Development Of Olfactory System Research Articles

Molecular, Cellular, and Developmental Organization of the Mouse Vomeronasal organ at Single Cell Resolution.

We have generated single cell transcriptomic atlases of vomeronasal organs (VNO) from juvenile and adult mice. Combined with spatial molecular imaging, we uncover a distinct, previously unidentified class of cells that express the vomeronasal receptors and a population of canonical olfactory sensory neurons in the VNO. High resolution trajectory and cluster analyses reveal the lineage relationship, spatial distribution of cell types, and a putative cascade of molecular events that specify the V1r, V2r, and OR lineages from a common stem cell population. The expression of vomeronasal and olfactory receptors follow power law distributions, but there is high variability in average expression levels between individual receptor and cell types. Substantial co-expression is found between receptors across clades, from different classes, and between olfactory and vomeronasal receptors, with nearly half from pairs located on the same chromosome. Interestingly, the expression of V2r, but not V1r, genes is associated with various transcription factors, suggesting distinct mechanisms of receptor choice associated with the two cell types. We identify association between transcription factors, surface axon guidance molecules, and individual VRs, thereby uncovering a molecular code that guides the specification of the vomeronasal circuitry. Our study provides a wealth of data on the development and organization of the accessory olfactory system at both cellular and molecular levels to enable a deeper understanding of vomeronasal system function.

Development of a noninvasive olfactory stimulation fMRI system in marmosets

Olfactory dysfunction is associated with aging and the earliest stages of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases; it is thought to be an early biomarker of cognitive decline. In marmosets, a small non-human primate model used in brain research, olfactory pathway activity during olfactory stimulation has not been well studied because of the difficulty in clearly switching olfactory stimuli inside a narrow MRI. Here, we developed an olfactory-stimulated fMRI system using a small-aperture MRI machine. The olfactory presentation system consisted of two tubes, one for supply and one for suction of olfactory stimulants and a balloon valve. A balloon valve installed in the air supply tube controlled the presentation of the olfactory stimulant, which enabled sharp olfactory stimulation within MRI, such as 30 s of stimulation repeated five times at five-minute intervals. The olfactory stimulation system was validated in vivo and in a simulated system. fMRI analysis showed a rapid increase in signal values within 30 s of olfactory stimulation in eight regions related to the sense of smell. As these regions include those associated with Alzheimer’s and Parkinson’s diseases, olfactory stimulation fMRI may be useful in clarifying the relationship between olfactory dysfunction and dementia in non-human primates.

Effects of prenatal alcohol exposure on the olfactory system development.

Fetal Alcohol Spectrum Disorders (FASD), resulting from maternal alcohol consumption during pregnancy, are a prominent non-genetic cause of physical disabilities and brain damage in children. Alongside common symptoms like distinct facial features and neurocognitive deficits, sensory anomalies, including olfactory dysfunction, are frequently noted in FASD-afflicted children. However, the precise mechanisms underpinning the olfactory abnormalities induced by prenatal alcohol exposure (PAE) remain elusive. Utilizing rodents as a model organism with varying timing, duration, dosage, and administration routes of alcohol exposure, prior studies have documented impairments in olfactory system development caused by PAE. Many reported a reduction in the olfactory bulb (OB) volume accompanied by reduced OB neuron counts, suggesting the OB is a brain region vulnerable to PAE. In contrast, no significant olfactory system defects were observed in some studies, though subtle alterations might exist. These findings suggest that the timing, duration, and extent of fetal alcohol exposure can yield diverse effects on olfactory system development. To enhance comprehension of PAE-induced olfactory dysfunctions, this review summarizes key findings from previous research on the olfactory systems of offspring prenatally exposed to alcohol.

Insertion of a neomycin selection cassette in the Amigo1 locus alters gene expression in the olfactory epithelium leading to region-specific defects in olfactory receptor neuron development.

