Neuronal integration in the adult mouse olfactory bulb is a non-selective addition process.
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ABSTRACT:
SUBMITTER: Platel JC
PROVIDER: S-EPMC6634973 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Immature neurons migrate tangentially within the rostral migratory stream (RMS) to the adult olfactory bulb (OB), then radially to their final positions as granule and periglomerular neurons; the controls over this transition are not well understood. Using adult transgenic mice with the human GFAP promoter driving expression of enhanced GFP, we identified a population of radial glia-like cells that we term adult olfactory radial glia-like cells (AORGs). AORGs have large, round somas and simple, radially oriented processes. Confocal reconstructions indicate that AORGs variably express typical radial glial markers, only rarely express mouse GFAP, and do not express astroglial, oligodendroglial, neuronal, or tanycyte markers. Electron microscopy provides further supporting evidence that AORGs are not immature neurons. Developmental analyses indicate that AORGs are present as early as P1, and are generated through adulthood. Tracing studies show that AORGs are not born in the SVZa, suggesting that they are born either in the RMS or the OB. Migrating immature neurons from the adult SVZa are closely apposed to AORGs during radial migration in vivo and in vitro. Taken together, these data indicate a newly-identified population of radial glia-like cells in the adult OB that might function uniquely in neuronal radial migration during adult OB neurogenesis.
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Project description:The rodent olfactory bulb (OB) is continuously supplied with adult-born cells maturing into GABAergic neurons. Using in vivo ratiometric Ca2+ imaging to readout ongoing and sensory-driven activity, we asked whether mature adult-born cells (mABCs) in the glomerular layer of the bulb become functionally identical to resident GABAergic (ResGABA) neurons. In awake head-restrained mice the two cell populations differed significantly in terms of ongoing spontaneous activity, with 24% of mABCs contributing to a strongly active cell cluster, absent among ResGABA cells. Odor-evoked responses of mABCs were sparse, less reliable, and had smaller amplitudes compared with ResGABA cells. The opposite was seen under anesthesia, with response reliability increasing and response size of mABCs becoming larger than that of ResGABA cells. Furthermore, ongoing activity of mABCs showed increased sensitivity to ketamine/xylazine and was selectively blocked by the antagonist of serotonin receptors methysergide. These functional features of mABCs clearly distinguish them from other OB interneurons.
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Project description:Although the role of noxious α-synuclein (α-SYN) in the degeneration of midbrain dopaminergic neurons and associated motor deficits of Parkinson's disease is recognized, its impact on non-motor brain circuits and related symptoms remains elusive. Through combining in vivo two-photon imaging with time-coded labelling of neurons in the olfactory bulb of A30P α-SYN transgenic mice, we show impaired growth and branching of dendrites of adult-born granule cells (GCs), with reduced gain and plasticity of dendritic spines. The spine impairments are especially pronounced during the critical phase of integration of new neurons into existing circuits. Functionally, retarded dendritic expansion translates into reduced electrical capacitance with enhanced intrinsic excitability and responsiveness of GCs to depolarizing inputs, while the spine loss correlates with decreased frequency of AMPA-mediated miniature EPSCs. Changes described here are expected to interfere with the functional integration and survival of new GCs into bulbar networks, contributing towards olfactory deficits and related behavioural impairments.
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Project description:Neurogenesis in the adult brain is largely restricted to the subependymal zone (SVZ) of the lateral ventricle, olfactory bulb (OB) and the dentate subgranular zone, and survival of adult-born cells in the OB is influenced by factors including sensory experience. We examined, in mice, whether survival of adult-born cells is also regulated by the rate of precursor proliferation in the SVZ. Precursor proliferation was decreased by depleting the SVZ of dopamine after lesioning dopamine neurons in the substantia nigra compacta with 6-hydroxydopamine. Subsequently, we examined the effect of reduced SVZ proliferation on the generation, migration and survival of neuroblasts and mature adult-born cells in the SVZ, rostral migratory stream (RMS) and OB. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU) injected 2 hours prior to death or by immunoreactivity against Ki67, were reduced by 47% or 36%, respectively, 7 days after dopamine depletion, and by 29% or 31% 42 days after dopamine depletion, compared to sham-treated animals. Neuroblast generation in the SVZ and their migration along the RMS were not affected, neither 7 nor 42 days after the 6-hydroxydopamine injection, since the number of doublecortin-immunoreactive neuroblasts in the SVZ and RMS, as well as the number of neuronal nuclei-immunoreactive cells in the OB, were stable compared to control. However, survival analysis 15 days after 6-hydroxydopamine and 6 days after BrdU injections showed that the number of BrdU+ cells in the SVZ was 70% higher. Also, 42 days after 6-hydroxydopamine and 30 days after BrdU injections, we found an 82% increase in co-labeled BrdU+/?-aminobutyric acid-immunoreactive cell bodies in the granular cell layer, while double-labeled BrdU+/tyrosine hydroxylase-immunoreactive cell bodies in the glomerular layer increased by 148%. We conclude that the number of OB interneurons following reduced SVZ proliferation is maintained through an increased survival of adult-born precursor cells, neuroblasts and interneurons.
