Olfactory deficit and gastrointestinal dysfunction precede motor abnormalities in alpha-Synuclein G51D knock-in mice.

Parkinson's disease (PD) is typically a sporadic late-onset disorder, which has made it difficult to model in mice. Several transgenic mouse models bearing mutations in SNCA, which encodes alpha-Synuclein (α-Syn), have been made, but these lines do not express SNCA in a physiologically accurate spatiotemporal pattern, which limits the ability of the mice to recapitulate the features of human PD. Here, we generated knock-in mice bearing the G51D SNCA mutation. After establishing that their motor symptoms begin at 9 mo of age, we then sought earlier pathologies. We assessed the phosphorylation at Serine 129 of α-Syn in different tissues and detected phospho-α-Syn in the olfactory bulb and enteric nervous system at 3 mo of age. Olfactory deficit and impaired gut transit followed at 6 mo, preceding motor symptoms. The SncaG51D mice thus parallel the progression of human PD and will enable us to study PD pathogenesis and test future therapies.

Abdominal contact of fluvalinate induces olfactory deficit in Apis mellifera.

τ-Fluvalinate (fluvalinate) is a highly selective pyrethroid insecticide compound used for controlling ectoparasitic mites that cause major damages in honey bee colonies. Although honey bees have resistance and low toxicity to this xenobiotic chemical, little is known about the effects of this chemical on sensory modulation and behaviors in honey bees. Here we addressed the effect on olfactory cognition at the behavioral, molecular, and neurophysiological levels. First, we found that topical application of fluvalinate to honeybee abdomen elicited somewhat severe toxicity to honey bees. Furthermore, honeybees treated with sublethal doses of fluvalinate showed a significant decrease in olfactory responses. At the molecular level, there was no change in gene expression levels of odorant receptor co-receptor (Orco), which is important for electrical conductivity induced by odorant binding in insects. Rather, small neuropeptide F (sNPF) signaling pathway was involved in olfactory fluctuation after treatment of fluvalinate. This indicates that olfactory deficits by abdominal contact of fluvalinate may stem from various internal molecular pathways in honey bees.

Association of Smell Identification Deficit with Alzheimer's Disease Assessment Scale-Cognitive Subscale, Japanese Version Scores and Brain Atrophy in Patients with Dementia.

INTRODUCTION: Olfactory dysfunction is commonly associated with Alzheimer's disease (AD) and may be related to disorder of the central olfactory processing system. In this work, therefore, we examined the relationships between olfactory changes and the most affected cognitive domain or degree of brain atrophy in patients with AD and mild cognitive impairment (MCI). METHODS: The subjects were 55 AD patients and 27 MCI patients. Smell identification tests were performed using Odor Stick Identification Test for Japanese -(OSIT-J). The severity and nature of cognitive dysfunctions were evaluated using the AD Assessment Scale-cognitive subscale, Japanese version (ADAS-Jcog). MRI with voxel-based specific regional analysis system for AD software was used for evaluation of brain atrophy. RESULTS: -OSIT-J scores were significantly correlated with total -ADAS-Jcog scores, as well as with ADAS-Jcog subscale items of word recall task, orientation (memory domain) and ideational praxis. Smell identification deficit was proportional to the degree of atrophy of the medial temporal lobe. CONCLUSION: Smell identification deficit in AD/MCI is strongly associated with the memory domain of cognitive function and with atrophy of the medial temporal lobe.

Environmental enrichment ameliorates high-fat diet induced olfactory deficit and decrease of parvalbumin neurons in the olfactory bulb in mice.

Overweight induced by high-fat diet (HFD) represents one of the major health concerns in modern societies, which can cause lasting peripheral and central metabolic disorders in all age groups. Specifically, childhood obesity could lead to life-long impact on brain development and functioning. On the other hand, environmental enrichment (EE) has been demonstrated to be beneficial for learning and memory. Here, we explored the impact of high-fat diet on olfaction and organization of olfactory bulb cells in adolescent mice, and the effect of EE intervention thereon. Puberty mice (3-week-old) fed with HFD for 10 weeks exhibited poorer odor sensitivity and olfactory memory relative to controls consuming standard chows. The behavioral deficits were rescued in the HFD group with EE intervention. Neuroanatomically, parvalbumin (PV) interneurons in the olfactory bulb (OB) were reduced in the HFD-fed animals relative to control, while EE intervention also normalized this alteration. In contrast, cells expressing calbindin (CB), doublecortin (DCX) in the OB were not altered. Our findings suggest that PV interneurons may play a crucial role in mediating the HFD-induced olfactory deficit in adolescent mice, and can also serve a protective effect of EE against the functional deficit.

