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1.
Nat Commun ; 12(1): 5916, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625548

RESUMO

Microglia are brain resident macrophages that play vital roles in central nervous system (CNS) development, homeostasis, and pathology. Microglia both remodel synapses and engulf apoptotic cell corpses during development, but whether unique molecular programs regulate these distinct phagocytic functions is unknown. Here we identify a molecularly distinct microglial subset in the synapse rich regions of the zebrafish (Danio rerio) brain. We found that ramified microglia increased in synaptic regions of the midbrain and hindbrain between 7 and 28 days post fertilization. In contrast, microglia in the optic tectum were ameboid and clustered around neurogenic zones. Using single-cell mRNA sequencing combined with metadata from regional bulk sequencing, we identified synaptic-region associated microglia (SAMs) that were highly enriched in the hindbrain and expressed multiple candidate synapse modulating genes, including genes in the complement pathway. In contrast, neurogenic associated microglia (NAMs) were enriched in the optic tectum, had active cathepsin activity, and preferentially engulfed neuronal corpses. These data reveal that molecularly distinct phagocytic programs mediate synaptic remodeling and cell engulfment, and establish the zebrafish hindbrain as a model for investigating microglial-synapse interactions.


Assuntos
Mesencéfalo/citologia , Microglia/citologia , Neurogênese/genética , Rombencéfalo/citologia , Colículos Superiores/citologia , Transcriptoma , Proteínas de Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Antígenos de Diferenciação de Linfócitos B/genética , Antígenos de Diferenciação de Linfócitos B/imunologia , Catepsina B/genética , Catepsina B/imunologia , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Mesencéfalo/crescimento & desenvolvimento , Mesencéfalo/imunologia , Microglia/imunologia , Neurogênese/imunologia , Neurônios/citologia , Neurônios/imunologia , Fagocitose , Rombencéfalo/crescimento & desenvolvimento , Rombencéfalo/imunologia , Análise de Célula Única , Colículos Superiores/crescimento & desenvolvimento , Colículos Superiores/imunologia , Sinapses/imunologia , Sinapses/metabolismo , Sinapses/ultraestrutura , Peixe-Zebra , Proteínas de Peixe-Zebra/imunologia
2.
Development ; 148(15)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34323269

RESUMO

During early development, the hindbrain is sub-divided into rhombomeres that underlie the organisation of neurons and adjacent craniofacial tissues. A gene regulatory network of signals and transcription factors establish and pattern segments with a distinct anteroposterior identity. Initially, the borders of segmental gene expression are imprecise, but then become sharply defined, and specialised boundary cells form. In this Review, we summarise key aspects of the conserved regulatory cascade that underlies the formation of hindbrain segments. We describe how the pattern is sharpened and stabilised through the dynamic regulation of cell identity, acting in parallel with cell segregation. Finally, we discuss evidence that boundary cells have roles in local patterning, and act as a site of neurogenesis within the hindbrain.


Assuntos
Padronização Corporal/fisiologia , Rombencéfalo/crescimento & desenvolvimento , Rombencéfalo/fisiologia , Vertebrados/crescimento & desenvolvimento , Vertebrados/fisiologia , Animais , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Redes Reguladoras de Genes/fisiologia , Humanos
3.
Am J Physiol Regul Integr Comp Physiol ; 321(2): R250-R259, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34259025

RESUMO

The peptide hormone amylin reduces food intake and body weight and is an attractive candidate target for novel pharmacotherapies to treat obesity. However, the short half-life of native amylin and amylin analogs like pramlintide limits these compounds' potential utility in promoting sustained negative energy balance. Here, we evaluate the ability of the novel long-acting amylin/calcitonin receptor agonist ZP5461 to reduce feeding and body weight in rats, and also test the role of calcitonin receptors (CTRs) in the dorsal vagal complex (DVC) of the hindbrain in the energy balance effects of chronic ZP5461 administration. Acute dose-response studies indicate that systemic ZP5461 (0.5-3 nmol/kg) robustly suppresses energy intake and body weight gain in chow- and high-fat diet (HFD)-fed rats. When HFD-fed rats received chronic systemic administration of ZP5461 (1-2 nmol/kg), the compound initially produced reductions in energy intake and weight gain but failed to produce sustained suppression of intake and body weight. Using virally mediated knockdown of DVC CTRs, the ability of chronic systemic ZP5461 to promote early reductions in intake and body weight gain was determined to be mediated in part by activation of DVC CTRs, implicating the DVC as a central site of action for ZP5461. Future studies should address other dosing regimens of ZP5461 to determine whether an alternative dose/frequency of administration would produce more sustained body weight suppression.


