RESUMEN
The thalamus plays a central coordinating role in the brain. Thalamic neurons are organized into spatially distinct nuclei, but the molecular architecture of thalamic development is poorly understood, especially in humans. To begin to delineate the molecular trajectories of cell fate specification and organization in the developing human thalamus, we used single-cell and multiplexed spatial transcriptomics. We show that molecularly defined thalamic neurons differentiate in the second trimester of human development and that these neurons organize into spatially and molecularly distinct nuclei. We identified major subtypes of glutamatergic neuron subtypes that are differentially enriched in anatomically distinct nuclei and six subtypes of γ-aminobutyric acid-mediated (GABAergic) neurons that are shared and distinct across thalamic nuclei.
Asunto(s)
Neuronas GABAérgicas , Neurogénesis , Tálamo , Humanos , Núcleos Talámicos/citología , Núcleos Talámicos/crecimiento & desarrollo , Tálamo/citología , Tálamo/crecimiento & desarrollo , Neuronas GABAérgicas/fisiología , Femenino , Embarazo , Análisis de la Célula Individual , Segundo Trimestre del EmbarazoRESUMEN
Songbirds learn vocalizations by hearing and practicing songs. As song develops, the tempo becomes faster and more precise. In the songbird brain, discrete nuclei form interconnected myelinated circuits that control song acquisition and production. The myelin sheath increases the speed of action potential propagation by insulating the axons of neurons and by reducing membrane capacitance. As the brain develops, myelin increases in density, but the time course of myelin development across discrete song nuclei has not been systematically studied in a quantitative fashion. We tested the hypothesis that myelination develops differentially across time and song nuclei. We examined myelin development in the brains of the zebra finch (Taeniopygia guttata) from chick at posthatch day (d) 8 to adult (up to 147 d) in five major song nuclei: HVC (proper name), robust nucleus of the arcopallium (RA), Area X, lateral magnocellular nucleus of the anterior nidopallium, and medial portion of the dorsolateral thalamic nucleus (DLM). All of these nuclei showed an increase in the density of myelination during development but at different rates and to different final degrees. Exponential curve fits revealed that DLM showed earlier myelination than other nuclei, and HVC showed the slowest myelination of song nuclei. Together, these data show differential maturation of myelination in different portions of the song system. Such differential maturation would be well placed to play a role in regulating the development of learned song.
Asunto(s)
Núcleo Basal de Meynert/crecimiento & desarrollo , Pinzones/fisiología , Vaina de Mielina/fisiología , Núcleos Talámicos/crecimiento & desarrollo , Vocalización Animal/fisiología , Factores de Edad , Animales , Núcleo Basal de Meynert/anatomía & histología , Pinzones/anatomía & histología , Pájaros Cantores , Núcleos Talámicos/anatomía & histologíaRESUMEN
The fast-spiking parvalbumin (PV) interneurons play a critical role in neural circuit activity and dysfunction of these cells has been implicated in the cognitive deficits typically observed in schizophrenia patients. Due to the high metabolic demands of PV neurons, they are particularly susceptible to oxidative stress. Given the extant literature exploring the pathological effects of oxidative stress on PV cells in cortical regions linked to schizophrenia, we decided to investigate whether PV neurons in other select brain regions, including sub-cortical structures, may be differentially affected by redox dysregulation induced oxidative stress during neurodevelopment in mice with a genetically compromised glutathione synthesis (Gclm KO mice). Our analyses revealed a spatio-temporal sequence of PV cell deficit in Gclm KO mice, beginning with the thalamic reticular nucleus at postnatal day (P) 20 followed by a PV neuronal deficit in the amygdala at P40, then in the lateral globus pallidus and the ventral hippocampus Cornu Ammonis 3 region at P90 and finally the anterior cingulate cortex at P180. We suggest that PV neurons in different brain regions are developmentally susceptible to oxidative stress and that anomalies in the neurodevelopmental calendar of metabolic regulation can interfere with neural circuit maturation and functional connectivity contributing to the emergence of developmental psychopathology.