During development of the nervous system, neurons connect to one another in a precisely organized manner. Sensory systems provide a good example of this organization, whereby the composition of the outside world is represented in the brain by neuronal maps. Establishing correct patterns of neural circuitry is crucial, as inaccurate map formation can lead to severe disruptions in sensory processing. In rodents, olfactory stimuli modulate a wide variety of behaviors essential for survival. The formation of the olfactory glomerular map is dependent on molecular cues that guide olfactory receptor neuron axons to broad regions of the olfactory bulb and on cell adhesion molecules that promote axonal sorting into specific synaptic units in this structure. Here, we demonstrate that the cell adhesion molecule Amigo1 is expressed in a subpopulation of olfactory receptor neurons, and we investigate its role in the precise targeting of olfactory receptor neuron axons to the olfactory bulb using a genetic loss-of-function approach in mice. While ablation of Amigo1 did not lead to alterations in olfactory sensory neuron axonal targeting, our experiments revealed that the presence of a neomycin resistance selection cassette in the Amigo1 locus can lead to off-target effects that are not due to loss of Amigo1 expression, including unexpected altered gene expression in olfactory receptor neurons and reduced glomerular size in the ventral region of the olfactory bulb. Our results demonstrate that insertion of a neomycin selection cassette into the mouse genome can have specific deleterious effects on the development of the olfactory system and highlight the importance of removing antibiotic resistance cassettes from genetic loss-of-function mouse models when studying olfactory system development.

Illuminating the terminal nerve: Uncovering the link between GnRH-1 neuron and olfactory development.

During embryonic development, the olfactory placode (OP) generates migratory neurons, including olfactory pioneer neurons, cells of the terminal nerve (TN), gonadotropin-releasing hormone-1 (GnRH-1) neurons, and other uncharacterized neurons. Pioneer neurons from the OP induce olfactory bulb (OB) morphogenesis. In mice, GnRH-1 neurons appear in the olfactory system around mid-gestation and migrate via the TN axons to different brain regions. The GnRH-1 neurons are crucial in controlling the hypothalamic-pituitary-gonadal axis. Kallmann syndrome is characterized by impaired olfactory system development, defective OBs, secretion of GnRH-1, and infertility. The precise mechanistic link between the olfactory system and GnRH-1 development remains unclear. Studies in humans and mice highlight the importance of the prokineticin-2/prokineticin-receptor-2 (Prokr2) signaling pathway in OB morphogenesis and GnRH-1 neuronal migration. Prokr2 loss-of-function mutations can cause Kallmann syndrome (KS), and hence the Prokr2 signaling pathway represents a unique model to decipher the olfactory/GnRH-1 connection. We discovered that Prokr2 is expressed in the TN neurons during the critical period of GnRH-1 neuron formation, migration, and induction of OB morphogenesis. Single-cell RNA sequencing identified that the TN is formed by neurons distinct from the olfactory neurons. The TN neurons express multiple genes associated with KS. Our study suggests that the aberrant development of pioneer/TN neurons might cause the KS spectrum.

Activity-dependent formation of the topographic map and the critical period in the development of mammalian olfactory system.

Neural activity influences every aspect of nervous system development. In olfactory systems, sensory neurons expressing the same odorant receptor project their axons to stereotypically positioned glomeruli, forming a spatial map of odorant receptors in the olfactory bulb. As individual odors activate unique combinations of glomeruli, this map forms the basis for encoding olfactory information. The establishment of this stereotypical olfactory map requires coordinated regulation of axon guidance molecules instructed by spontaneous activity. Recent studies show that sensory experiences also modify innervation patterns in the olfactory bulb, especially during a critical period of the olfactory system development. This review examines evidence in the field to suggest potential mechanisms by which various aspects of neural activity regulate axon targeting. We also discuss the precise functions served by neural plasticity during the critical period.

Spatiotemporal dynamics of the development of mouse olfactory system from prenatal to postnatal period.