Assuntos
Agonistas dos Receptores da Amilina/farmacologia , Depressores do Apetite/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Receptores da Calcitonina/agonistas , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/efeitos dos fármacos , Rombencéfalo/efeitos dos fármacos , Nervo Vago/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Ingestão de Energia/efeitos dos fármacos , Masculino , Ratos Sprague-Dawley , Receptores da Calcitonina/genética , Receptores da Calcitonina/metabolismo , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/genética , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo , Rombencéfalo/metabolismo , Transdução de Sinais , Fatores de Tempo , Nervo Vago/metabolismo
4.
Methods Mol Biol ; 2319: 87-92, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34331246

RESUMO

Blood vessel formation is a fine-regulated process and interfering with blood vessel formation causes embryonic lethality as well as associated with many diseases in the adult, including inflammatory, ischemic, and cancer metastatic diseases. Brain contains abundant blood vessels and has some unique physiological functions, such as blood-brain barrier. Due to the thickness and opaque characters of the tissues, it is a challenge to visualize the three-dimensional structures of the brain blood vessels in the mouse. Therefore, establishing a protocol to display the three-dimensional structures in the brain is required for exploring the regulatory molecular mechanisms in brain blood vessel formation. In this manuscript, we introduced a whole-mount and a vibratome thick section of mouse embryonic hindbrain to display the three-dimensional structures of brain vascular system.


Assuntos
Dissecação/métodos , Neovascularização Fisiológica , Rombencéfalo/irrigação sanguínea , Coloração e Rotulagem/métodos , Animais , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/metabolismo , Dissecação/instrumentação , Células Endoteliais/metabolismo , Imunofluorescência , Camundongos , Microscopia Confocal , Rombencéfalo/crescimento & desenvolvimento , Rombencéfalo/metabolismo
5.
Nat Genet ; 53(8): 1221-1232, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34294917

RESUMO

Driver mutations in genes encoding histone H3 proteins resulting in p.Lys27Met substitutions (H3-K27M) are frequent in pediatric midline brain tumors. However, the precise mechanisms by which H3-K27M causes tumor initiation remain unclear. Here, we use human hindbrain neural stem cells to model the consequences of H3.3-K27M on the epigenomic landscape in a relevant developmental context. Genome-wide mapping of epitope-tagged histone H3.3 revealed that both the wild type and the K27M mutant incorporate abundantly at pre-existing active enhancers and promoters, and to a lesser extent at Polycomb repressive complex 2 (PRC2)-bound regions. At active enhancers, H3.3-K27M leads to focal H3K27ac loss, decreased chromatin accessibility and reduced transcriptional expression of nearby neurodevelopmental genes. In addition, H3.3-K27M deposition at a subset of PRC2 target genes leads to increased PRC2 and PRC1 binding and augmented transcriptional repression that can be partially reversed by PRC2 inhibitors. Our work suggests that, rather than imposing de novo transcriptional circuits, H3.3-K27M drives tumorigenesis by locking initiating cells in their pre-existing, immature epigenomic state, via disruption of PRC2 and enhancer functions.


Assuntos
Elementos Facilitadores Genéticos , Histonas/metabolismo , Células-Tronco Neurais/fisiologia , Complexo Repressor Polycomb 2/genética , Rombencéfalo/citologia , Animais , Neoplasias Encefálicas/genética , Diferenciação Celular/genética , Linhagem Celular , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Epigenoma , Regulação da Expressão Gênica no Desenvolvimento , Glioma/genética , Histonas/genética , Humanos , Lisina/metabolismo , Masculino , Camundongos Endogâmicos , Mutação , Células-Tronco Neurais/transplante , Oncogenes , Complexo Repressor Polycomb 2/antagonistas & inibidores , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas , Rombencéfalo/fisiologia
6.
Dev Biol ; 479: 61-76, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34310923