Asunto(s)
Amígdala del Cerebelo , Globo Pálido , Giro del Cíngulo , Hipocampo , Interneuronas/metabolismo , Red Nerviosa , Oxidación-Reducción , Estrés Oxidativo/fisiología , Parvalbúminas , Esquizofrenia/metabolismo , Núcleos Talámicos , Amígdala del Cerebelo/crecimiento & desarrollo , Amígdala del Cerebelo/metabolismo , Animales , Modelos Animales de Enfermedad , Globo Pálido/crecimiento & desarrollo , Globo Pálido/metabolismo , Glutamato-Cisteína Ligasa/genética , Giro del Cíngulo/crecimiento & desarrollo , Giro del Cíngulo/metabolismo , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Red Nerviosa/crecimiento & desarrollo , Red Nerviosa/metabolismo , Núcleos Talámicos/crecimiento & desarrollo , Núcleos Talámicos/metabolismoRESUMEN
Dysfunction of thalamo-cortical networks involving particularly the thalamic reticular nucleus (TRN) is implicated in schizophrenia. In the neonatal ventral hippocampal lesion (NVHL), a heuristic animal model of schizophrenia, brain oscillation changes similar to those of schizophrenic patients have been reported. The aim of this study was to analyze the effects of short-term deep brain stimulation (DBS) in the thalamic reticular nucleus on electroencephalographic (EEG) activity in the NVHL. Male and female Sprague-Dawley rats were used and the model was prepared by excitotoxicity damage of the ventral hippocampus on postnatal day 7 (PD-7). Chronic bilateral stainless steel electrodes were implanted in the TRN, thalamic dorsomedial nucleus and prelimbic area at PD-90. Rats were classified as follows: sham and NVHL groups, both groups received bilateral DBS in the TRN for one hour (100Hz, 100µs pulses, 200µA). All animals showed a sudden behavioral arrest accompanied by widespread symmetric bilateral spike-wave discharges, this activity was affected by DBS-TRN. Additionally, the power spectra of 0.5-100Hz and the coherence of 0.5-4.5 and 35-55Hz frequencies were modified by DBS-TRN. Our results suggest that DBS in the TRN may modify functional connectivity between different parts of the thalamo-cortical network. Additionally, our findings may suggest a beneficial effect of DBS-TRN on some preclinical aberrant oscillatory activities in a neurodevelopmental model of schizophrenia.
Asunto(s)
Ondas Encefálicas/fisiología , Esquizofrenia/fisiopatología , Esquizofrenia/terapia , Núcleos Talámicos/fisiopatología , Animales , Estimulación Encefálica Profunda , Modelos Animales de Enfermedad , Electrocorticografía , Femenino , Hipocampo/crecimiento & desarrollo , Hipocampo/fisiopatología , Ácido Iboténico , Masculino , Actividad Motora/fisiología , Distribución Aleatoria , Ratas Sprague-Dawley , Núcleos Talámicos/crecimiento & desarrolloRESUMEN
The molecular mechanisms underlying the formation of the thalamus during development have been investigated intensively. Although transcription factors distinguishing the thalamic primordium from adjacent brain structures have been uncovered, those involved in patterning inside the thalamus are largely unclear. Here, we show that Foxp2, a member of the forkhead transcription factor family, regulates thalamic patterning during development. We found a graded expression pattern of Foxp2 in the thalamic primordium of the mouse embryo. The expression levels of Foxp2 were high in the posterior region and low in the anterior region of the thalamic primordium. In Foxp2 (R552H) knockin mice, which have a missense loss-of-function mutation in the forkhead domain of Foxp2, thalamic nuclei of the posterior region of the thalamus were shrunken, while those of the intermediate region were expanded. Consistently, Foxp2 (R552H) knockin mice showed changes in thalamocortical projection patterns. Our results uncovered important roles of Foxp2 in thalamic patterning and thalamocortical projections during development.
Asunto(s)
Tipificación del Cuerpo/genética , Regulación del Desarrollo de la Expresión Génica/genética , Factor Nuclear 3-beta del Hepatocito/metabolismo , Mutación/genética , Vías Nerviosas/fisiología , Núcleos Talámicos , Factores de Edad , Animales , Animales Recién Nacidos , Calbindina 2/metabolismo , Desoxirribonucleasas/metabolismo , Electroporación/métodos , Embrión de Mamíferos , Regulación del Desarrollo de la Expresión Génica/fisiología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Factor Nuclear 3-beta del Hepatocito/genética , Proteínas con Homeodominio LIM/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , Ratones Endogámicos ICR , Ratones Transgénicos , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptor EphA8/metabolismo , Núcleos Talámicos/embriología , Núcleos Talámicos/crecimiento & desarrollo , Núcleos Talámicos/metabolismo , Factores de Transcripción/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/genética , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Proteína Fluorescente RojaRESUMEN
Corticothalamic projection systems arise from 2 main cortical layers. Layer V neurons project exclusively to higher-order thalamic nuclei, while layer VIa fibers project to both first-order and higher-order thalamic nuclei. During early postnatal development, layer VIa and VIb fibers accumulate at the borders of the dorsal lateral geniculate nucleus (dLGN) before they innervate it. After neonatal monocular enucleation or silencing of the early retinal activity, there is premature entry of layer VIa and VIb fibers into the dLGN contralateral to the manipulation. Layer V fibers do not innervate the superficial gray layer of the superior colliculus during the first postnatal week, but also demonstrate premature entry to the contralateral superficial gray layer following neonatal enucleation. Normally, layer V driver projections to the thalamus only innervate higher-order nuclei. Our results demonstrate that removal of retinal input from the dLGN induces cortical layer V projections to aberrantly enter, arborize, and synapse within the first-order dLGN. These results suggest that there is cross-hierarchical corticothalamic plasticity after monocular enucleation. Cross-hierarchical rewiring has been previously demonstrated in the thalamocortical system (Pouchelon et al. 2014), and now we provide evidence for cross-hierarchical corticothalamic rewiring after loss of the peripheral sensory input.
