Correction: Lgl1 Is Required for Olfaction and Development of Olfactory Bulb in Mice.
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ABSTRACT:
SUBMITTER: Li Z
PROVIDER: S-EPMC5531526 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:The olfactory bulb (OB) receives odor information from the olfactory epithelium and relays this to the olfactory cortex. Using a mouse model, we found that development and maturation of OB interneurons depends on the zinc finger homeodomain factor teashirt zinc finger family member 1 (TSHZ1). In mice lacking TSHZ1, neuroblasts exhibited a normal tangential migration to the OB; however, upon arrival to the OB, the neuroblasts were distributed aberrantly within the radial dimension, and many immature neuroblasts failed to exit the rostral migratory stream. Conditional deletion of Tshz1 in mice resulted in OB hypoplasia and severe olfactory deficits. We therefore investigated olfaction in human subjects from families with congenital aural atresia that were heterozygous for TSHZ1 loss-of-function mutations. These individuals displayed hyposmia, which is characterized by impaired odor discrimination and reduced olfactory sensitivity. Microarray analysis, in situ hybridization, and ChIP revealed that TSHZ1 bound to and regulated expression of the gene encoding prokineticin receptor 2 (PROKR2), a G protein–coupled receptor essential for OB development. Mutations in PROKR2 lead to Kallmann syndrome, characterized by anosmia and hypogonadotrophic hypogonadism. Our data indicate that TSHZ1 is a key regulator of mammalian OB development and function and controls the expression of molecules involved in human Kallmann syndrome.
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Project description:The olfactory bulb (OB) neurons establish a complex network that ensures the correct processing of the olfactory inputs. Moreover, the OB presents a lifelong addition of new neurons into its existing circuitry. This neurogenesis is considered essential for the OB function. However, its functional impact on physiology and behavior is still unclear. Here, we investigate the mechanisms of OB plasticity that underlie bulbar physiology in relation to severe damage of neurogenesis. The neurogenesis of young mice was altered by ionizing radiation. Afterwards, both multi-channel olfactometry and electrophysiological studies were performed. Furthermore, neurogenesis and differentiation of the newly formed cells were assessed using bromodeoxyuridine labeling combined with a wide battery of neuronal markers. Our results demonstrate a reduction in both neurogenesis and volume of the OB in irradiated animals. The number of neuroblasts reaching the OB was reduced and their differentiation rate into interneurons selectively changed; some populations were noticeably affected whereas others remained preserved. Surprisingly, both olfactory detection and discrimination as well as electrophysiology presented almost no alterations in irradiated mice. Our findings suggest that after damaging postnatal neurogenesis, the neurochemical fate of some interneurons changes within a new biological scenario, while maintaining homeostasis and olfaction.
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Project description:Prokineticins, multifunctional secreted proteins, activate two endogenous G protein-coupled receptors PKR1 and PKR2. From in situ analysis of the mouse brain, we discovered that PKR2 is predominantly expressed in the olfactory bulb (OB). To examine the role of PKR2 in the OB, we created PKR1- and PKR2-gene-disrupted mice (Pkr1(-/-) and Pkr2(-/-), respectively). Phenotypic analysis indicated that not Pkr1(-/-)but Pkr2(-/-)mice exhibited hypoplasia of the OB. This abnormality was observed in the early developmental stages of fetal OB in the Pkr2(-/-) mice. In addition, the Pkr2(-/-) mice showed severe atrophy of the reproductive system, including the testis, ovary, uterus, vagina, and mammary gland. In the Pkr2(-/-) mice, the plasma levels of testosterone and follicle-stimulating hormone were decreased, and the mRNA transcription levels of gonadotropin-releasing hormone in the hypothalamus and luteinizing hormone and follicle-stimulating hormone in the pituitary were also significantly reduced. Immunohistochemical analysis revealed that gonadotropin-releasing hormone neurons were absent in the hypothalamus in the Pkr2(-/-) mice. The phenotype of the Pkr2(-/-) mice showed similarity to the clinical features of Kallmann syndrome, a human disease characterized by association of hypogonadotropic hypogonadism and anosmia. Our current findings demonstrated that physiological activation of PKR2 is essential for normal development of the OB and sexual maturation.
