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1.
Front Neural Circuits ; 18: 1408187, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38818309

RESUMO

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.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Animais , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Feminino , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Transtornos do Espectro Alcoólico Fetal/patologia , Humanos , Etanol/efeitos adversos , Etanol/administração & dosagem , Etanol/farmacologia , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/crescimento & desenvolvimento , Condutos Olfatórios/efeitos dos fármacos , Condutos Olfatórios/crescimento & desenvolvimento
2.
Cell Rep ; 43(6): 114267, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38795344

RESUMO

In the adult brain, structural and functional parameters, such as synaptic sizes and neuronal firing rates, follow right-skewed and heavy-tailed distributions. While this organization is thought to have significant implications, its development is still largely unknown. Here, we address this knowledge gap by investigating a large-scale dataset recorded from the prefrontal cortex and the olfactory bulb of mice aged 4-60 postnatal days. We show that firing rates and spike train interactions have a largely stable distribution shape throughout the first 60 postnatal days and that the prefrontal cortex displays a functional small-world architecture. Moreover, early brain activity exhibits an oligarchical organization, where high-firing neurons have hub-like properties. In a neural network model, we show that analogously right-skewed and heavy-tailed synaptic parameters are instrumental to consistently recapitulate the experimental data. Thus, functional and structural parameters in the developing brain are already extremely distributed, suggesting that this organization is preconfigured and not experience dependent.


Assuntos
Encéfalo , Animais , Camundongos , Encéfalo/crescimento & desenvolvimento , Bulbo Olfatório/crescimento & desenvolvimento , Neurônios/metabolismo , Camundongos Endogâmicos C57BL , Sinapses/metabolismo , Sinapses/fisiologia , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/citologia , Potenciais de Ação/fisiologia , Rede Nervosa/crescimento & desenvolvimento , Modelos Neurológicos
3.
Science ; 382(6673): 958-963, 2023 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-37995223

RESUMO

Adult neural stem cells (NSCs) contribute to lifelong brain plasticity. In the adult mouse ventricular-subventricular zone, NSCs are heterogeneous and, depending on their location in the niche, give rise to different subtypes of olfactory bulb (OB) interneurons. Here, we show that multiple regionally distinct NSCs, including domains that are usually quiescent, are recruited on different gestation days during pregnancy. Synchronized activation of these adult NSC pools generates transient waves of short-lived OB interneurons, especially in layers with less neurogenesis under homeostasis. Using spatial transcriptomics, we identified molecular markers of pregnancy-associated interneurons and showed that some subsets are temporarily needed for own pup recognition. Thus, pregnancy triggers transient yet behaviorally relevant neurogenesis, highlighting the physiological relevance of adult stem cell heterogeneity.


Assuntos
Interneurônios , Ventrículos Laterais , Comportamento Materno , Neurogênese , Plasticidade Neuronal , Bulbo Olfatório , Gravidez , Olfato , Animais , Feminino , Camundongos , Gravidez/fisiologia , Células-Tronco Adultas/fisiologia , Interneurônios/citologia , Interneurônios/fisiologia , Ventrículos Laterais/citologia , Ventrículos Laterais/crescimento & desenvolvimento , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Bulbo Olfatório/citologia , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/metabolismo , Transcriptoma , Comportamento Materno/fisiologia
4.
Development ; 149(4)2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35156680

RESUMO

The striatum is a central regulator of behavior and motor function through the actions of D1 and D2 medium-sized spiny neurons (MSNs), which arise from a common lateral ganglionic eminence (LGE) progenitor. The molecular mechanisms of cell fate specification of these two neuronal subtypes are incompletely understood. Here, we found that deletion of murine Meis2, which is highly expressed in the LGE and derivatives, led to a large reduction in striatal MSNs due to a block in their differentiation. Meis2 directly binds to the Zfp503 and Six3 promoters and is required for their expression and specification of D1 and D2 MSNs, respectively. Finally, Meis2 expression is regulated by Dlx1/2 at least partially through the enhancer hs599 in the LGE subventricular zone. Overall, our findings define a pathway in the LGE whereby Dlx1/2 drives expression of Meis2, which subsequently promotes the fate determination of striatal D1 and D2 MSNs via Zfp503 and Six3.