RESUMO

Meis genes are known to play important roles in the hindbrain and neural crest cells of jawed vertebrates. To explore the roles of Meis genes in head development during evolution of vertebrates, we have identified four meis genes in the sea lamprey genome and characterized their patterns of expression and regulation, with a focus on the hindbrain and pharynx. Each of the lamprey meis genes displays temporally and spatially dynamic patterns of expression, some of which are coupled to rhombomeric domains in the developing hindbrain and select pharyngeal arches. Studies of Meis loci in mouse and zebrafish have identified enhancers that are bound by Hox and TALE (Meis and Pbx) proteins, implicating these factors in the direct regulation of Meis expression. We examined the lamprey meis loci and identified a series of cis-elements conserved between lamprey and jawed vertebrate meis genes. In transgenic reporter assays we demonstrated that these elements act as neural enhancers in lamprey embryos, directing reporter expression in appropriate domains when compared to expression of their associated endogenous meis gene. Sequence alignments reveal that these conserved elements are in similar relative positions of the meis loci and contain a series of consensus binding motifs for Hox and TALE proteins. This suggests that ancient Hox and TALE-responsive enhancers regulated expression of ancestral vertebrate meis genes in segmental domains in the hindbrain and have been retained in the meis loci during vertebrate evolution. The presence of conserved Meis, Pbx and Hox binding sites in these lamprey enhancers links Hox and TALE factors to regulation of lamprey meis genes in the developing hindbrain, indicating a deep ancestry for these regulatory interactions prior to the divergence of jawed and jawless vertebrates.


Assuntos
Lampreias/genética , Tubo Neural/embriologia , Rombencéfalo/embriologia , Animais , Sítios de Ligação , Padronização Corporal/genética , Sequência Conservada , Elementos Facilitadores Genéticos , Expressão Gênica/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Genes Homeobox/genética , Proteínas de Homeodomínio/metabolismo , Lampreias/metabolismo , Proteína Meis1/genética , Proteína Meis1/metabolismo , Crista Neural/metabolismo , Tubo Neural/metabolismo , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Fator de Transcrição 1 de Leucemia de Células Pré-B/metabolismo , Rombencéfalo/metabolismo , Fatores de Transcrição/metabolismo
7.
Nat Commun ; 12(1): 4145, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230474

RESUMO

Organisms have the capacity to make decisions based solely on internal drives. However, it is unclear how neural circuits form decisions in the absence of sensory stimuli. Here we provide a comprehensive map of the activity patterns underlying the generation of saccades made in the absence of visual stimuli. We perform calcium imaging in the larval zebrafish to discover a range of responses surrounding spontaneous saccades, from cells that display tonic discharge only during fixations to neurons whose activity rises in advance of saccades by multiple seconds. When we lesion cells in these populations we find that ablation of neurons with pre-saccadic rise delays saccade initiation. We analyze spontaneous saccade initiation using a ramp-to-threshold model and are able to predict the times of upcoming saccades using pre-saccadic activity. These findings suggest that ramping of neuronal activity to a bound is a critical component of self-initiated saccadic movements.


Assuntos
Controle da População , Rombencéfalo/patologia , Rombencéfalo/fisiologia , Movimentos Sacádicos/fisiologia , Animais , Potenciais Evocados Visuais , Movimentos Oculares , Tecnologia de Rastreamento Ocular/psicologia , Larva , Neurônios/patologia , Neurônios/fisiologia , Tempo de Reação/fisiologia , Peixe-Zebra
8.
Sci Rep ; 11(1): 12644, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135354

RESUMO

Saccades are rapid eye movements that redirect gaze. Their magnitudes and directions are tightly controlled by the oculomotor system, which is capable of generating conjugate, monocular, convergent and divergent saccades. Recent studies suggest a mainly monocular control of saccades in mammals, although the development of binocular control and the interaction of different functional populations is less well understood. For zebrafish, a well-established model in sensorimotor research, the nature of binocular control in this key oculomotor behavior is unknown. Here, we use the optokinetic response and calcium imaging to characterize how the developing zebrafish oculomotor system encodes the diverse repertoire of saccades. We find that neurons with phasic saccade-associated activity (putative burst neurons) are most frequent in dorsal regions of the hindbrain and show elements of both monocular and binocular encoding, revealing a mix of the response types originally hypothesized by Helmholtz and Hering. Additionally, we observed a certain degree of behavior-specific recruitment in individual neurons. Surprisingly, calcium activity is only weakly tuned to saccade size. Instead, saccade size is apparently controlled by a push-pull mechanism of opposing burst neuron populations. Our study reveals the basic layout of a developing vertebrate saccade system and provides a perspective into the evolution of the oculomotor system.