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Project description:The olfactory bulb receives rich glutamatergic projections from the piriform cortex. However, the dynamics and importance of these feedback signals remain unknown. Here, we use multiphoton calcium imaging to monitor cortical feedback in the olfactory bulb of awake mice and further probe its impact on the bulb output. Responses of feedback boutons were sparse, odor specific, and often outlasted stimuli by several seconds. Odor presentation either enhanced or suppressed the activity of boutons. However, any given bouton responded with stereotypic polarity across multiple odors, preferring either enhancement or suppression. Feedback representations were locally diverse and differed in dynamics across bulb layers. Inactivation of piriform cortex increased odor responsiveness and pairwise similarity of mitral cells but had little impact on tufted cells. We propose that cortical feedback differentially impacts these two output channels of the bulb by specifically decorrelating mitral cell responses to enable odor separation.
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Project description:Alzheimer's disease (AD) involves the progressive degeneration of neurons critical for learning and memory. In addition, patients with AD typically exhibit impaired olfaction associated with neuronal degeneration in the olfactory bulb (OB). Because DNA base excision repair (BER) is reduced in brain cells during normal aging and AD, we determined whether inefficient BER due to reduced DNA polymerase-? (Pol?) levels renders OB neurons vulnerable to degeneration in the 3xTgAD mouse model of AD. We interrogated OB histopathology and olfactory function in wild-type and 3xTgAD mice with normal or reduced Pol? levels. Compared to wild-type control mice, Pol? heterozygous (Pol?+/- ), and 3xTgAD mice, 3xTgAD/Pol?+/- mice exhibited impaired performance in a buried food test of olfaction. Pol? deficiency did not affect the proliferation of OB neural progenitor cells in the subventricular zone. However, numbers of newly generated neurons were reduced by approximately 25% in Pol?+/- and 3xTgAD mice, and by over 60% in the 3xTgAD/Pol?+/- mice compared to wild-type control mice. Analyses of DNA damage and apoptosis revealed significantly greater degeneration of OB neurons in 3xTgAD/Pol?+/- mice compared to 3xTgAD mice. Levels of amyloid ?-peptide (A?) accumulation in the OB were similar in 3xTgAD and 3xTgAD/Pol?+/- mice, and cultured Pol?-deficient neurons exhibited increased vulnerability to A?-induced death. Olfactory deficit is an early sign in human AD, but the mechanism is not yet understood. Our findings in a new AD mouse model demonstrate that diminution of BER can endanger OB neurons, and suggest a mechanism underlying early olfactory impairment in AD.
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Project description:Olfactory sensory neurons (OSNs) located in the dorsomedial and ventromedial regions of the olfactory epithelium (OE) are distinguished from one another based on their molecular expression patterns. This difference is reflected in the separation of the glomerular layer of the olfactory bulb (OB) into dorsomedial and ventrolateral regions. However, it is unclear whether a complementary separation is also evident in the projection neurons that innervate the OB glomeruli. In this study, we compared the development of the OB between different regions by focusing on the transcription factor, Tbx21, which is expressed by mitral and tufted cells in the mature OB. Examining the OB at different developmental ages, we found that Tbx21 expression commenced in the anteromedial region called the tongue-shaped area, followed by the dorsomedial and then ventrolateral areas. We also showed that the tongue-shaped area was innervated by the OSNs located in the most dorsomedial part of the ventrolateral OE, the V-zone:DM. Interestingly, the generation of OSNs occurred first in the dorsomedial zone including the V-zone:DM, suggesting a correlation between the time course of OSN generation in the OE and Tbx21 expression in their target region of the OB. In contrast, expression of vGluT1, which is also found in all mitral cells in the mature OB, was first detected in the ventrolateral region during development. Our findings demonstrate that the development of projection neurons occurs in a compartmentalized manner in the OB; tongue-shaped, dorsomedial, and ventrolateral areas, and that not all projection neurons follow the same developmental pathway.
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