Assuntos
Corpo Estriado/metabolismo , Proteínas de Homeodomínio/metabolismo , Neurônios/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Proteínas de Homeodomínio/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ventrículos Laterais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese , Neurônios/citologia , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Fatores de Transcrição/genética , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Proteína Homeobox SIX3
5.
Development ; 149(3)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35147186

RESUMO

The mammalian main olfactory bulb is a crucial processing centre for the sense of smell. The olfactory bulb forms early during development and is functional from birth. However, the olfactory system continues to mature and change throughout life as a target of constitutive adult neurogenesis. Our Review synthesises current knowledge of prenatal, postnatal and adult olfactory bulb development, focusing on the maturation, morphology, functions and interactions of its diverse constituent glutamatergic and GABAergic cell types. We highlight not only the great advances in the understanding of olfactory bulb development made in recent years, but also the gaps in our present knowledge that most urgently require addressing.


Assuntos
Bulbo Olfatório/crescimento & desenvolvimento , Animais , Axônios/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Neurogênese , Bulbo Olfatório/metabolismo , Neurônios Receptores Olfatórios/metabolismo , Transdução de Sinais , Sinapses/metabolismo
6.
Development ; 149(5)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35132995

RESUMO

Distinct neural stem cells (NSCs) reside in different regions of the subventricular zone (SVZ) and generate multiple olfactory bulb (OB) interneuron subtypes in the adult brain. However, the molecular mechanisms underlying such NSC heterogeneity remain largely unknown. Here, we show that the basic helix-loop-helix transcription factor Olig2 defines a subset of NSCs in the early postnatal and adult SVZ. Olig2-expressing NSCs exist broadly but are most enriched in the ventral SVZ along the dorsoventral axis complementary to dorsally enriched Gsx2-expressing NSCs. Comparisons of Olig2-expressing NSCs from early embryonic to adult stages using single cell transcriptomics reveal stepwise developmental changes in their cell cycle and metabolic properties. Genetic studies further show that cross-repression contributes to the mutually exclusive expression of Olig2 and Gsx2 in NSCs/progenitors during embryogenesis, but that their expression is regulated independently from each other in adult NSCs. Finally, lineage-tracing and conditional inactivation studies demonstrate that Olig2 plays an important role in the specification of OB interneuron subtypes. Altogether, our study demonstrates that Olig2 defines a unique subset of adult NSCs enriched in the ventral aspect of the adult SVZ.


Assuntos
Interneurônios/metabolismo , Ventrículos Laterais/crescimento & desenvolvimento , Ventrículos Laterais/metabolismo , Células-Tronco Neurais/metabolismo , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/metabolismo , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Animais , Ciclo Celular/genética , Linhagem da Célula/genética , Células Cultivadas , Feminino , Técnicas de Inativação de Genes , Ventrículos Laterais/embriologia , Masculino , Camundongos , Camundongos Knockout , Neurogênese/genética , Bulbo Olfatório/embriologia , Fator de Transcrição 2 de Oligodendrócitos/genética , Transdução de Sinais/genética , Transcriptoma/genética
7.
Eur J Neurosci ; 54(9): 7092-7108, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34549475

RESUMO

Olfactory dysfunction is observed in several neurological disorders including Mild Cognitive Impairment (MCI) and Alzheimer disease (AD). These deficits occur early and correlate with global cognitive performance, depression and degeneration of olfactory regions in the brain. Despite extensive human studies, there has been little characterization of the olfactory system in models of AD. In order to determine if olfactory structural and/or molecular phenotypes are observed in a model expressing a genetic risk factor for AD, we assessed the olfactory bulb (OB) in APOE4 transgenic mice. A significant decrease in OB weight was observed at 12 months of age in APOE4 mice concurrent with inflammation and decreased NeuN expression. In order to determine if a diet rich in omega-3s may alleviate the olfactory system phenotypes observed, we assessed WT and APOE4 mice on a docosahexaenoic acid (DHA) diet. APOE4 mice on a DHA diet did not present with atrophy of the OB, and the alterations in NeuN and IBA-1 expression were alleviated. Furthermore, alterations in caspase mRNA and protein expression in the APOE4 OB were not observed with a DHA diet. Similar to the human AD condition, OB atrophy is an early phenotype in the APOE4 mice and concurrent with inflammation. These data support a link between the structural olfactory brain region atrophy and the olfactory dysfunction observed in AD and suggest that inflammation and cell death pathways may contribute to the olfactory deficits observed. Furthermore, the results suggest that diets enriched in DHA may provide benefit to APOE4 allele carriers.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Ácidos Docosa-Hexaenoicos/fisiologia , Transtornos do Olfato/dietoterapia , Bulbo Olfatório , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Animais , Apolipoproteína E4/genética , Atrofia , Dieta , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Transtornos do Olfato/etiologia , Transtornos do Olfato/genética , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/metabolismo , Bulbo Olfatório/patologia
8.
PLoS Biol ; 19(4): e3001101, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33793547