Assuntos
Movimentos Sacádicos/fisiologia , Visão Binocular/fisiologia , Peixe-Zebra/fisiologia , Animais , Neurônios/fisiologia , Rombencéfalo/citologia , Rombencéfalo/fisiologia
9.
PLoS Comput Biol ; 17(6): e1009077, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34161317

RESUMO

The vertebrate hindbrain is segmented into rhombomeres (r) initially defined by distinct domains of gene expression. Previous studies have shown that noise-induced gene regulation and cell sorting are critical for the sharpening of rhombomere boundaries, which start out rough in the forming neural plate (NP) and sharpen over time. However, the mechanisms controlling simultaneous formation of multiple rhombomeres and accuracy in their sizes are unclear. We have developed a stochastic multiscale cell-based model that explicitly incorporates dynamic morphogenetic changes (i.e. convergent-extension of the NP), multiple morphogens, and gene regulatory networks to investigate the formation of rhombomeres and their corresponding boundaries in the zebrafish hindbrain. During pattern initiation, the short-range signal, fibroblast growth factor (FGF), works together with the longer-range morphogen, retinoic acid (RA), to specify all of these boundaries and maintain accurately sized segments with sharp boundaries. At later stages of patterning, we show a nonlinear change in the shape of rhombomeres with rapid left-right narrowing of the NP followed by slower dynamics. Rapid initial convergence improves boundary sharpness and segment size by regulating cell sorting and cell fate both independently and coordinately. Overall, multiple morphogens and tissue dynamics synergize to regulate the sizes and boundaries of multiple segments during development.


Assuntos
Padronização Corporal/fisiologia , Modelos Biológicos , Peixe-Zebra/embriologia , Animais , Padronização Corporal/genética , Biologia Computacional , Desenvolvimento Embrionário/genética , Desenvolvimento Embrionário/fisiologia , Fatores de Crescimento de Fibroblastos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Substâncias de Crescimento/fisiologia , Rombencéfalo/citologia , Rombencéfalo/embriologia , Transdução de Sinais , Processos Estocásticos , Tretinoína/fisiologia , Peixe-Zebra/genética
10.
J Neuroimmunol ; 357: 577623, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34082192

RESUMO

A wide number of neurological manifestations have been described in association with coronavirus disease 19 (COVID-19). We describe an unusual case of a young man who developed severe rhombencephalitis after COVID-19. He demonstrated clinical and radiological improvement with high dose corticosteroids, plasma exchange and intravenous immune globulin. Our findings, along with previously reported cases that we review here, support an autoimmune para- or post-infectious mechanism and highlight a possible role for immunotherapy in patients with rhombencephalitis after COVID-19.


Assuntos
COVID-19/complicações , COVID-19/diagnóstico por imagem , Encefalite Viral/diagnóstico por imagem , Encefalite Viral/etiologia , Rombencéfalo/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Masculino , Adulto Jovem
11.
Nutrients ; 13(5)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068091

RESUMO

The mesencephalic trigeminal nucleus (Mes5) processes oral sensory-motor information, but its role in the control of energy balance remains unexplored. Here, using fluorescent in situ hybridization, we show that the Mes5 expresses the melanocortin-4 receptor. Consistent with MC4R activation in other areas of the brain, we found that Mes5 microinjection of the MC4R agonist melanotan-II (MTII) suppresses food intake and body weight in the mouse. Furthermore, NTS POMC-projecting neurons to the Mes5 can be chemogenetically activated to drive a suppression in food intake. Taken together, these findings highlight the Mes5 as a novel target of melanocortinergic control of food intake and body weight regulation, although elucidating the endogenous role of this circuit requires future study. While we observed the sufficiency of Mes5 MC4Rs for food intake and body weight suppression, these receptors do not appear to be necessary for food intake or body weight control. Collectively, the data presented here support the functional relevance of the NTS POMC to Mes5 projection pathway as a novel circuit that can be targeted to modulate food intake and body weight.