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Project description:BackgroundNew neurons are generated in the adult brain from stem cells found in the subventricular zone (SVZ). These cells proliferate in the SVZ, generating neuroblasts which then migrate to the main olfactory bulb (MOB), ending their migration in the glomerular layer (GLL) and the granule cell layer (GCL) of the MOB. Neuronal populations in these layers undergo turnover throughout life, but whether all neuronal subtypes found in these areas are replaced and when neurons begin to express subtype-specific markers is not known.ResultsHere we use BrdU injections and immunohistochemistry against (calretinin, calbindin, N-copein, tyrosine hydroxylase and GABA) and show that adult-generated neurons express markers of all major subtypes of neurons in the GLL and GCL. Moreover, the fractions of new neurons that express subtype-specific markers at 40 and 75 days post BrdU injection are very similar to the fractions of all neurons expressing these markers. We also show that many neurons in the glomerular layer do not express NeuN, but are readily and specifically labeled by the fluorescent nissl stain Neurotrace.ConclusionThe expression of neuronal subtype-specific markers by new neurons in the GLL and GCL changes rapidly during the period from 14-40 days after BrdU injection before reaching adult levels. This period may represent a critical window for cell fate specification similar to that observed for neuronal survival.
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Project description:Reduced olfactory function (hyposmia) is one of the most common non-motor symptoms experienced by those living with Parkinson's disease (PD), however, the underlying pathology of the dysfunction is unclear. Recent evidence indicates that ?-synuclein (?-syn) pathology accumulates in the anterior olfactory nucleus of the olfactory bulb years before the motor symptoms are present. It is well established that neuronal cells in the olfactory bulb are affected by ?-syn, but the involvement of other non-neuronal cell types is unknown. The occurrence of intracellular ?-syn inclusions were quantified in four non-neuronal cell types - microglia, pericytes, astrocytes and oligodendrocytes as well as neurons in the anterior olfactory nucleus of post-mortem human PD olfactory bulbs (n?=?11) and normal olfactory bulbs (n?=?11). In the anterior olfactory nucleus, ?-syn inclusions were confirmed to be intracellular in three of the four non-neuronal cell types, where 7.78% of microglia, 3.14% of pericytes and 1.97% of astrocytes were affected. Neurons containing ?-syn inclusions comprised 8.60% of the total neuron population. Oligodendrocytes did not contain ?-syn. The data provides evidence that non-neuronal cells in the PD olfactory bulb contain ?-syn inclusions, suggesting that they may play an important role in the progression of PD.
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Project description:In this study, we demonstrate that insulin is produced not only in the mammalian pancreas but also in adult neuronal cells derived from hippocampus and olfactory bulb. Paracrine Wnt3 plays an essential role in promoting the active expression of insulin in both hippocampus and olfactory bulb-derived neural stem cells. Our analysis indicates that the balance between Wnt3, which triggers the expression of insulin via NeuroD1 transcription factor, and IGFBP-4, which inhibits the original Wnt3 action, is regulated depending on the diabetic status. We also show that adult neural progenitors derived from diabetic animals retain the ability to give rise to insulin-producing cells and that grafting neuronal progenitors into the pancreas of diabetic animals reduces glucose levels. This study provides an example of a simple and direct use of adult stem cells from one organ to another, without introducing additional inductive genes. In this study, we demonstrate that insulin is produced not only in the mammalian pancreas but also in adult neuronal cells derived from hippocampus and olfactory bulb. Paracrine Wnt3 plays an essential role in promoting the active expression of insulin in both hippocampus and olfactory bulb-derived neural stem cells. Our analysis indicates that the balance between Wnt3, which triggers the expression of insulin via NeuroD1 transcription factor, and IGFBP-4, which inhibits the original Wnt3 action, is regulated depending on the diabetic status. We also show that adult neural progenitors derived from diabetic animals retain the ability to give rise to insulin-producing cells and that grafting neuronal progenitors into the pancreas of diabetic animals reduces glucose levels. This study provides an example of a simple and direct use of adult stem cells from one organ to another, without introducing additional inductive genes. Total four different samples, gene expressions in hippocampal derived neural stem cells (HPC NSC), that in Olfactory bulb-derived neural stem cells (OB NSC), that in neurons derived from the HPC NSCs (HPC Neu) and that in neurons derived from the OB NSCs (OB Neu) were independently analyzed. Three independent experiments were performed to prepare each cell sample, and the extracted total RNAs from each cell source were mixed to apply following microarray analysis (Four independent RNA sample; HPC NSC, OB NSC, HPC Neu and OB Neu).
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