Asunto(s)
Corteza Cerebral/crecimiento & desarrollo , Retina/crecimiento & desarrollo , Núcleos Talámicos/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Aumento de la Célula , Corteza Cerebral/citología , Corteza Cerebral/fisiología , Inmunohistoquímica , Ratones Transgénicos , Vías Nerviosas/citología , Vías Nerviosas/crecimiento & desarrollo , Vías Nerviosas/fisiología , Agonistas Nicotínicos/farmacología , Células Piramidales/citología , Células Piramidales/fisiología , Piridinas/farmacología , Retina/citología , Retina/efectos de los fármacos , Retina/fisiología , Sinaptofisina/metabolismo , Núcleos Talámicos/citología , Núcleos Talámicos/fisiología , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
Comparative embryonic studies are the most effective way to discern phylogenetic changes. To gain insight into the constitution and evolution of mammalian somatosensory thalamic nuclei, we first studied how calbindin (CB) and parvalbumin (PV) immunoreactivities appear during embryonic development in the first-order relaying somatosensory nuclei, i.e., the ventral posteromedial (VPM) and posterolateral (VPL) nuclei, and their neighboring higher-order modulatory regions, including the ventromedial or ventrolateral nucleus, posterior, and the reticular nucleus. The results indicated that cell bodies that were immunoreactive for CB were found earlier (embryonic day 12 [E12]) in the dorsal thalamus than were cells positive for PV (E14), and the adult somatosensory thalamus was characterized by complementary CB and PV distributions with PV dominance in the first-order relaying nuclei and CB dominance in the higher-order regions. We then labeled proliferating cells with [(3) H]-thymidine from E11 to 19 and found that the onset of neurogenesis began later (E12) in the first-order relaying nuclei than in the higher-order regions (E11). Using double-labeling with [(3) H]-thymidine autoradiography and CB or PV immunohistochemistry, we found that CB neurons were born earlier (E11-12) than PV neurons (E12-13) in the studied areas. Thus, similar to auditory nuclei, the first and the higher-order somatosensory nuclei exhibited significant distinctions in CB/PV immunohistochemistry and birthdates during embryonic development. These data, combined with the results of a cladistic analysis of the thalamic somatosensory nuclei, are discussed from an evolutionary perspective of sensory nuclei.
Asunto(s)
Calbindinas/metabolismo , Neurogénesis , Parvalbúminas/metabolismo , Núcleos Talámicos/citología , Núcleos Talámicos/metabolismo , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Autorradiografía , Embrión de Mamíferos , Ratones , Neuronas , Núcleos Talámicos/embriología , Núcleos Talámicos/crecimiento & desarrollo , Timidina/metabolismo , Tritio/metabolismoRESUMEN
Anophthalmia is a condition in which the eye does not develop from the early embryonic period. Early blindness induces cross-modal plastic modifications in the brain such as auditory and haptic activations of the visual cortex and also leads to a greater solicitation of the somatosensory and auditory cortices. The visual cortex is activated by auditory stimuli in anophthalmic mice and activity is known to alter the growth pattern of the cerebral cortex. The size of the primary visual, auditory and somatosensory cortices and of the corresponding specific sensory thalamic nuclei were measured in intact and enucleated C57Bl/6J mice and in ZRDCT anophthalmic mice (ZRDCT/An) to evaluate the contribution of cross-modal activity on the growth of the cerebral cortex. In addition, the size of these structures were compared in intact, enucleated and anophthalmic fourth generation backcrossed hybrid C57Bl/6J×ZRDCT/An mice to parse out the effects of mouse strains and of the different visual deprivations. The visual cortex was smaller in the anophthalmic ZRDCT/An than in the intact and enucleated C57Bl/6J mice. Also the auditory cortex was larger and the somatosensory cortex smaller in the ZRDCT/An than in the intact and enucleated C57Bl/6J mice. The size differences of sensory cortices between the enucleated and anophthalmic mice were no longer present in the hybrid mice, showing specific genetic differences between C57Bl/6J and ZRDCT mice. The post natal size increase of the visual cortex was less in the enucleated than in the anophthalmic and intact hybrid mice. This suggests differences in the activity of the visual cortex between enucleated and anophthalmic mice and that early in-utero spontaneous neural activity in the visual system contributes to the shaping of functional properties of cortical networks.