Abnormal Antennal Olfactory Sensilla Phenotypes Involved in Olfactory Deficit in Bactrocera correcta (Diptera: Tephritidae).

The guava fruit fly, Bactrocera correcta, is one of the most destructive pests in the genus Bactrocera and detects environmental odorants mainly through antennal olfactory sensilla phenotypes with nanopores. However, it is unclear whether there are naturally occurring abnormal antennal olfactory sensilla phenotypes that affect olfaction. Here, we found that there were abnormal bulges besides nanopores on the surface of trichoid and basiconic olfactory sensilla in the antennal flagellum of long-term laboratory rearing colony (LTC), and that nanopore number in these olfactory sensilla was also remarkably reduced. Notably, the electroantennogram (EAG) responses of LTC insects to methyl eugenol or ß-caryophyllene were inhibited, and their behavioral responses elicited by the same odorants were also impaired. These results revealed naturally occurring abnormal antennal olfactory sensilla phenotypes which were involved in olfactory deficit in B. correcta, providing a platform to further study nanopore-targeted pest control technologies in the future.

Neuroimmunoendocrine Link Between Chronic Kidney Disease and Olfactory Deficits.

Chronic kidney disease (CKD) is a multifactorial pathology that progressively leads to the deterioration of metabolic functions and results from deficient glomerular filtration and electrolyte imbalance. Its economic impact on public health is challenging. Mexico has a high prevalence of CKD that is strongly associated with some of the most common metabolic disorders like diabetes and hypertension. The gradual loss of kidney functions provokes an inflammatory state and endocrine alterations affecting several systems. High serum levels of prolactin have been associated with CKD progression, inflammation, and olfactory function. Also, the nutritional status is altered due to impaired renal function. The decrease in calorie and protein intake is often accompanied by malnutrition, which can be severe at advanced stages of the disease. Nutrition and olfactory functioning are closely interconnected, and CKD patients often complain of olfactory deficits, which ultimately can lead to deficient food intake. CKD patients present a wide range of deficits in olfaction like odor discrimination, identification, and detection threshold. The chronic inflammatory status in CKD damages the olfactory epithelium leading to deficiencies in the chemical detection of odor molecules. Additionally, the decline in cognitive functioning impairs the capacity of odor differentiation. It is not clear whether peritoneal dialysis and hemodialysis improve the olfactory deficits, but renal transplants have a strong positive effect. In the present review, we discuss whether the olfactory deficiencies caused by CKD are the result of the induced inflammatory state, the hyperprolactinemia, or a combination of both.

Severe Zinc Deficiency Causes the Loss and Apoptosis of Olfactory Ensheathing Cells (OECs) and Olfactory Deficit.

Dietary zinc deficiency may lead to olfactory deficits, whose mechanism remains largely elusive. Olfactory ensheathing cells (OECs), a type of glial cells that support the function and neurogenesis in the olfactory bulb (OB), may play a pivotal role in the maintenance of the olfactory system. In the present study, we established a rat model of dietary zinc deficiency and found that severe zinc deficiency, but not marginal zinc deficiency, caused significantly reduced food intake, growth retardation, and apparent olfactory deficit in growing rats. We showed that severe zinc deficiency resulted in the loss of OECs in the olfactory nerve layer (ONL) of the olfactory bulb. In addition, we revealed that the number of TUNEL-positive cells increased markedly in the region, suggesting an involvement of apoptotic cell death in zinc deficiency-induced loss of OECs. Moreover, we found that treatment with zinc chelator N,N,N'N',-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN) triggered the apoptosis of in vitro-cultured primary OECs. The apoptosis of OECs was correlated with significantly elevated expression of p53. Importantly, TUNEL and CCK-8 assays both demonstrated that treatment with p53 antagonist pifithrin-α (PFT-α) markedly attenuated TPEN-induced OEC apoptosis. These findings implicated that p53-triggered apoptosis of OECs might play an integral role in zinc deficiency-induced olfactory malfunction.

Neural processing of odor-associated words: an fMRI study in patients with acquired olfactory loss.