Assuntos
Regulação do Apetite/fisiologia , Peso Corporal/fisiologia , Pró-Opiomelanocortina/fisiologia , Rombencéfalo/fisiologia , Tegmento Mesencefálico/fisiologia , Animais , Ingestão de Alimentos/fisiologia , Feminino , Hibridização in Situ Fluorescente , Masculino , Camundongos , Camundongos Knockout , Neurônios/fisiologia , Rombencéfalo/anatomia & histologia , Técnicas Estereotáxicas
12.
Diabetes ; 70(9): 1945-1955, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34176785

RESUMO

The dorsal vagal complex (DVC) in the hindbrain, composed of the area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus, plays a critical role in modulating satiety. The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) act directly in the brain to modulate feeding, and receptors for both are expressed in the DVC. Given the impressive clinical responses to pharmacologic manipulation of incretin signaling, understanding the central mechanisms by which incretins alter metabolism and energy balance is of critical importance. Here, we review recent single-cell approaches used to detect molecular signatures of GLP-1 and GIP receptor-expressing cells in the DVC. In addition, we discuss how current advancements in single-cell transcriptomics, epigenetics, spatial transcriptomics, and circuit mapping techniques have the potential to further characterize incretin receptor circuits in the hindbrain.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptores dos Hormônios Gastrointestinais/metabolismo , Rombencéfalo/metabolismo , Animais , Comportamento Alimentar/fisiologia , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Análise de Célula Única
13.
Sci Rep ; 11(1): 10840, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035395

RESUMO

Understanding how neural populations encode natural stimuli with complex spatiotemporal structure to give rise to perception remains a central problem in neuroscience. Here we investigated population coding of natural communication stimuli by hindbrain neurons within the electrosensory system of weakly electric fish Apteronotus leptorhynchus. Overall, we found that simultaneously recorded neural activities were correlated: signal but not noise correlations were variable depending on the stimulus waveform as well as the distance between neurons. Combining the neural activities using an equal-weight sum gave rise to discrimination performance between different stimulus waveforms that was limited by redundancy introduced by noise correlations. However, using an evolutionary algorithm to assign different weights to individual neurons before combining their activities (i.e., a weighted sum) gave rise to increased discrimination performance by revealing synergistic interactions between neural activities. Our results thus demonstrate that correlations between the neural activities of hindbrain electrosensory neurons can enhance information about the structure of natural communication stimuli that allow for reliable discrimination between different waveforms by downstream brain areas.


Assuntos
Peixe Elétrico/fisiologia , Rombencéfalo/fisiologia , Comunicação Animal , Animais , Órgão Elétrico/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Transmissão Sináptica
14.
Epilepsia ; 62(7): 1689-1700, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33997963

RESUMO

OBJECTIVE: Fetal exposure to the anticonvulsant drug valproic acid (VPA), used to treat certain types of epilepsy, increases the risk for birth defects, including neural tube defects, as well as learning difficulties and behavioral problems. Here, we investigated neurotoxic effects of VPA exposure using zebrafish as a model organism. The capacity of folic acid (FA) supplementation to rescue the VPA-induced neuronal and behavioral perturbations was also examined. METHODS: Zebrafish embryos of different transgenic lines with neuronal green fluorescent protein expression were exposed to increasing concentrations of VPA with or without FA supplementation. Fluorescence microscopy was used to visualize alterations in brain structures and neural progenitor cells, as well as motor neurons and neurite sprouting. A twitching behavioral assay was used to examine the functional consequences of VPA and FA treatment. RESULTS: In zebrafish embryos, VPA exposure caused a decrease in the midbrain size, an increase in the midline gap of the hindbrain, and perturbed neurite sprouting of secondary motor neurons, in a concentration-dependent manner. VPA exposure also decreased the fluorescence intensity of neuronal progenitor cells in early developmental stages, indicating fewer cells. Furthermore, VPA exposure significantly altered embryonic twitching activity, causing hyperactivity in dark and hypoactivity in light. Supplementation of FA rescued the VPA-induced smaller midbrain size and hindbrain midline gap defects. FA treatment also increased the number of neuronal progenitor cells in VPA-treated embryos and salvaged neurite sprouting of the secondary motor neurons. FA rescued the VPA-induced alterations in twitching activity in light but not in dark. SIGNIFICANCE: We conclude that VPA exposure induces specific neurotoxic perturbations in developing zebrafish embryos, and that FA reversed most of the identified defects. The results demonstrate that zebrafish is a promising model to study VPA-induced teratogenesis and to screen for countermeasures.