RESUMO

Here, we reveal that the regulation of Drosophila odorant receptor (OR) expression during the pupal stage is permissive and imprecise. We found that directly after hatching an OR feedback mechanism both directs and refines OR expression. We demonstrate that, as in mice, dLsd1 and Su(var)3-9 balance heterochromatin formation to direct OR expression. We show that the expressed OR induces dLsd1 and Su(var)3-9 expression, linking OR level and possibly function to OR expression. OR expression refinement shows a restricted duration, suggesting that a gene regulatory critical period brings olfactory sensory neuron differentiation to an end. Consistent with a change in differentiation, stress during the critical period represses dLsd1 and Su(var)3-9 expression and makes the early permissive OR expression permanent. This induced permissive gene regulatory state makes OR expression resilient to stress later in life. Hence, during a critical period OR feedback, similar to in mouse OR selection, defines adult OR expression in Drosophila.


Assuntos
Drosophila , Neurogênese/genética , Neurônios Receptores Olfatórios/fisiologia , Receptores Odorantes/fisiologia , Estresse Fisiológico/fisiologia , Animais , Animais Geneticamente Modificados , Diferenciação Celular/genética , Montagem e Desmontagem da Cromatina/genética , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiologia , Retroalimentação Fisiológica/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Heterocromatina/metabolismo , Humanos , Masculino , Neurogênese/fisiologia , Bulbo Olfatório/citologia , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/metabolismo , Oxirredutases N-Desmetilantes/genética , Oxirredutases N-Desmetilantes/metabolismo , Pupa , Receptores Odorantes/genética , Receptores Odorantes/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Tempo
9.
J Mol Neurosci ; 71(9): 1772-1785, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33433852

RESUMO

A neuropeptidase, neprilysin (NEP), is a major amyloid (Aß)-degrading enzyme involved in the pathogenesis of Alzheimer's disease (AD). The olfactory system is affected early in AD with characteristic Aß accumulation, but data on the dynamics of NEP expression in the olfactory system are absent. Our study demonstrates that NEP mRNA expression in rat olfactory bulbs (OB), entorhinal cortex (ECx), hippocampus (Hip), parietal cortex (PCx) and striatum (Str) increases during the first postnatal month being the highest in the OB and Str. By 3 months, NEP mRNA levels sharply decrease in the ECx, Hip and PCx and by 9 months in the OB, but not in the Str, which correlates with declining olfaction in aged rats tested in the food search paradigm. One-month-old rats subjected to prenatal hypoxia on E14 had lower NEP mRNA levels in the ECx, Hip and PCx (but not in the OB and Str) compared with the control offspring and demonstrated impaired olfaction in the odour preference and food search paradigms. Administration to these rats of a histone deacetylase inhibitor, sodium valproate, restored NEP expression in the ECx, Hip and PCx and improved olfaction. Our data support NEP involvement in olfactory function.


Assuntos
Neprilisina/metabolismo , Bulbo Olfatório/metabolismo , Percepção Olfatória , Olfato , Animais , Comportamento Animal , Feminino , Masculino , Neprilisina/genética , Neurogênese , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
10.
Cell Death Dis ; 12(1): 91, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462220