Asunto(s)
Anoftalmos/patología , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/patología , Enucleación del Ojo/efectos adversos , Animales , Anoftalmos/fisiopatología , Corteza Cerebral/fisiopatología , Ratones Endogámicos C57BL , Tamaño de los Órganos , Especificidad de la Especie , Núcleos Talámicos/crecimiento & desarrollo , Núcleos Talámicos/patología , Núcleos Talámicos/fisiopatologíaRESUMEN
Kisspeptin, encoded by Kiss1, stimulates reproduction. In rodents, one Kiss1 population resides in the hypothalamic anterior ventral periventricular nucleus and neighboring rostral periventricular nucleus (AVPV/PeN). AVPV/PeN Kiss1 neurons are sexually dimorphic (greater in females), yet the mechanisms regulating their development and sexual differentiation remain poorly understood. Neonatal estradiol (E2) normally defeminizes AVPV/PeN kisspeptin neurons, but emerging evidence suggests that developmental E2 may also influence feminization of kisspeptin, although exactly when in development this process occurs is unknown. In addition, the obligatory role of GnRH signaling in governing sexual differentiation of Kiss1 or other sexually dimorphic traits remains untested. Here, we assessed whether AVPV/PeN Kiss1 expression is permanently impaired in adult hpg (no GnRH or E2) or C57BL6 mice under different E2 removal or replacement paradigms. We determined that 1) despite lacking GnRH signaling in development, marked sexual differentiation of Kiss1 still occurs in hpg mice; 2) adult hpg females, who lack lifetime GnRH and E2 exposure, have reduced AVPV/PeN Kiss1 expression compared to wild-type females, even after chronic adulthood E2 treatment; 3) E2 exposure to hpg females during the pubertal period does not rescue their submaximal adult Kiss1 levels; and 4) in C57BL6 females, removal of ovarian E2 before the pubertal or juvenile periods does not impair feminization and maximal adult AVPV/PeN Kiss1 expression nor the ability to generate LH surges, indicating that puberty is not a critical period for Kiss1 development. Thus, sexual differentiation still occurs without GnRH, but GnRH or downstream E2 signaling is needed sometime before juvenile development for complete feminization and maximal Kiss1 expression in adult females.
Asunto(s)
Hormona Liberadora de Gonadotropina/metabolismo , Kisspeptinas/metabolismo , Neuronas/metabolismo , Diferenciación Sexual , Transducción de Señal , Núcleos Talámicos/metabolismo , Regulación hacia Arriba , Animales , Núcleos Talámicos Anteriores/citología , Núcleos Talámicos Anteriores/efectos de los fármacos , Núcleos Talámicos Anteriores/crecimiento & desarrollo , Núcleos Talámicos Anteriores/metabolismo , Estradiol/farmacología , Estradiol/uso terapéutico , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Terapia de Reemplazo de Estrógeno , Estrógenos/farmacología , Estrógenos/uso terapéutico , Femenino , Hormona Liberadora de Gonadotropina/genética , Hipogonadismo/tratamiento farmacológico , Hipogonadismo/metabolismo , Hipogonadismo/patología , Núcleos Talámicos Intralaminares/citología , Núcleos Talámicos Intralaminares/efectos de los fármacos , Núcleos Talámicos Intralaminares/crecimiento & desarrollo , Núcleos Talámicos Intralaminares/metabolismo , Kisspeptinas/biosíntesis , Kisspeptinas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Ovariectomía/efectos adversos , Diferenciación Sexual/efectos de los fármacos , Desarrollo Sexual/efectos de los fármacos , Núcleos Talámicos/citología , Núcleos Talámicos/efectos de los fármacos , Núcleos Talámicos/crecimiento & desarrollo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Neurons in the brains of newborns are usually connected with many other neurons through weak synapses. This early pattern of connectivity is refined through pruning of many immature connections and strengthening of the remaining ones. NMDA receptors (NMDARs) are essential for the development of excitatory synapses, but their role in synaptic refinement is controversial. Although chronic application of blockers or global knockdown of NMDARs disrupts developmental refinement in many parts of the brain, the ubiquitous presence of NMDARs makes it difficult to dissociate direct effects from indirect ones. We addressed this question in the thalamus by using genetic mosaic deletion of NMDARs. We demonstrate that pruning and strengthening of immature synapses are blocked in neurons without NMDARs, but occur normally in neighboring neurons with NMDARs. Our data support a model in which activation of NMDARs in postsynaptic neurons initiates synaptic refinement.
Asunto(s)
Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Tálamo/crecimiento & desarrollo , Tálamo/metabolismo , Animales , Animales Recién Nacidos , Proteínas Portadoras/genética , Fenómenos Electrofisiológicos , Potenciales Postsinápticos Excitadores , Ratones , Ratones Noqueados , Modelos Neurológicos , Mosaicismo , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Densidad Postsináptica/metabolismo , Receptores de N-Metil-D-Aspartato/deficiencia , Receptores de N-Metil-D-Aspartato/genética , Transmisión Sináptica , Núcleos Talámicos/crecimiento & desarrollo , Núcleos Talámicos/metabolismoRESUMEN
Whisker trimming produces depression of cortical responses in the barrel cortex. However, it is unclear how the developmental timing modifies the effects of whisker trimming. We investigated cortical responses in thalamocortical slices that included the mouse barrel cortex using flavoprotein fluorescence imaging. A topological relationship was observed between the thalamic stimulated sites and cortical areas showing fluorescence changes. By adjusting the position of the thalamic stimulated sites and the cortical windows in which amplitudes of the fluorescence changes were measured, we succeeded to reduce the variability of cortical responses between slices. We then investigated the effects of whisker trimming in the thalamocortical slices. Whisker trimming from 4 weeks to 8 weeks (at 4-8 weeks) of age significantly reduced cortical responses at 8 weeks. However, whisker trimming started before 4 weeks produced only slight depression or no significant effect on the thalamocortical responses. As sensory deprivation during a critical developmental period is known to prevent elimination of synapses, the presence of aberrant synapses may compensate the cortical depression induced by whisker trimming started before 4 weeks. To test this possibility, whisker trimming performed at 0-6 or 0-7 weeks of age was followed by regrowth of whiskers for 1-2 weeks. Clear and significant potentiation of cortical responses was observed in these mice at 8 weeks when compared with those of naive mice of the same age. Overall, these data suggest that whisker trimming, producing depression of thalamocortical responses, prevents elimination of aberrant synapses during a critical developmental period before 4 weeks in the mouse barrel cortex.