The olfactory epithelium (OE) and olfactory bulb (OB) are the major components of the olfactory system and play critical roles in olfactory perception. However, the embryonic development of OE and OB by using the olfactory specific genes has not been comprehensively investigated yet. Most previous studies were limited to a specific embryonic stage, and very little is known, till date, about the development of OE. The current study aimed to explore the development of mouse olfactory system by spatiotemporal analysis of the histological features by using the olfactory specific genes of olfactory system from the prenatal to postnatal period. We found that OE is divided into endo-turbinate, ecto-turbinate, and vomeronasal organs, and that putative OB with putative main and accessory OB is formed in the early developmental stage. The OE and OB became multilayered in the later developmental stages, accompanied by the differentiation of olfactory neurons. Remarkably, we found the development of layers of olfactory cilia and differentiation of OE to progress dramatically after birth, suggesting that the exposure to air may facilitate the final development of OE. Overall, the present study laid the groundwork for a better understanding of the spatial and temporal developmental events of the olfactory system.

Embryology and Clinical Development of the Human Olfactory System

AbstractThe olfactory system is unique as a special sensory system in its developmental neuroanatomy and function. Neonatal olfactory reflexes can be detected in the fetus from 30 weeks gestation and can be tested in term and preterm neonates and older children. Most efferent axons from the olfactory bulb terminate in the anterior olfactory nucleus within the olfactory tract, with secondary projections to the amygdala, hypothalamus, hippocampus, and entorhinal cortex (parahippocampal gyrus), with tertiary projections also to the insula and other cortical regions. The olfactory bulb and tract incorporate an intrinsic thalamic equivalent. The olfactory bulb may be primary in generating olfactory auras in some cases of temporal lobe epilepsy. Developmental malformations may involve the olfactory bulb and tract, isolated or as part of complex cerebral malformations and genetic syndromes. Primary neural tumors may arise in the olfactory bulb or nerve. Impaired olfaction occurs in neonatal hypoxic/ischemic and some metabolic encephalopathies. Loss of sense of smell are early symptoms in some neurodegenerative diseases and in some viral respiratory diseases including coronavirus disease 2019. Testing cranial nerve I is easy and reliable at all ages, and is recommended in selected neonates with suspected brain malformations or encephalopathy.

Neurotrophic and immunomodulatory effects of olfactory ensheathing cells as a strategy for neuroprotection and regeneration.

Accumulating evidence sustains glial cells as critical players during central nervous system (CNS) development, homeostasis and disease. Olfactory ensheathing cells (OECs), a type of specialized glia cells sharing properties with both Schwann cells and astrocytes, are of critical importance in physiological condition during olfactory system development, supporting its regenerative potential throughout the adult life. These characteristics prompted research in the field of cell-based therapy to test OEC grafts in damaged CNS. Neuroprotective mechanisms exerted by OEC grafts are not limited to axonal regeneration and cell differentiation. Indeed, OEC immunomodulatory properties and their phagocytic potential encourage OEC-based approaches for tissue regeneration in case of CNS injury. Herein we reviewed recent advances on the immune role of OECs, their ability to modulate CNS microenvironment via bystander effects and the potential of OECs as a cell-based strategy for tissue regeneration.

Progress of Research on the Application of Nanoelectronic Smelling in the Field of Food.

In the past 20 years, the development of an artificial olfactory system has made great progress and improvements. In recent years, as a new type of sensor, nanoelectronic smelling has been widely used in the food and drug industry because of its advantages of accurate sensitivity and good selectivity. This paper reviews the latest applications and progress of nanoelectronic smelling in animal-, plant-, and microbial-based foods. This includes an analysis of the status of nanoelectronic smelling in animal-based foods, an analysis of its harmful composition in plant-based foods, and an analysis of the microorganism quantity in microbial-based foods. We also conduct a flavor component analysis and an assessment of the advantages of nanoelectronic smelling. On this basis, the principles and structures of nanoelectronic smelling are also analyzed. Finally, the limitations and challenges of nanoelectronic smelling are summarized, and the future development of nanoelectronic smelling is proposed.