RESUMO

A proper number of oligodendrocytes in the nerve system is essential for neuronal functions. In the olfactory bulb (OB), enriched oligodendrocytes are crucial for olfactory information processing. However, how the precise number of oligodendrocytes in the OB is regulated remains elusive. Here we identified that the transcription factor 4 (Tcf4)-mediated cell death is essential for generating an appropriate number of oligodendrocyte progenitor cells (OPCs) and thereby oligodendrocytes in the OB. We showed that Nkx2.1-positive progenitors in the medial ganglionic eminence (MGE) and anterior entopeduncular area (AEP) provide the first source of OPCs in the OB. Conditional depletion of Tcf4 leads to an increase of OPCs in the OB, which is mediated by the suppression of programmed cell death. Furthermore, we showed that Tcf4 mediated OPC survival is cell-autonomous by transplantation assay. Mechanistically, we identified Bax/Bak as a potential key pathway to promote OPC elimination during OB development. Depletion of Bax/Bak in Nkx2.1 lineage results in an increase of OPCs in the OB. Mutations in TCF4 causes Pitt-Hopkins syndrome, a severe neurodevelopmental disorder. Thus, our findings reveal an important intrinsic mechanism underlying the survival control of OPCs in the OB and provide new insights into the pathogenesis of Pitt-Hopkins syndrome.


Assuntos
Bulbo Olfatório/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Fator de Transcrição 4/metabolismo , Animais , Sobrevivência Celular/fisiologia , Humanos , Camundongos , Camundongos Knockout , Neurogênese , Bulbo Olfatório/citologia , Bulbo Olfatório/crescimento & desenvolvimento , Células Precursoras de Oligodendrócitos/citologia , Oligodendroglia/citologia
11.
Learn Mem ; 27(12): 493-502, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33199474

RESUMO

During the first ten postnatal days (P), infant rodents can learn olfactory preferences for novel odors if they are paired with thermo-tactile stimuli that mimic components of maternal care. After P10, the thermo-tactile pairing becomes ineffective for conditioning. The current explanation for this change in associative learning is the alteration in the norepinephrine (NE) inputs from the locus coeruleus (LC) to the olfactory bulb (OB) and the anterior piriform cortex (aPC). By combining patch-clamp electrophysiology and computational simulations, we showed in a recent work that a transitory high responsiveness of the OB-aPC circuit to the maternal odor is an alternative mechanism that could also explain early olfactory preference learning and its cessation after P10. That result relied solely on the maturational properties of the aPC pyramidal cells. However, the GABAergic system undergoes important changes during the same period. To address the importance of the maturation of the GABAergic system for early olfactory learning, we incorporated data from the GABA inputs, obtained from in vitro patch-clamp experiment in the aPC of rat pups aged P5-P7 reported here, to the model proposed in our previous publication. In the younger than P10 OB-aPC circuit with GABA synaptic input, the number of responsive aPC pyramidal cells to the conditioned maternal odor was amplified in 30% compared to the circuit without GABAergic input. When compared with the circuit with other younger than P10 OB-aPC circuit with adult GABAergic input profile, this amplification was 88%. Together, our results suggest that during the olfactory preference learning in younger than P10, the GABAergic synaptic input presumably acts by depolarizing the aPC pyramidal neurons in such a way that it leads to the amplification of the pyramidal neurons response to the conditioned maternal odor. Furthermore, our results suggest that during this developmental period, the aPC pyramidal cells themselves seem to resolve the apparent lack of GABAergic synaptic inhibition by a strong firing adaptation in response to increased depolarizing inputs.


Assuntos
Aprendizagem/fisiologia , Odorantes , Condutos Olfatórios/crescimento & desenvolvimento , Condutos Olfatórios/fisiologia , Percepção Olfatória/fisiologia , Córtex Piriforme/crescimento & desenvolvimento , Córtex Piriforme/fisiologia , Ácido gama-Aminobutírico/fisiologia , Envelhecimento/psicologia , Animais , Animais Recém-Nascidos , Feminino , Masculino , Modelos Neurológicos , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/fisiologia , Córtex Olfatório , Técnicas de Patch-Clamp , Células Piramidais/fisiologia , Ratos , Sinapses/fisiologia
12.
Hum Mol Genet ; 29(18): 3003-3013, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-32821949

