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1.
Cell ; 157(7): 1552-64, 2014 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-24949968

RESUMEN

The hippocampus, as part of the cerebral cortex, is essential for memory formation and spatial navigation. Although it has been extensively studied, especially as a model system for neurophysiology, the cellular processes involved in constructing and organizing the hippocampus remain largely unclear. Here, we show that clonally related excitatory neurons in the developing hippocampus are progressively organized into discrete horizontal, but not vertical, clusters in the stratum pyramidale, as revealed by both cell-type-specific retroviral labeling and mosaic analysis with double markers (MADM). Moreover, distinct from those in the neocortex, sister excitatory neurons in the cornu ammonis 1 region of the hippocampus rarely develop electrical or chemical synapses with each other. Instead, they preferentially receive common synaptic input from nearby fast-spiking (FS), but not non-FS, interneurons and exhibit synchronous synaptic activity. These results suggest that shared inhibitory input may specify horizontally clustered sister excitatory neurons as functional units in the hippocampus.


Asunto(s)
Hipocampo/citología , Hipocampo/fisiología , Animales , Embrión de Mamíferos/citología , Técnicas Genéticas , Interneuronas , Ratones , Neuronas/fisiología , Coloración y Etiquetado/métodos , Sinapsis
2.
Elife ; 122024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38470230

RESUMEN

In the process of synaptic formation, neurons must not only adhere to specific principles when selecting synaptic partners but also possess mechanisms to avoid undesirable connections. Yet, the strategies employed to prevent unwarranted associations have remained largely unknown. In our study, we have identified the pivotal role of combinatorial clustered protocadherin gamma (γ-PCDH) expression in orchestrating synaptic connectivity in the mouse neocortex. Through 5' end single-cell sequencing, we unveiled the intricate combinatorial expression patterns of γ-PCDH variable isoforms within neocortical neurons. Furthermore, our whole-cell patch-clamp recordings demonstrated that as the similarity in this combinatorial pattern among neurons increased, their synaptic connectivity decreased. Our findings elucidate a sophisticated molecular mechanism governing the construction of neural networks in the mouse neocortex.


Asunto(s)
Proteínas Relacionadas con las Cadherinas , Neocórtex , Animales , Ratones , Cadherinas/genética , Redes Neurales de la Computación
3.
Curr Biol ; 33(22): 4827-4843.e7, 2023 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-37848038

RESUMEN

Food cues serve as pivotal triggers for eliciting physiological responses that subsequently influence food consumption. The magnitude of response induced by these cues stands as a critical determinant in the context of obesity risk. Nonetheless, the underlying neural mechanism that underpins how cues associated with edible food potentiate feeding behaviors remains uncertain. In this study, we revealed that corticotropin-releasing hormone (CRH)-expressing neurons in the lateral hypothalamic area played a crucial role in promoting consummatory behaviors in mice, shedding light on this intricate process. By employing an array of diverse assays, we initially established the activation of these neurons during feeding. Manipulations using optogenetic and chemogenetic assays revealed that their activation amplified appetite and promoted feeding behaviors, whereas inhibition decreased them. Additionally, our investigation identified downstream targets, including the ventral tegmental area, and underscored the pivotal involvement of the CRH neuropeptide itself in orchestrating this regulatory network. This research casts a clarifying light on the neural mechanism underlying the augmentation of appetite and the facilitation of feeding behaviors in response to food cues. VIDEO ABSTRACT.


Asunto(s)
Hormona Liberadora de Corticotropina , Área Hipotalámica Lateral , Ratones , Animales , Área Hipotalámica Lateral/fisiología , Hormona Liberadora de Corticotropina/metabolismo , Conducta Alimentaria/fisiología , Neuronas/fisiología , Apetito
4.
Neurosci Bull ; 38(6): 591-606, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35147909

RESUMEN

Abnormal synchronous neuronal activity has been widely detected by brain imaging of autistic patients, but its underlying neural mechanism remains unclear. Compared with wild-type mice, our in vivo two-photon imaging showed that transgenic (Tg1) mice over-expressing human autism risk gene MeCP2 exhibited higher neuronal synchrony in the young but lower synchrony in the adult stage. Whole-cell recording of neuronal pairs in brain slices revealed that higher neuronal synchrony in young postnatal Tg1 mice was attributed mainly to more prevalent giant slow inward currents (SICs). Both in vivo and slice imaging further demonstrated more dynamic activity and higher synchrony in astrocytes from young Tg1 mice. Blocking astrocytic gap junctions markedly decreased the generation of SICs and overall cell synchrony in the Tg1 brain. Furthermore, the expression level of Cx43 protein and the coupling efficiency of astrocyte gap junctions remained unchanged in Tg1 mice. Thus, astrocytic gap junctions facilitate but do not act as a direct trigger for the abnormal neuronal synchrony in young Tg1 mice, revealing the potential role of the astrocyte network in the pathogenesis of MeCP2 duplication syndrome.