Loss-of-function variants in SEMA3F and PLXNA3 encoding semaphorin-3F and its receptor plexin-A3 respectively cause idiopathic hypogonadotropic hypogonadism

PurposeIdiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent puberty and subsequent infertility due to gonadotropin-releasing hormone (GnRH) deficiency. IHH can be accompanied by normal or compromised olfaction (Kallmann syndrome). Several semaphorins are known potent modulators of GnRH, olfactory, and vomeronasal system development. In this study, we investigated the role of Semaphorin-3F signaling in the etiology of IHH. MethodsWe screened 216 IHH patients by exome sequencing. We transiently transfected HEK293T cells with plasmids encoding wild type (WT) or corresponding variants to investigate the functional consequences. We performed fluorescent IHC to assess SEMA3F and PLXNA3 expression both in the nasal region and at the nasal/forebrain junction during the early human fetal development. ResultsWe identified ten rare missense variants in SEMA3F and PLXNA3 in 15 patients from 11 independent families. Most of these variants were predicted to be deleterious by functional assays. SEMA3F and PLXNA3 are both expressed along the olfactory nerve and intracranial projection of the vomeronasal nerve/terminal nerve. PLXNA1-A3 are expressed in the early migratory GnRH neurons. ConclusionSEMA3F signaling through PLXNA1-A3 is involved in the guidance of GnRH neurons and of olfactory and vomeronasal nerve fibers in humans. Overall, our findings suggest that Semaphorin-3F signaling insufficiency contributes to the pathogenesis of IHH.

Functional-genomic analysis reveals intraspecies diversification of antiviral receptor transporter proteins in Xenopus laevis.

The Receptor Transporter Protein (RTP) family is present in most, if not all jawed vertebrates. Most of our knowledge of this protein family comes from studies on mammalian RTPs, which are multi-function proteins that regulate cell-surface G-protein coupled receptor levels, influence olfactory system development, regulate immune signaling, and directly inhibit viral infection. However, mammals comprise less than one-tenth of extant vertebrate species, and our knowledge about the expression, function, and evolution of non-mammalian RTPs is limited. Here, we explore the evolutionary history of RTPs in vertebrates. We identify signatures of positive selection in many vertebrate RTP clades and characterize multiple, independent expansions of the RTP family outside of what has been described in mammals. We find a striking expansion of RTPs in the African clawed frog, Xenopus laevis, with 11 RTPs in this species as opposed to 1 to 4 in most other species. RNA sequencing revealed that most X. laevis RTPs are upregulated following immune stimulation. In functional assays, we demonstrate that at least three of these X. laevis RTPs inhibit infection by RNA viruses, suggesting that RTP homologs may serve as antiviral effectors outside of Mammalia.

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.

Ant Olfaction: Smells Like an Insect, Develops Like a Mammal

A detailed description of olfactory system development in ants reveals that- unlike in Drosophila and as in mammals- olfactory receptors may play a role, providing new insights into the developmental evolution of complex chemosensory systems.

Development of artificial olfactory system

Development of artificial olfactory system

Association between olfactory sulcus morphology and olfactory functioning in schizophrenia and psychosis high-risk status

Olfactory impairment has been reported in patients with schizophrenia and individuals with a high risk of psychosis, but its neural basis is largely unknown. We used magnetic resonance imaging to investigate the morphology of the olfactory sulcus (an indicator of olfactory system development) and its relation to olfactory function in 38 persons with an at-risk mental state (ARMS), 62 patients with schizophrenia, and 61 healthy controls. Odor detection and identification were examined with a T & T olfactometer. Compared with the controls, the olfactory sulcus was significantly shallower and odor identification was inferior among the ARMS and schizophrenia subjects. Across all subjects, but not within each group, the olfactory sulcus depth was significantly related to better identification of odors. Our results support the concept that olfactory sulcus morphology reflects the neurodevelopmental process of the olfactory system.