RESUMO

Pathogenic mutations in the solute carrier family 7 member 5 (SLC7A5) gene, which encodes an amino acid transporter cause microcephaly and seizures, yet the mechanisms responsible for these phenotypes are unclear. Models have demonstrated that Slc7a5 deletion is embryonic lethal and that these embryos lack a fully formed telencephalon. This phenotype is similar to that of mammalian target of rapamycin (mTOR) protein kinase deletion or mTOR inhibition. Notably, in many cells, Slc7a5 import of amino acids is required to maintain mTOR activity. Slc7a5 is present within neurogenic regions during embryogenesis, is found in cultured neurons and can modulate neuronal electrophysiological properties. However, Slc7a5 is also highly expressed within endothelial cells of the blood-brain barrier where removal in conditional mice leads to severe behavioral defects and non-cell autonomous changes in neurons. Therefore, the extent that neural Slc7a5 is required for development is unclear. Here, subventricular zone neural stem cells that generate olfactory bulb granule cell neurons were electroporated with SLC7A5 or Slc7a5 short hairpin RNA encoding plasmids. Although early phases of neural development were unaltered, Slc7a5 knockdown effected late phases of GC dendrite maturation and survival. Slc7a5 knockdown also decreased mTOR pathway activity. Ras homolog enriched in brain, an mTOR activator, rescued the effect of Slc7a5 knockdown on mTOR pathway activity and dendrite arbors. The data presented here demonstrate that Slc7a5 is required for GC mTOR pathway activity, maturation and survival, which may help explain why Slc7a5 mutations prevent normal brain development and function.


Assuntos
Transportador 1 de Aminoácidos Neutros Grandes/genética , Microcefalia/genética , Convulsões/genética , Serina-Treonina Quinases TOR/genética , Aminoácidos/genética , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Fenômenos Eletrofisiológicos/genética , Desenvolvimento Embrionário/genética , Humanos , Camundongos , Microcefalia/patologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neurônios/metabolismo , Neurônios/patologia , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/patologia , Convulsões/patologia , Deleção de Sequência/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores
13.
J Anat ; 237(2): 225-240, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32314400

RESUMO

Despite the long-held assumption that olfaction plays a relatively minor role in the behavioral ecology of birds, crown-group avians exhibit marked phylogenetic variation in the size and form of the olfactory apparatus. As part of a larger effort to better understand the role of olfaction and olfactory tissues in the evolution and development of the avian skull, we present the first quantitative analysis of ontogenetic scaling between olfactory features [olfactory bulbs (OBs) and olfactory turbinates] and neighboring structures (cerebrum, total brain, respiratory turbinates) based on the model organism Gallus gallus. The OB develops under the predictions of a concerted evolutionary model with rapid early growth that is quickly overcome by the longer, sustained growth of the larger cerebrum. A similar pattern is found in the nasal cavity where the morphologically simple (non-scrolled) olfactory turbinates appear and mature early, with extended growth characterizing the larger and scrolled respiratory turbinates. Pairwise regressions largely recover allometric relationships among the examined structures, with a notable exception being the isometric trajectory of the OB and olfactory turbinate. Their parallel growth suggests a unique regulatory pathway that is likely driven by the morphogenesis of the olfactory nerve, which serves as a structural bridge between the two features. Still, isometry was not necessarily expected given that the olfactory epithelium covers more than just the turbinate. These data illuminate a number of evolutionary hypotheses that, moving forward, should inform tradeoffs and constraints between the olfactory and neighboring systems in the avian head.


Assuntos
Cavidade Nasal/anatomia & histologia , Bulbo Olfatório/anatomia & histologia , Conchas Nasais/anatomia & histologia , Animais , Embrião de Galinha , Galinhas , Cavidade Nasal/embriologia , Cavidade Nasal/crescimento & desenvolvimento , Bulbo Olfatório/embriologia , Bulbo Olfatório/crescimento & desenvolvimento , Mucosa Olfatória/anatomia & histologia , Mucosa Olfatória/embriologia , Mucosa Olfatória/crescimento & desenvolvimento , Conchas Nasais/embriologia , Conchas Nasais/crescimento & desenvolvimento
14.
Development ; 147(10)2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32253238

RESUMO

The transcription factor Zeb2 controls fate specification and subsequent differentiation and maturation of multiple cell types in various embryonic tissues. It binds many protein partners, including activated Smad proteins and the NuRD co-repressor complex. How Zeb2 subdomains support cell differentiation in various contexts has remained elusive. Here, we studied the role of Zeb2 and its domains in neurogenesis and neural differentiation in the young postnatal ventricular-subventricular zone (V-SVZ), in which neural stem cells generate olfactory bulb-destined interneurons. Conditional Zeb2 knockouts and separate acute loss- and gain-of-function approaches indicated that Zeb2 is essential for controlling apoptosis and neuronal differentiation of V-SVZ progenitors before and after birth, and we identified Sox6 as a potential downstream target gene of Zeb2. Zeb2 genetic inactivation impaired the differentiation potential of the V-SVZ niche in a cell-autonomous fashion. We also provide evidence that its normal function in the V-SVZ also involves non-autonomous mechanisms. Additionally, we demonstrate distinct roles for Zeb2 protein-binding domains, suggesting that Zeb2 partners co-determine neuronal output from the mouse V-SVZ in both quantitative and qualitative ways in early postnatal life.