Asunto(s)
Astrocitos , Discapacidad Intelectual Ligada al Cromosoma X , Animales , Astrocitos/metabolismo , Modelos Animales de Enfermedad , Uniones Comunicantes/metabolismo , Humanos , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones , Neuronas/metabolismo
5.
Curr Biol ; 32(14): 3137-3145.e3, 2022 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-35659861

RESUMEN

Dissecting neural connectivity patterns within local brain regions is an essential step to understanding the function of the brain.1 Neural microcircuits in brain regions, such as the neocortex and the hippocampus, have been extensively studied.2 By contrast, the microcircuit in the hypothalamus remains largely uncharacterized. The hypothalamus is crucial for animals' survival and reproduction.3 Knowledge of how different hypothalamic nuclei coordinate with each other and outside brain regions for hypothalamus-related functions has been significantly advanced.4-9 Although there are limited studies on the neural microcircuit in the lateral hypothalamus (LHA)10,11 and the suprachiasmatic nucleus (SCN),12,13 the patterns of neural microcircuits in most of the given hypothalamic nuclei remain largely unknown. This study applied combinatory approaches to address the local neural circuit pattern in the ventromedial hypothalamus (VMH) and other hypothalamic nuclei. We discovered a unique neural circuit design in the VMH. Neurons in the VMH were electrically coupled at the early postnatal stage like ones in the neocortex.14 However, unlike neocortical neurons,14,15 they developed very few chemical synapses after the disappearance of electrical synapses. Instead, VMH neurons communicated with neuropeptides. The similar scarceness of synaptic connectivity found in other hypothalamic nuclei further indicated that the lack of synaptic connections is a unique feature for local neural circuits in most adult hypothalamic nuclei. Thus, our findings provide a solid synaptic basis at the cellular level to understand hypothalamic functions better.


Asunto(s)
Hipotálamo , Neuropéptidos , Animales , Comunicación Celular , Área Hipotalámica Lateral/fisiología , Hipotálamo/fisiología , Neuronas/fisiología , Núcleo Hipotalámico Ventromedial/fisiología
6.
Nat Neurosci ; 10(5): 549-51, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17417634

RESUMEN

Determining the degree of synapse formation and elimination is essential for understanding the structural basis of brain plasticity and pathology. We show that in vivo imaging of dendritic spine dynamics through an open-skull glass window, but not a thinned-skull window, is associated with high spine turnover and substantial glial activation during the first month after surgery. These findings help to explain existing discrepancies in the degree of dendritic spine plasticity observed in the mature cortex.


Asunto(s)
Craneotomía , Espinas Dendríticas/ultraestructura , Plasticidad Neuronal/fisiología , Corteza Somatosensorial/citología , Animales , Receptor 1 de Quimiocinas CX3C , Craneotomía/métodos , Espinas Dendríticas/metabolismo , Diagnóstico por Imagen/métodos , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , Ratones Transgénicos , Microscopía Confocal/métodos , Neuroglía/metabolismo , Receptores de Quimiocina/genética , Receptores de Quimiocina/metabolismo , Factores de Tiempo
7.
Neurosci Bull ; 36(6): 570-584, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32144612

RESUMEN

Methyl-CpG binding protein 2 (MeCP2) is a basic nuclear protein involved in the regulation of gene expression and microRNA processing. Duplication of MECP2-containing genomic segments causes MECP2 duplication syndrome, a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, heightened anxiety, epilepsy, autistic phenotypes, and early death. Reversal of the abnormal phenotypes in adult mice with MECP2 duplication (MECP2-TG) by normalizing the MeCP2 levels across the whole brain has been demonstrated. However, whether different brain areas or neural circuits contribute to different aspects of the behavioral deficits is still unknown. Here, we found that MECP2-TG mice showed a significant social recognition deficit, and were prone to display aversive-like behaviors, including heightened anxiety-like behaviors and a fear generalization phenotype. In addition, reduced locomotor activity was observed in MECP2-TG mice. However, appetitive behaviors and learning and memory were comparable in MECP2-TG and wild-type mice. Functional magnetic resonance imaging illustrated that the differences between MECP2-TG and wild-type mice were mainly concentrated in brain areas regulating emotion and social behaviors. We used the CRISPR-Cas9 method to restore normal MeCP2 levels in the medial prefrontal cortex (mPFC) and bed nuclei of the stria terminalis (BST) of adult MECP2-TG mice, and found that normalization of MeCP2 levels in the mPFC but not in the BST reversed the social recognition deficit. These data indicate that the mPFC is responsible for the social recognition deficit in the transgenic mice, and provide new insight into potential therapies for MECP2 duplication syndrome.