Assuntos
Anticonvulsivantes/toxicidade , Comportamento Animal/efeitos dos fármacos , Ácido Fólico/uso terapêutico , Síndromes Neurotóxicas/prevenção & controle , Síndromes Neurotóxicas/psicologia , Ácido Valproico/toxicidade , Vitaminas/uso terapêutico , Peixe-Zebra , Animais , Animais Geneticamente Modificados , Suplementos Nutricionais , Desenvolvimento Embrionário/efeitos dos fármacos , Larva , Iluminação , Mesencéfalo/anatomia & histologia , Mesencéfalo/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Defeitos do Tubo Neural/induzido quimicamente , Neuritos/efeitos dos fármacos , Rombencéfalo/anatomia & histologia , Rombencéfalo/efeitos dos fármacos , Ácido Valproico/antagonistas & inibidores
15.
Integr Comp Biol ; 61(1): 269-282, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-33974077

RESUMO

In seasonally breeding vertebrates, hormones coordinate changes in nervous system structure and function to facilitate reproductive readiness and success. Steroid hormones often exert their effects indirectly via regulation of neuromodulators, which in turn can coordinate the modulation of sensory input with appropriate motor output. Female plainfin midshipman fish (Porichthys notatus) undergo increased peripheral auditory sensitivity in time for the summer breeding season, improving their ability to detect mates, which is regulated by steroid hormones. Reproductive females also show differences in catecholaminergic innervation of auditory circuitry compared with winter, non-reproductive females as measured by tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholaminergic synthesis. Importantly, catecholaminergic input to the inner ear from a dopaminergic-specific forebrain nucleus is decreased in the summer and dopamine inhibits the sensitivity of the inner ear, suggesting that gonadal steroids may alter auditory sensitivity by regulating dopamine innervation. In this study, we gonadectomized non-reproductive females, implanted them with estradiol (E2) or testosterone (T), and measured TH immunoreactive (TH-ir) fibers in auditory nuclei where catecholaminergic innervation was previously shown to be seasonally plastic. We found that treatment with T, but not E2, reduced TH-ir innervation in the auditory hindbrain. T-treatment also reduced TH-ir fibers in the forebrain dopaminergic cell group that projects to the inner ear, and likely to the auditory hindbrain. Higher T plasma in the treatment group was correlated with reduced-ir TH terminals in the inner ear. These T-treatment induced changes in TH-ir fibers mimic the seasonal downregulation of dopamine in the midshipman inner ear and provide evidence that steroid hormone regulation of peripheral auditory sensitivity is mediated, in part, by dopamine.


Assuntos
Batracoidiformes , Dopamina , Orelha Interna/inervação , Rombencéfalo/fisiologia , Estações do Ano , Testosterona/farmacologia , Animais , Batracoidiformes/fisiologia , Regulação para Baixo , Orelha Interna/efeitos dos fármacos , Feminino
16.
Dev Genes Evol ; 231(3-4): 57-71, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34003345

RESUMO

Hoxa2 genes provide critical patterning signals during development, and their regulation and function have been extensively studied. We report a previously uncharacterized significant sequence divergence of a highly conserved hindbrain hoxa2b enhancer element in the family syngnathidae (pipefishes, seahorses, pipehorses, seadragons). We compared the hox cis-regulatory element variation in the Gulf pipefish and two species of seahorse against eight other species of fish, as well as human and mouse. We annotated the hoxa2b enhancer element binding sites across three species of seahorse, four species of pipefish, and one species of ghost pipefish. Finally, we performed in situ hybridization analysis of hoxa2b expression in Gulf pipefish embryos. We found that all syngnathid fish examined share a modified rhombomere 4 hoxa2b enhancer element, despite the fact that this element has been found to be highly conserved across all vertebrates examined previously. Binding element sequence motifs and spacing between binding elements have been modified for the hoxa2b enhancer in several species of pipefish and seahorse, and that the loss of the Prep/Meis binding site and further space shortening happened after ghost pipefish split from the rest of the syngnathid clade. We showed that expression of this gene in rhombomere 4 is lower relative to the surrounding rhombomeres in developing Gulf pipefish embryos, reflecting previously published functional tests for this enhancer. Our findings highlight the benefits of studying highly derived, diverse taxa for understanding of gene regulatory evolution and support the hypothesis that natural mutations can occur in deeply conserved pathways in ways potentially related to phenotypic diversity.