Assuntos
Ventrículos Laterais/embriologia , Ventrículos Laterais/crescimento & desenvolvimento , Neurogênese/genética , Bulbo Olfatório/embriologia , Bulbo Olfatório/crescimento & desenvolvimento , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Animais , Apoptose/genética , Movimento Celular/genética , Proliferação de Células/genética , Técnicas de Inativação de Genes , Interneurônios/metabolismo , Ventrículos Laterais/metabolismo , Camundongos , Camundongos Knockout , Células-Tronco Neurais/metabolismo , Bulbo Olfatório/metabolismo , Fatores de Transcrição SOXD/metabolismo , Transdução de Sinais/imunologia , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
15.
Genes (Basel) ; 11(3)2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32183100

RESUMO

The large phenotypic variation in the olfactory bulb may be related to heterogeneity in the progenitor cells. Accordingly, the progeny of subventricular zone (SVZ) progenitor cells that are destined for the olfactory bulb is of particular interest, specifically as there are many facets of these progenitors and their molecular profiles remain unknown. Using modified StarTrack genetic tracing strategies, specific SVZ progenitor cells were targeted in E12 mice embryos, and the cell fate of these neural progenitors was determined in the adult olfactory bulb. This study defined the distribution and the phenotypic diversity of olfactory bulb interneurons from specific SVZ-progenitor cells, focusing on their spatial pallial origin, heterogeneity, and genetic profile.


Assuntos
Diferenciação Celular/genética , Linhagem da Célula/genética , Bulbo Olfatório/crescimento & desenvolvimento , Células-Tronco/metabolismo , Animais , Movimento Celular/genética , Interneurônios/citologia , Interneurônios/metabolismo , Ventrículos Laterais , Camundongos , Bulbo Olfatório/citologia , Células-Tronco/classificação
16.
Cereb Cortex ; 30(7): 4092-4109, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32108222

RESUMO

Even after birth, neuronal production continues in the ventricular-subventricular zone (V-SVZ) and hippocampus in many mammals. The immature new neurons ("neuroblasts") migrate and then mature at their final destination. In humans, neuroblast production and migration toward the neocortex and the olfactory bulb (OB) occur actively only for a few months after birth and then sharply decline with age. However, the precise spatiotemporal profiles and fates of postnatally born neurons remain unclear due to methodological limitations. We previously found that common marmosets, small nonhuman primates, share many features of V-SVZ organization with humans. Here, using marmosets injected with thymidine analogue(s) during various postnatal periods, we demonstrated spatiotemporal changes in neurogenesis during development. V-SVZ progenitor proliferation and neuroblast migration toward the OB and neocortex sharply decreased by 4 months, most strikingly in a V-SVZ subregion from which neuroblasts migrated toward the neocortex. Postnatally born neurons matured within a few months in the OB and hippocampus but remained immature until 6 months in the neocortex. While neurogenic activity was sustained for a month after birth, the distribution and/or differentiation diversity was more restricted in 1-month-born cells than in the neonatal-born population. These findings shed light on distinctive features of postnatal neurogenesis in primates.


Assuntos
Proliferação de Células , Hipocampo/crescimento & desenvolvimento , Ventrículos Laterais/crescimento & desenvolvimento , Neocórtex/crescimento & desenvolvimento , Células-Tronco Neurais/citologia , Neurogênese , Bulbo Olfatório/crescimento & desenvolvimento , Animais , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Callithrix , Movimento Celular , Ventrículos Cerebrais/citologia , Ventrículos Cerebrais/crescimento & desenvolvimento , Hipocampo/citologia , Ventrículos Laterais/citologia , Neocórtex/citologia , Bulbo Olfatório/citologia , Análise Espaço-Temporal
17.
J Comp Physiol B ; 190(2): 161-167, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31915911