Asunto(s)
Depresión de Propagación Cortical/fisiología , Corteza Somatosensorial/fisiología , Núcleos Talámicos/fisiología , Vibrisas/fisiología , Factores de Edad , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Corteza Somatosensorial/crecimiento & desarrollo , Núcleos Talámicos/crecimiento & desarrollo , Tálamo/crecimiento & desarrollo , Tálamo/fisiología , Factores de Tiempo , Vibrisas/inervaciónRESUMEN
The modification of the neural cell adhesion molecule (NCAM) with polysialic acid (polySia) is tightly linked to neural development. Genetic ablation of the polySia-synthesizing enzymes ST8SiaII and ST8SiaIV generates polySia-negative but NCAM-positive (II(-/-)IV(-/-)) mice characterized by severe defects of major brain axon tracts, including internal capsule hypoplasia. Here, we demonstrate that misguidance of thalamocortical fibers and deficiencies of corticothalamic connections contribute to internal capsule defects in II(-/-)IV(-/-) mice. Thalamocortical fibers cross the primordium of the reticular thalamic nucleus (Rt) at embryonic day 14.5, before they fail to turn into the ventral telencephalon, thus deviating from their normal trajectory without passing through the internal capsule. At postnatal day 1, a reduction and massive disorganization of fibers traversing the Rt was observed, whereas terminal deoxynucleotidyl transferase dUTP nick end labeling and cleaved caspase-3 staining indicated abundant apoptotic cell death of Rt neurons at postnatal day 5. Furthermore, during postnatal development, the number of Rt neurons was drastically reduced in 4-week-old II(-/-)IV(-/-) mice, but not in the NCAM-deficient N(-/-) or II(-/-)IV(-/-)N(-/-) triple knock-out animals displaying no internal capsule defects. Thus, degeneration of the Rt in II(-/-)IV(-/-) mice may be a consequence of malformation of thalamocortical and corticothalamic fibers providing major excitatory input into the Rt. Indeed, apoptotic death of Rt neurons could be induced by lesioning corticothalamic fibers on whole-brain slice cultures. We therefore propose that anterograde transneuronal degeneration of the Rt in polysialylation-deficient, NCAM-positive mice is caused by defective afferent innervation attributable to thalamocortical pathfinding defects.
Asunto(s)
Corteza Cerebral/patología , Neuronas/patología , Ácidos Siálicos/genética , Tálamo/patología , Vías Aferentes/anomalías , Animales , Animales Recién Nacidos , Apoptosis , Axones/patología , Corteza Cerebral/embriología , Corteza Cerebral/crecimiento & desarrollo , Dopamina/metabolismo , Cápsula Interna/anomalías , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fibras Nerviosas/patología , Moléculas de Adhesión de Célula Nerviosa/genética , Núcleos Talámicos/embriología , Núcleos Talámicos/crecimiento & desarrollo , Núcleos Talámicos/patología , Tálamo/embriología , Tálamo/crecimiento & desarrolloRESUMEN
Methyl-CpG binding protein 2 (MeCP2) is highly expressed in neurons in the vertebrate brain, and mutations of the gene encoding MeCP2 cause the neurodevelopmental disorder Rett syndrome. This study examines the role of MeCP2 in the development and function of thalamic GABAergic circuits. Whole cell recordings were carried out in excitatory neurons of the ventrobasal complex (VB) of the thalamus and in inhibitory neurons of the reticular thalamic nucleus (RTN) in acute brain slices from mice aged P6 through P23. At P14-P16, the number of quantal GABAergic events was decreased in VB neurons but increased in RTN neurons of Mecp2-null mice, without any change in the amplitude or kinetics of quantal events. There was no difference between mutant and wild-type mice in paired-pulse ratios of evoked GABAergic responses in the VB or the RTN. On the other hand, unitary responses evoked by minimal stimulation were decreased in the VB but increased in the RTN of mutants. Similar changes in the frequency of quantal events were observed at P21-P23 in both the VB and RTN. At P6, however, quantal GABAergic transmission was altered only in the VB not the RTN. Immunostaining of vesicular GABA transporter showed opposite changes in the number of GABAergic synaptic terminals in the VB and RTN of Mecp2-null mice at P18-P20. The loss of MeCP2 had no significant effect on intrinsic properties of RTN neurons recorded at P15-P17. Our findings suggest that MeCP2 differentially regulates the development of GABAergic synapses in excitatory and inhibitory neurons in the thalamus.