Asunto(s)
Proteína 2 de Unión a Metil-CpG , Corteza Prefrontal , Reconocimiento en Psicología , Conducta Social , Animales , Ansiedad , China , Modelos Animales de Enfermedad , Miedo , Duplicación de Gen , Masculino , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones , Ratones Transgénicos , Corteza Prefrontal/metabolismo
8.
Sci Rep ; 8(1): 8808, 2018 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-29892075

RESUMEN

U0126 (1,4-diamino-2,3-dicyano-1,4-bis (2-aminophenylthio) butadiene), a widely used mitogen-activated protein kinase kinase (MEK) inhibitor, was found to accelerate voltage-gated K+ channel (KV) inactivation in heterologous cells expressing several types of KV. The goal of this study was to examine whether U0126 at a concentration thought to specifically inhibit MEK signaling also inhibits KV in native neurons of primary cultures or brain slices. U0126 caused a dose-dependent inhibition of both the transient (IA) and sustained (IDR) components of K+ currents in hippocampal neurons. U0126 also exhibited much higher potency on the IA and IDR than the classical KV blockers 4-aminopyridine (4-AP) and tetraethylammonium (TEA). Consistent with its inhibitory effect on KV, U0126 broadened action potential duration, profoundly affected the repolarizing phase, and dramatically reduced firing frequency in response to current pulse injections. Despite the potent and reversible action of U0126 on Kv channels, PD98059, a structurally-unrelated MEK inhibitor, did not induce such an effect, suggesting U0126 may act independently of MEK inhibition. Together, these results raise cautions for using U0126 as a specific inhibitor for studying MEK signaling in neurons; on the other hand, further studies on the blocking mechanisms of U0126 as a potent inhibitor of KV may provide useful insights into the structure-function relationship of KV in general.


Asunto(s)
Butadienos/farmacología , Hipocampo/enzimología , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Neuronas/enzimología , Nitrilos/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Células Cultivadas , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp
9.
Cell ; 129(2): 385-95, 2007 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-17448996

RESUMEN

Neuronal migration and growth-cone extension are both guided by extracellular factors in the developing brain, but whether these two forms of guidance are mechanistically linked is unclear. Application of a Slit-2 gradient in front of the leading process of cultured cerebellar granule cells led to the collapse of the growth cone and the reversal of neuronal migration, an event preceded by a propagating Ca(2+) wave from the growth cone to the soma. The Ca(2+) wave was required for the Slit-2 effect and was sufficient by itself to induce the reversal of migration. The Slit-2-induced reversal of migration required active RhoA, which was accumulated at the front of the migrating neuron, and this polarized RhoA distribution was reversed during the migration reversal induced by either the Slit-2 gradient or the Ca(2+) wave. Thus, long-range Ca(2+) signaling coordinates the Slit-2-induced changes in motility at two distant parts of migrating neurons by regulating RhoA distribution.


Asunto(s)
Señalización del Calcio , Movimiento Celular , Conos de Crecimiento/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Animales , Calcio/metabolismo , Células Cultivadas , Cerebelo/citología , Ratas , Ratas Sprague-Dawley , Proteína de Unión al GTP rhoA/metabolismo
10.
Proc Natl Acad Sci U S A ; 101(12): 4296-301, 2004 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-15020772

RESUMEN

Migration of neuronal precursor cells in the developing brain is guided by extracellular cues, but intracellular signaling processes underlying the guidance of neuronal migration are largely unknown. By examining the migration of cerebellar granule neurons along the surface of cocultured astroglial cells, we found that an extracellular gradient of Slit2, a chemorepellant for neuronal migration in vivo, caused a reversal in the direction of migration without affecting the migration speed. A Slit2 gradient elevated the intracellular concentration of Ca2+, probably due to calcium release from the internal store, led to a reversal of the preexisting asymmetric intracellular Ca2+ distribution in the soma of migrating neurons, and this reversal was closely related with its action of reversing the migrating direction. Asymmetric Ca2+ distribution in the soma was both necessary and sufficient for directing neuronal migration. These results have demonstrated an important role for Ca2+ in mediating neuronal responses to Slit2 and suggest a general mechanism for neuronal guidance.


Asunto(s)
Señalización del Calcio/fisiología , Movimiento Celular/fisiología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Animales , Cerebelo/metabolismo , Péptidos y Proteínas de Señalización Intercelular , Ratas , Factores de Tiempo
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