RESUMO

The decrease in ocean pH that results from the increased concentration of dissolved carbon dioxide (CO2) is likely to influence many physiological functions in organisms. It has been shown in different fish species that ocean acidification (OA) mainly affects sensory systems, including olfaction. Impairment of olfactory function may be due to a dysfunction of the GABAergic system and to an alteration of neuronal plasticity in the whole brain and particularly in olfactory bulbs. Recent studies revealed that OA-driven effects on sensory systems are partly mediated by the regulation of the expression of genes involved in neurotransmission and neuronal development. However, these studies were performed in fish exposed to acidified waters for short periods, of only a few days. In the present paper, we investigated whether such effects could be observed in adult (4-years old) European sea bass (Dicentrarchus labrax) exposed to two hypercapnic and acidified conditions (PCO2 ≈ 980 µatm; pH total = 7.7 and PCO2 ≈ 1520 µatm; pH total = 7.5) from the larval stage. In a first approach, we analyzed by qPCR the expression of five genes involved in neurogenesis (DCX) or expressed in GABAergic (Gabra3), glutamatergic (Gria1) or dopaminergic (TH and DDC) neurons in the olfactory bulbs. The tested experimental conditions did not change the expression of any of the five genes. This result would indicate that a potential disruption of the olfactory function of sea bass exposed for a long term to near-future OA, either occurs at a level other than the transcriptional one or involves other actors of the sensory function.


Assuntos
Dióxido de Carbono/farmacologia , Proteínas de Peixes/genética , Bulbo Olfatório/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Bass , Proteínas de Peixes/metabolismo , Homeostase , Concentração de Íons de Hidrogênio , Neurogênese/genética , Oceanos e Mares , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/metabolismo , Bulbo Olfatório/fisiologia , Água do Mar , Transmissão Sináptica/genética
18.
Cell Rep ; 30(1): 187-201.e4, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31914386

RESUMO

More than one-half of the interneurons in a mouse olfactory bulb (OB) develop during the first week after birth and predominantly connect to excitatory tufted cells near the superficial granule cell layer (sGCL), unlike late-born interneurons. However, the molecular mechanisms underlying the temporal specification are yet to be identified. In this study, we determined the role of Abelson tyrosine-protein kinase 1 (Abl1) in the temporal development of early-born OB interneurons. Lentiviral knockdown of Abl1 disrupts the sGCL circuit of early-born interneurons through defects in function and circuit integration, resulting in olfactory hyper-sensitivity. We show that doublecortin (Dcx) is phosphorylated by Abl1, which contributes to the stabilization of Dcx, thereby regulating microtubule dynamics. Finally, Dcx overexpression rescues Abl1 knockdown-induced anatomic or functional defects. In summary, specific signaling by Abl1-Dcx in early-born interneurons facilitates the temporal development of the sGCL circuit to regulate innate olfactory functions, such as detection and sensitivity.


Assuntos
Comportamento Animal , Inibição Neural , Proteínas Proto-Oncogênicas c-abl/metabolismo , Olfato , Animais , Animais Recém-Nascidos , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Ativação Enzimática , Feminino , Células HEK293 , Humanos , Interneurônios/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Neuritos/metabolismo , Neurogênese , Neuropeptídeos/metabolismo , Bulbo Olfatório/crescimento & desenvolvimento , Fosforilação , Estabilidade Proteica
19.
Learn Mem ; 27(1): 20-32, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31843979

RESUMO

Studies have shown that neonate rodents exhibit high ability to learn a preference for novel odors associated with thermo-tactile stimuli that mimics maternal care. Artificial odors paired with vigorous strokes in rat pups younger than 10 postnatal days (P), but not older, rapidly induce an orientation-approximation behavior toward the conditioned odor in a two-choice preference test. The olfactory bulb (OB) and the anterior olfactory cortex (aPC), both modulated by norepinephrine (NE), have been identified as part of a neural circuit supporting this transitory olfactory learning. One possible explanation at the neuronal level for why the odor-stroke pairing induces consistent orientation-approximation behavior in P10, is the coincident activation of prior existent neurons in the aPC mediating this behavior. Specifically, odor-stroke conditioning in P10 pups, promoting orientation-approximation behavior in the former but not in the latter. In order to test this hypothesis, we performed in vitro patch-clamp recordings of the aPC pyramidal neurons from rat pups from two age groups (P5-P8 and P14-P17) and built computational models for the OB-aPC neural circuit based on this physiological data. We conditioned the P5-P8 OB-aPC artificial circuit to an odor associated with NE activation (representing the process of maternal odor learning during mother-infant interactions inside the nest) and then evaluated the response of the OB-aPC circuit to the presentation of the conditioned odor. The results show that the number of responsive aPC neurons to the presentation of the conditioned odor in the P14-P17 OB-aPC circuit was lower than in the P5-P8 circuit, suggesting that at P14-P17, the reduced number of responsive neurons to the conditioned (maternal) odor might not be coincident with the responsive neurons for a second conditioned odor.