Assuntos
Elementos Facilitadores Genéticos , Proteínas de Peixes/genética , Peixes/genética , Especiação Genética , Proteínas de Homeodomínio/genética , Animais , Evolução Molecular , Peixes/classificação , Filogenia , Rombencéfalo/metabolismo
17.
Cells ; 10(4)2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807497

RESUMO

BACKGROUND: Consecutive adult neurogenesis is a well-known phenomenon in the ventricular-subventricular zone of the lateral wall of the lateral ventricles (V-SVZ) and has been controversially discussed in so-called "non-neurogenic" brain areas such as the periventricular regions (PVRs) of the aqueduct and the fourth ventricle. Dopamine is a known modulator of adult neural stem cell (aNSC) proliferation and dopaminergic neurogenesis in the olfactory bulb, though a possible interplay between local dopaminergic neurodegeneration and induction of aNSC proliferation in mid/hindbrain PVRs is currently enigmatic. OBJECTIVE/HYPOTHESIS: To analyze the influence of chronic-progressive dopaminergic neurodegeneration on both consecutive adult neurogenesis in the PVRs of the V-SVZ and mid/hindbrain aNSCs in two mechanistically different transgenic animal models of Parkinson´s disease (PD). METHODS: We used Thy1-m[A30P]h α synuclein mice and Leu9'Ser hypersensitive α4* nAChR mice to assess the influence of midbrain dopaminergic neuronal loss on neurogenic activity in the PVRs of the V-SVZ, the aqueduct and the fourth ventricle. RESULTS: In both animal models, overall proliferative activity in the V-SVZ was not altered, though the proportion of B2/activated B1 cells on all proliferating cells was reduced in the V-SVZ in Leu9'Ser hypersensitive α4* nAChR mice. Putative aNSCs in the mid/hindbrain PVRs are known to be quiescent in vivo in healthy controls, and dopaminergic deficiency did not induce proliferative activity in these regions in both disease models. CONCLUSIONS: Our data do not support an activation of endogenous aNSCs in mid/hindbrain PVRs after local dopaminergic neurodegeneration. Spontaneous endogenous regeneration of dopaminergic cell loss through resident aNSCs is therefore unlikely.


Assuntos
Dopamina/deficiência , Mesencéfalo/fisiologia , Neurogênese , Animais , Proliferação de Células , Humanos , Ventrículos Laterais/fisiologia , Camundongos Endogâmicos C57BL , Receptores Nicotínicos/metabolismo , Rombencéfalo/fisiologia , alfa-Sinucleína/metabolismo
18.
Am J Physiol Regul Integr Comp Physiol ; 320(6): R791-R799, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33825506

RESUMO

Astrocyte glycogen is dynamically remodeled during metabolic stability and provides oxidizable l-lactate equivalents during neuroglucopenia. Current research investigated the hypothesis that ventromedial hypothalamic nucleus (VMN) glycogen metabolism controls glucostimulatory nitric oxide (NO) and/or glucoinhibitory gamma-aminobutyric acid (GABA) neuron 5'-AMP-activated protein kinase (AMPK) and transmitter marker, e.g., neuronal nitric oxide synthase (nNOS), and glutamate decarboxylase65/67 (GAD) protein expression. Adult ovariectomized estradiol-implanted female rats were injected into the VMN with the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) before vehicle or l-lactate infusion. Western blot analysis of laser-catapult-microdissected nitrergic and GABAergic neurons showed that DAB caused lactate-reversible upregulation of nNOS and GAD proteins. DAB suppressed or increased total AMPK content of NO and GABA neurons, respectively, by lactate-independent mechanisms, but lactate prevented drug enhancement of pAMPK expression in nitrergic neurons. Inhibition of VMN glycogen disassembly caused divergent changes in counter-regulatory hormone, e.g. corticosterone (increased) and glucagon (decreased) secretion. Outcomes show that VMN glycogen metabolism controls local glucoregulatory transmission by means of lactate signal volume. Results implicate glycogen-derived lactate deficiency as a physiological stimulus of corticosterone release. Concurrent normalization of nitrergic neuron nNOS and pAMPK protein and corticosterone secretory response to DAB by lactate infers that the hypothalamic-pituitary-adrenal axis may be activated by VMN NO-mediated signals of cellular energy imbalance.