Perception of olfactory information is mediated by both bottom-up (from molecules to perception) and top-down (e.g. cross-modal associative learning) processes. Acquired olfactory loss is a frequent disorder which is typically due to alterations in the bottom-up pathway. However, it is unclear how the top-down modulation of olfactory processing is affected by olfactory impairment. Our study aimed to investigate the top-down olfactory processing in patients with acquired olfactory loss and participants with normal olfaction. Using functional MRI, brain responses from 14 patients and 16 healthy controls were assessed during a task of expectation and reading of words with strong olfactory associations (OW) (e.g. "Rose") and control words with little to no olfactory associations (CW) (e.g. "Door"). The expectation but not reading of the OW was associated with stronger neural activation in the angular gyrus and the inferior frontal gyrus extending to insula in the group of patients. During OW reading, the brain activation in the left OFC and right putamen was negatively correlated with odor identification score in patient and control groups, respectively. In addition, the duration of olfactory loss among patients was positively associated with activation in the left putamen during OW expectation. Taken together, these findings suggest an enhanced top-down olfactory modulation in patients with olfactory loss.

Interneurons and beta-amyloid in the olfactory bulb, anterior olfactory nucleus and olfactory tubercle in APPxPS1 transgenic mice model of Alzheimer's disease.

Impaired olfaction has been described as an early symptom in Alzheimer's disease (AD). Neuroanatomical changes underlying this deficit in the olfactory system are largely unknown. Given that interneuron populations are crucial in olfactory information processing, we have quantitatively analyzed somatostatin- (SOM), parvalbumin- (PV), and calretinin-expressing (CR) cells in the olfactory bulb, anterior olfactory nucleus, and olfactory tubercle in PS1 x APP double transgenic mice model of AD. The experiments were performed in wild type and double transgenic homozygous animal groups of 2, 4, 6, and 8 months of age to analyze early stages of the pathology. In addition, beta-amyloid (Aß) expression and its correlation with SOM cells have been quantified under confocal microscopy. The results indicate increasing expressions of Aß with aging as well as an early fall of SOM and CR expression, whereas PV was decreased later in the disease progression. These observations evidence an early, preferential vulnerability of SOM and CR cells in rostral olfactory structures during AD that may be useful to unravel neural basis of olfactory deficits associated to this neurodegenerative disorder.

El cultivo de precursores neuronales del epitelio olfatorio: Un modelo para estudiar la neurofisiopatología de la esquizofrenia / The culture of olfactory ephitelium neuronal precursors: A model for studying schizophrenia neurophysiopathology

Schizophrenia is a mental disorder characterized by delusions, hallucinations, disorganization in speech and thinking as well as alterations in social behavior, and affective flattening. Schizophrenic patients also have an olfactory deficit since prodromal stages of this disorder. The olfactory deficit could be present in schizophrenic patients due to anatomic and structural alteration of the Central Nervous System, or peripheral abnormalities in the olfactory epithelium. The major alterations of the Central Nervous System are diminished volumes of olfactory bulb and structures of primary olfactory cortex, hippocampus and amygdala. While, olfactory epithelium has functional abnormalities in cellular differentiation and electric response of sensory olfactory neurons, which suggest an impairment of the odor transduction. The cellular culture of olfactory epithelium has allowed isolating multipotential progenitor cells that have the ability to proliferate and differentiate in mature neurons and glia. This model could provide evidences on the causes that could explain the olfactory deficits in schizophrenia. Moreover, it will allow testing hypothesis on pathophysiological causes of this mental disorder in different of stages of the neurodevelopment. In addition, olfactory epithelial neuronal precursors constitute a novel model to detect genetic, proteomic and functional biomarkers that allow a biological diagnosis.

La esquizofrenia (EZ) es un trastorno psiquiátrico que se caracteriza por la presencia de delirios, alucinaciones, pensamiento desorganizado, lenguaje desestructurado, alteraciones del comportamiento social y aplanamiento afectivo, entre otros síntomas. Los pacientes con EZ también presentan un déficit en la capacidad olfatoria desde la fase prodrómica del trastorno. El déficit olfatorio en la EZ puede presentarse por alteraciones anatómico-estructurales del SNC o por anomalías a nivel periférico en el epitelio olfatorio. Las alteraciones principales del SNC son la disminución del volumen de los bulbos olfatorios, de estructuras de la corteza olfatoria primaria, del hipocampo y de la amígdala coronal. El epitelio olfatorio en los estadios tempranos de la EZ presenta anomalías funcionales en la diferenciación y en la respuesta biofísica de las neuronas sensoriales olfatorias, lo que sugiere que existe un desacoplamiento de la transducción olfatoria. El cultivo celular del epitelio olfatorio ha permitido aislar células progenitoras multipotenciales que poseen la capacidad de proliferar y diferenciarse en neuronas y glía. El estudio de este modelo podría aportar evidencia sobre las causas que explicarían el déficit olfatorio en la esquizofrenia y permitiría estudiar hipótesis que intenten explicar las causas de la fisiopatología de este trastorno en el neurodesarrollo así como detectar biomarcadores genéticos, proteómicos o funcionales que permitan un diagnóstico biológico.