Assuntos
Aprendizagem/fisiologia , Comportamento Materno , Bulbo Olfatório/fisiologia , Córtex Piriforme/fisiologia , Células Piramidais/fisiologia , Olfato/fisiologia , Animais , Comportamento Animal , Condicionamento Clássico , Feminino , Masculino , Potenciais da Membrana , Modelos Neurológicos , Norepinefrina/fisiologia , Odorantes , Bulbo Olfatório/crescimento & desenvolvimento , Percepção Olfatória , Córtex Piriforme/crescimento & desenvolvimento
20.
J Neurosci ; 40(2): 311-326, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31767679

RESUMO

During mammalian development, gonadotropin-releasing-hormone-1 neurons (GnRH-1ns) migrate from the developing vomeronasal organ (VNO) into the brain asserting control of pubertal onset and fertility. Recent data suggest that correct development of the olfactory ensheathing cells (OEC) is imperative for normal GnRH-1 neuronal migration. However, the full ensemble of molecular pathways that regulate OEC development remains to be fully deciphered. Loss-of-function of the transcription factor Gli3 is known to disrupt olfactory development, however, if Gli3 plays a role in GnRH-1 neuronal development is unclear. By analyzing Gli3 extra-toe mutants (Gli3Xt/Xt), we found that Gli3 loss-of-function compromises the onset of achaete-scute family bHLH transcription factor 1 (Ascl-1)+ vomeronasal progenitors and the formation of OEC in the nasal mucosa. Surprisingly, GnRH-1 neurogenesis was intact in Gli3Xt/Xt mice but they displayed significant defects in GnRH-1 neuronal migration. In contrast, Ascl-1null mutants showed reduced neurogenesis for both vomeronasal and GnRH-1ns but less severe defects in OEC development. These observations suggest that Gli3 is critical for OEC development in the nasal mucosa and subsequent GnRH-1 neuronal migration. However, the nonoverlapping phenotypes between Ascl-1 and Gli3 mutants indicate that Ascl-1, while crucial for GnRH-1 neurogenesis, is not required for normal OEC development. Because Kallmann syndrome (KS) is characterized by abnormal GnRH-1ns migration, we examined whole-exome sequencing data from KS subjects. We identified and validated a GLI3 loss-of-function variant in a KS individual. These findings provide new insights into GnRH-1 and OECs development and demonstrate that human GLI3 mutations contribute to KS etiology.SIGNIFICANCE STATEMENT The transcription factor Gli3 is necessary for correct development of the olfactory system. However, if Gli3 plays a role in controlling GnRH-1 neuronal development has not been addressed. We found that Gli3 loss-of-function compromises the onset of Ascl-1+ vomeronasal progenitors, formation of olfactory ensheathing cells in the nasal mucosa, and impairs GnRH-1 neuronal migration to the brain. By analyzing Ascl-1null mutants we dissociated the neurogenic defects observed in Gli3 mutants from lack of olfactory ensheathing cells in the nasal mucosa, moreover, we discovered that Ascl-1 is necessary for GnRH-1 ontogeny. Analyzing human whole-exome sequencing data, we identified a GLI3 loss-of-function variant in a KS individual. Our data suggest that GLI3 is a candidate gene contributing to KS etiology.


Assuntos
Síndrome de Kallmann/genética , Neurogênese/fisiologia , Neuroglia/fisiologia , Neurônios/fisiologia , Órgão Vomeronasal/fisiologia , Proteína Gli3 com Dedos de Zinco/metabolismo , Animais , Movimento Celular/fisiologia , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Bulbo Olfatório/crescimento & desenvolvimento , Mucosa Olfatória/metabolismo , Precursores de Proteínas/metabolismo , Proteína Gli3 com Dedos de Zinco/genética
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