Assuntos
Ácido Láctico/metabolismo , Norepinefrina/farmacologia , Células Receptoras Sensoriais/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Estradiol/farmacologia , Neurotransmissores/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Ratos Sprague-Dawley , Receptores de Estrogênio/efeitos dos fármacos , Rombencéfalo/metabolismo
19.
Nutrients ; 13(3)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799575

RESUMO

The regulation of energy balance requires the complex integration of homeostatic and hedonic pathways, but sensory inputs from the gastrointestinal (GI) tract are increasingly recognized as playing critical roles. The stomach and small intestine relay sensory information to the central nervous system (CNS) via the sensory afferent vagus nerve. This vast volume of complex sensory information is received by neurons of the nucleus of the tractus solitarius (NTS) and is integrated with responses to circulating factors as well as descending inputs from the brainstem, midbrain, and forebrain nuclei involved in autonomic regulation. The integrated signal is relayed to the adjacent dorsal motor nucleus of the vagus (DMV), which supplies the motor output response via the efferent vagus nerve to regulate and modulate gastric motility, tone, secretion, and emptying, as well as intestinal motility and transit; the precise coordination of these responses is essential for the control of meal size, meal termination, and nutrient absorption. The interconnectivity of the NTS implies that many other CNS areas are capable of modulating vagal efferent output, emphasized by the many CNS disorders associated with dysregulated GI functions including feeding. This review will summarize the role of major CNS centers to gut-related inputs in the regulation of gastric function with specific reference to the regulation of food intake.


Assuntos
Vias Aferentes , Encéfalo/fisiologia , Ingestão de Alimentos , Vias Eferentes , Trato Gastrointestinal/inervação , Trato Gastrointestinal/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Diabetes Mellitus/fisiopatologia , Hipocampo/fisiologia , Humanos , Hipotálamo/fisiologia , Inflamação/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Obesidade/fisiopatologia , Rombencéfalo/fisiologia , Nervo Vago/fisiologia
20.
J Int Med Res ; 49(4): 300060521998568, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33866842

RESUMO

Listeria monocytogenes is a Gram-positive facultative intracellular bacterium that causes central nervous system infection. We report a case of rhombencephalitis caused by L. monocytogenes infection, which mimicked Bickerstaff's brainstem encephalitis, and GQ1b antibody positivity and multiple intracranial foci were observed. A 68-year-old male patient presented with a nonspecific prodrome of faintness, forehead tightness, and walking instability. This was followed by progressive cranial nerve palsies, limb weakness, cerebellar signs, hyperpyrexia, and impaired consciousness. Brain imaging showed multiple abnormal brainstem and cerebellar signals that were accompanied by blood infiltration without any lesion enhancement. Serum GQ1b antibody positivity led to an initial diagnosis of Bickerstaff's brainstem encephalitis, which was treated with immunosuppressive therapy with limited efficacy. A pathogen examination helped confirm L. monocytogenes infection. A combination of meropenem and trimethoprim-sulfamethoxazole therapy was applied and the patient recovered without sequelae. The symptoms and imaging of Listeria rhombencephalitis are nonspecific. Accurate diagnosis and prompt treatment of this condition are essential. Whether Listeria infection triggers an autoimmune response remains unclear.


Assuntos
Hemorragias Intracranianas/etiologia , Listeria monocytogenes/isolamento & purificação , Listeriose/diagnóstico , Rombencéfalo/diagnóstico por imagem , Idoso , Infecções do Sistema Nervoso Central , Encefalite/diagnóstico por imagem , Encefalite/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Listeria monocytogenes/genética , Listeriose/tratamento farmacológico , Masculino , Neuroimagem
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