Olfactory bulb and olfactory tract abnormalities in acrocallosal syndrome and Greig cephalopolysyndactyly syndrome

We describe association of olfactory bulb and olfactory tract abnormalities in a child with acrocallosal syndrome caused by kinesin family membrane 7 (KIF7) mutation in sonic hedgehog pathway. The child also had fontanellar bone in the anterior fontanelle, short sagittal suture, sagittal synostosis, hippocampal malrotation and Joubert malformation. Fontanellar bone has been described in GLI3 mutation and mutant mice models but has not been reported in KIF7 mutation. We briefly review the role of sonic hedgehog pathway and its components KIF7 and GLI3 in forebrain and olfactory system development and also describe olfactory system abnormality in a child with GLI3 mutation.

Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of Amhr2-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.

Chapter 3 - Development of the human olfactory system

This chapter focuses on the development of the human olfactory system. In this system, function does not require full neuroanatomical maturity. Thus, discrimination of odorous molecules, including a number within the mother's diet, occurs in amniotic fluid after 28-30 weeks of gestation, at which time the olfactory bulbs are identifiable by MRI. Hypoplasia/aplasia of the bulbs is documented in the third trimester and postnatally. Interestingly, olfactory axons project from the nasal epithelium to the telencephalon before formation of the olfactory bulbs and lack a peripheral ganglion, but the synaptic glomeruli of the future olfactory bulb serves this function. Histologic lamination of the olfactory bulb is present by 14 weeks, but maturation remains incomplete at term for neuronal differentiation, synaptogenesis, myelination, and persistence of the normal transitory fetal ventricular recess. Myelination occurs postnatally. Although olfaction is the only sensory system without direct thalamic projections, the olfactory bulb and anterior olfactory nucleus are, in effect, thalamic surrogates. For example, many dendro-dendritic synapses occur within the bulb between GABAergic granular neurons and periglomerular neurons. Moreover, bulbar synaptic glomeruli are analogous to peripheral ganglia of other sensory cranial nerves. The olfactory tract contains much gray as well as white matter. The olfactory epithelium and bulb both incorporate progenitor cells at all ages. Diverse malformations of the olfactory bulb can be detected by clinical examination, imaging, and neuropathology; indeed, olfactory reflexes of the neonate can be reliably tested. We recommend that such testing be routine in the neonatal neurologic examination, especially in children with brain malformations, endocrinopathies, chromosomopathies, genetic/metabolic disorders, and perinatal hypoxic/ischemic encephalopathy.

Low survival rate of young adult-born olfactory sensory neurons in the undamaged mouse olfactory epithelium.

Olfactory sensory neurons (OSNs) are generated throughout life from progenitor cells in the olfactory epithelium. OSN axons project in an odorant receptor-specific manner to the olfactory bulb (OB), forming an ordered array of glomeruli where they provide sensory input to OB neurons. The tetracycline transactivator (tTA) system permits developmental stage-specific expression of reporter genes in OSNs and has been widely used for structural and functional studies of the development and plasticity of the mouse olfactory system. However, the cellular ages at which OSNs stop expressing reporters driven by the immature OSN-specific Gγ8-tTA driver line and begin to express reporters driven by the mature OSN-specific OMP-tTA driver line have not been directly determined. We pulse-labeled terminally dividing cells in the olfactory epithelium of 28-day-old (P28) mice with EdU and analyzed EdU labeling in OSNs expressing fluorescent reporter proteins under control of either the Gγ8-tTA or OMP-tTA driver line 5-14days later. Expression of OMP-tTA-driven reporters began in 6-day-old OSNs, while the vast majority of newborn OSNs did not express Gγ8-tTA-driven fluorescent proteins beyond 8days of cellular age. Surprisingly, we also found a low survival rate for P28-born OSNs, very few of which survived for more than 14days. We propose that OSN survival requires the formation of stable synaptic connections and hence may be dependent on organismal age.