Asunto(s)
Proteína 2 de Unión a Metil-CpG/metabolismo , Neuronas/fisiología , Tálamo/crecimiento & desarrollo , Tálamo/fisiología , Ácido gamma-Aminobutírico/metabolismo , Envejecimiento , Animales , Animales Recién Nacidos , Potenciales Evocados/fisiología , Inmunohistoquímica , Técnicas In Vitro , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Inhibición Neural/fisiología , Vías Nerviosas/crecimiento & desarrollo , Vías Nerviosas/fisiología , Técnicas de Placa-Clamp , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Núcleos Talámicos/crecimiento & desarrollo , Núcleos Talámicos/fisiología , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismoRESUMEN
The number of neurons in the ventrobasal thalamus (VB) in the adolescent rat is unaffected by prenatal exposure to ethanol. This is in sharp contrast to other parts of the trigeminal-somatosensory system, which exhibit 30-35% fewer neurons after prenatal ethanol exposure. The present study tested the hypothesis that prenatal ethanol exposure affects dynamic changes in the numbers of VB neurons; such changes reflect the sum of cell proliferation and death. Neuronal number in the VB was determined during the first postnatal month in the offspring of pregnant Long-Evans rats fed an ethanol-containing diet or pair-fed an isocaloric non-alcoholic liquid diet. Offspring were examined between postnatal day (P) 1 and P30. The size of the VB and neuronal number were determined stereologically. Prenatal exposure to ethanol did not significantly alter neuronal number on any individual day, nor was the prenatal generation of VB neurons affected. Interestingly, prenatal ethanol exposure did affect the pattern of the change in neuronal number over time; total neuronal number was stable in the ethanol-treated pups after P12, but it continued to rise in the controls until P21. In addition, the rate of cell proliferation during the postnatal period was greater in ethanol-treated animals. Thus, the rate of neuronal acquisition is altered by ethanol, and by deduction, there appears to be less ethanol-induced neuronal loss in the VB. A contributor to these changes is a latent effect of ethanol on postnatal neurogenesis in the VB and the apparent survival of new neurons.
Asunto(s)
Etanol/toxicidad , Trastornos del Espectro Alcohólico Fetal/patología , Neurogénesis/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/patología , Núcleos Talámicos/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Animales , Recuento de Células , División Celular/efectos de los fármacos , Depresores del Sistema Nervioso Central/toxicidad , Femenino , Proteínas Ligadas a GPI , Neuronas/patología , Embarazo , Ratas , Ratas Long-Evans , Núcleos Talámicos/crecimiento & desarrollo , Núcleos Talámicos/patologíaRESUMEN
Spontaneous neuronal activity plays an important role during the final development of the brain circuits and the formation of the primary sensory maps. In young rats, spindle bursts have been recorded in the primary somatosensory cortex. They are correlated with spontaneous muscle twitches and occur before active whisking. They bear similarities with the spindles recorded in adult brain that occur during early stages of sleep and rely on a thalamic feedback loop between the glutamatergic nucleus ventroposterior medialis (nVPM) and the GABAergic nucleus reticularis thalami (nRT). However, whether a functional nVPM-nRT loop exists in newborn rodents is unknown. We studied the reciprocal synaptic connections between nVPM and nRT in thalamic acute slices from mice from birth [postnatal day 0 (P0)] until P9. We first demonstrated that nVPM-to-nRT EPSCs could be distinguished from corticothalamic EPSCs by their inhibition by 5-HT attributable to the transient expression of functional presynaptic serotonin 1B receptors. The nVPM-to-nRT EPSCs and nRT-to-nVPM IPSCs were both detected the first day after birth; their amplitude near 2 nS was relatively stable until P5. At P6-P7, there was a rapid and simultaneous increase of both nVPM-to-nRT EPSCs and nRT-to-nVPM IPSCs that reached 8 and 9 nS, respectively. Our results show that the thalamic synapses implicated in spindle activity are functional shortly after birth, suggesting that they could already generate spindles during the first postnatal week. Our results also suggest an inhibitory action of 5-HT on the spindle bursts of the newborn mice.
