been considered as dominant in odor and emotion perception, whereas little is known about odor influence on emotion recognition.

  Effects of unpleasant odors on emotion recognition: The right hemisphere and valence-specific hypotheses · 2019 · DOI

• Whether neonatal odor memory can persist into toddlerhood and influence behaviors that tap processes related to cognition (attention and exploration), motivation (choice and consumption), and emotion (hedonic processing) remains under-researched.

  Long‐lasting memory for an odor acquired at the mother's breast · 2010 · DOI

• Phenomenological evidence for olfactory sensation in the absence of appropriate stimulation—imagery—is inconclusive and draws most support from reports of olfactory hallucinations.

  Olfactory Dreams: Phenomenology, Relationship to Volitional Imagery and Odor Identification · 2004 · DOI

• Although numerous studies have investigated the content of laboratory and home dream reports, surprisingly little is known about the prevalence of various sensory modes in dreams.

  Prevalence of Auditory, Olfactory, and Gustatory Experiences in Home Dreams · 1998 · DOI

Most-cited papers in Olfactory and Sensory Function Studies

• Prevalence of Olfactory Impairment in Older Adults · JAMA · 2002 · 917 citations
• Association of an odor with an activation of olfactory bulb noradrenergic β-receptors or locus coeruleus stimulation is sufficient to produce learned approach responses to that odor in neonatal rats. · Behavioral Neuroscience · 2000 · 144 citations
• Product Scent and Memory · Journal of Consumer Research · 2009 · 142 citations
• Chemosensory Function and Dysfunction · Critical Reviews in Oral Biology & Medicine · 1998 · 73 citations
• Long‐lasting memory for an odor acquired at the mother's breast · Developmental Science · 2010 · 72 citations
• Simultaneous single-cell three-dimensional genome and gene expression profiling uncovers dynamic enhancer connectivity underlying olfactory receptor choice · Nature Methods · 2024 · 71 citations
• Olfactory Sensitivity in Mammalian Species · Physiological Research · 2016 · 61 citations
• Single-neuron representations of odours in the human brain · Nature · 2024 · 55 citations
• Prevalence of Auditory, Olfactory, and Gustatory Experiences in Home Dreams · Perceptual and Motor Skills · 1998 · 55 citations
• A honeybee's ability to learn, recognize, and discriminate odors depends upon odor sampling time and concentration. · Behavioral Neuroscience · 2009 · 53 citations

Most recent work

• Mice navigate scent trails using predictive policies · bioRxiv · 2026
• The posteroventral part of the medial amygdala nucleus glutamatergic neurons encodes conspecifics’ individual identity in rodents · Science Advances · 2026
• Odor preference maps to cohesive transcriptional domains in the olfactory bulb · bioRxiv · 2026
• Elucidating Odorant Masking Effects in Food Matrices through Olfactory Receptor-Based Profiling · Journal of Agricultural and Food Chemistry · 2026
• Olfactory radiomics signatures link pTau217 to cognitive impairment in probable Alzheimer’s disease: a multi-cohort machine learning study · Alzheimer's Research & Therapy · 2026
• Here, where? A puzzle for olfactory experience’s spatiality · Philosophy and the Mind Sciences · 2026
• Experience-dependent critical period for synaptic plasticity in the rat olfactory amygdala · Frontiers in Synaptic Neuroscience · 2026
• Decorrelation by gain control in the mouse olfactory bulb · bioRxiv · 2026
• Receptor-Anchored Olfaction Representation through Perception-Consistent Metric Learning · bioRxiv · 2026
• A Frontal-Sensory Cortex Circuit Encoding Context-Dependent Stimulus Statistics · bioRxiv · 2026

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