Asunto(s)
Corteza Somatosensorial/crecimiento & desarrollo , Tálamo/crecimiento & desarrollo , Envejecimiento , Análisis de Varianza , Animales , Animales Recién Nacidos , Potenciales Postsinápticos Excitadores , Ácido Glutámico/metabolismo , Técnicas In Vitro , Potenciales Postsinápticos Inhibidores , Ratones , Vías Nerviosas/crecimiento & desarrollo , Vías Nerviosas/metabolismo , Técnicas de Placa-Clamp , Receptor de Serotonina 5-HT1B/metabolismo , Receptores AMPA/metabolismo , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Serotonina/metabolismo , Agonistas del Receptor de Serotonina 5-HT1 , Corteza Somatosensorial/metabolismo , Núcleos Talámicos/crecimiento & desarrollo , Núcleos Talámicos/metabolismo , Tálamo/metabolismo , Factores de TiempoRESUMEN
To study whether the core-versus-shell pattern of neurogenesis occurred in the mesencephalic and diencephalic auditory areas of amniotes also appears in the amphibian, [(3)H]-thymidine was injected into tadpoles at serial developmental stages of Xenopus laevis. Towards the end of metamorphism, [(3)H]-thymidine labeling was examined and led to two main observations: 1) neuron generation in the principal nucleus (Tp) started at stage 50, and peaked at stage 53, whereas it began at stage 48.5, and peaked around stage 49 in the other two mesencephalic auditory areas, the laminar nucleus (Tl) and the magnocellular nucleus (Tmc). 2) Neuron generation appeared at stage 40, and peaked around stage 52 in the posterior thalamic nucleus (P) and the central thalamic nucleus (C). Our study revealed that, like the cores of mesencephalic auditory nuclei in amniotes, Tp showed differences from Tl and Tmc in the onset and the peak of neurogenesis. However, such differences did not occur in the P and C. Our neurogenetic data were consistent with anatomical and physiological reports indicating a clear distinction between the mesencephalic, but not the diencephalic auditory areas of the amphibian. Our data are helpful to get insights into the organization of auditory nuclei and its evolution in vertebrates.
Asunto(s)
Vías Auditivas/crecimiento & desarrollo , Mesencéfalo/crecimiento & desarrollo , Neuronas/citología , Núcleos Talámicos/crecimiento & desarrollo , Xenopus laevis/crecimiento & desarrollo , Animales , Antígenos de Superficie/metabolismo , Corteza Auditiva/citología , Corteza Auditiva/crecimiento & desarrollo , Corteza Auditiva/metabolismo , Vías Auditivas/citología , Vías Auditivas/metabolismo , Evolución Biológica , Diferenciación Celular , Diencéfalo/citología , Diencéfalo/crecimiento & desarrollo , Diencéfalo/metabolismo , Proteínas ELAV , Proteína 1 Similar a ELAV , Inmunohistoquímica , Mesencéfalo/citología , Mesencéfalo/metabolismo , Metamorfosis Biológica/fisiología , Neuronas/metabolismo , Proteínas de Unión al ARN/metabolismo , Células Madre/citología , Células Madre/metabolismo , Núcleos Talámicos/citología , Núcleos Talámicos/metabolismo , Xenopus laevis/metabolismoRESUMEN
The thalamic reticular nucleus (TRN) can been subdivided into sectors based on thalamic and cortical input. Additionally, in carnivores the visual sector of the TRN can be subdivided into first order (perigeniculate nucleus: PGN) and higher order (TRN) regions. This report examines whether TRN development reflects the nature of its higher order visual connections. 170 cells from 12 kittens aged between postnatal day 0 (P0) and P125 were fully analysed after single cell injections in 400-500 microm fixed brain slices. TRN cells have a period of exuberant dendritic branching that peaks between P3 and P12, around the time of eye opening (P7), followed by branch pruning until P68. Similarly, most dendritic appendages are added between P12 and P22 followed by pruning, which is also largely complete by P68. Most branch points occur within the first 10-30% of the dendritic arbor, peaking between 10 and 20% (roughly equivalent to 100 mum from the soma), while appendages were concentrated between 20 and 30% of the arbour; appendages tend to be distributed over a larger proportion of the arbor up to P14 compared to later ages. TRN and PGN maturation were not significantly different. The present data suggest that clear distinctions cannot be made between the maturation of first and higher order pathways and indicate that GABAergic cells of the ventral thalamus may mature earlier than relay cells of the dorsal thalamus. Furthermore, dendritic development in the TRN may be less dependent on extrinsic factors than an intrinsic growth pattern or factors other than a functional hierarchy within the visual pathway.
Asunto(s)
Núcleos Talámicos/crecimiento & desarrollo , Vías Visuales/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Gatos , Dendritas/fisiología , Dendritas/ultraestructura , Neuronas/citología , Núcleos Talámicos/citología , Núcleos Talámicos/ultraestructura , Factores de Tiempo , Vías Visuales/citología , Vías Visuales/ultraestructuraRESUMEN
Retinal ganglion cells (RGCs) innervate several specific CNS targets serving cortical and subcortical visual pathways and the entrainment of circadian rhythms. Recent studies have shown that retinal ganglion cells express specific combinations of POU- and LIM-domain transcription factors, but how these factors relate to the subsequent development of the retinofugal pathways and the functional identity of RGCs is mostly unknown. Here, we use targeted expression of an genetic axonal tracer, tau/beta-galactosidase, to examine target innervation by retinal ganglion cells expressing the POU-domain factor Brn3a. Brn3a is expressed in RGCs innervating the principal retinothalamic/retinocollicular pathway mediating cortical vision but is not expressed in RGCs of the accessory optic, pretectal, and hypothalamic pathways serving subcortical visuomotor and circadian functions. In the thalamus, Brn3a ganglion cell fibers are primarily restricted to the outer shell of the dorsal lateral geniculate, providing new evidence for the regionalization of this nucleus in rodents. Brn3a RGC axons have a relative preference for the contralateral hemisphere, but known mediators of the laterality of RGC axons are not repatterned in the absence of Brn3a. Brn3a is coexpressed extensively with the closely related factor Brn3b in the embryonic retina, and the effects of the loss of Brn3a in retinal development are not severe, suggesting partial redundancy of function in this gene class.
Asunto(s)
Corteza Cerebral/metabolismo , Células Ganglionares de la Retina/metabolismo , Colículos Superiores/metabolismo , Núcleos Talámicos/metabolismo , Factor de Transcripción Brn-3A/biosíntesis , Vías Visuales/metabolismo , Animales , Animales Recién Nacidos , Corteza Cerebral/embriología , Corteza Cerebral/crecimiento & desarrollo , Regulación del Desarrollo de la Expresión Génica/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Colículos Superiores/embriología , Colículos Superiores/crecimiento & desarrollo , Núcleos Talámicos/embriología , Núcleos Talámicos/crecimiento & desarrollo , Factor de Transcripción Brn-3A/genética , Vías Visuales/embriología , Vías Visuales/crecimiento & desarrolloRESUMEN
Expression patterns of genes implicated in development of the thalamus were examined in mice and monkeys, using in situ hybridization with RNA probes complementary to Cad6, Dlx1, Dlx2, Dlx5, Gbx2, Id2, and Lef1 cDNAs. Expression patterns were related to the evolving cytoarchitecture in mice at birth (P0) and in adulthood, and in fetal monkeys early and late in the period of gestation when thalamic nuclei are becoming histologically differentiated out of a series of pronuclear masses. At the earlier developmental stage, each gene was expressed in a pattern that appeared to be pronucleus-specific and maintained a nucleus-specific pattern into adulthood, with the possible exception of Gbx2. Each gene displayed a unique expression pattern in the dorsal thalamus, ventral thalamus, and epithalamus, and no gene was expressed throughout all three divisions or in every nucleus of a division. With the exception of Dlx2, whose expression disappeared at the later time point, all continued to be expressed into adulthood at higher levels and with identical patterns. Despite late appearance of gamma-aminobutyric acid (GABA)ergic cells in the dorsal lateral geniculate nucleus of mice, no Dlx genes, which promote formation of a GABAergic phenotype elsewhere, were detected in dorsal thalamus. Each thalamic nucleus was distinguished by expression of a combination of genes, and homologous nuclei in mouse and monkey exhibited the same combination. The presence of a centre médian nucleus and four pulvinar nuclei in monkeys was marked by patterns of expression not found in mice. The centre médian nucleus was marked by high expression of Id2, which was expressed only weakly in very few nuclei of mice.
Asunto(s)
Diferenciación Celular/fisiología , Regulación del Desarrollo de la Expresión Génica , Genes Reguladores/fisiología , Núcleos Talámicos/metabolismo , Animales , Animales Recién Nacidos , Corteza Cerebral/embriología , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/metabolismo , Embrión de Mamíferos , Haplorrinos , Hibridación in Situ/métodos , Ratones , Ratones Endogámicos ICR , Neuronas/metabolismo , ARN Complementario/metabolismo , Especificidad de la Especie , Núcleos Talámicos/citología , Núcleos Talámicos/embriología , Núcleos Talámicos/crecimiento & desarrolloRESUMEN
The nucleus rotundus (ROT) is a major relay station in the tectofugal pathway of the avian visual system. In this study, some quantitative features of ROT in developing chicks were analysed using new stereological methods. Total neuron number (N) and mean volume (V) of ROT were estimated by the optical fractionator method and by the Cavalieri principle, respectively. Neuronal density of neurons in ROT was calculated from these data. The eyes of the chick embryo are not normally stimulated by light until days E19/20. Therefore in this study, chicks at three developmental stages were investigated: on the 17th embryonic day (E17), that is before light stimulation of the visual system, at the time of hatch (0-day, stimulated by light) and 10 days after hatch (10-day). The results showed that N was reduced by 27% between E17 and 0-day, and 7.8% between 0- and 10-day while neuronal density was reduced by 15% and 32% over the same periods. It is concluded that the reduction of neuronal density during the pre-hatch period may be due to neuron loss, whereas the post-hatch decrease of neuronal density may be the result of an increase in ROT total volume. Cell loss was more prominent in the pre-hatch than in the post-hatch period. Estimates of neuronal density in the developing ROT are not useful indicators of developmental status, since they do not relate to total neuron number.