RESUMO
GABAergic inhibitory interneurons, originating from the embryonic ventral forebrain territories, traverse a convoluted migratory path to reach the neocortex. These interneuron precursors undergo sequential phases of tangential and radial migration before settling into specific laminae during differentiation. Here, we show that the developmental trajectory of FoxG1 expression is dynamically controlled in these interneuron precursors at critical junctures of migration. By utilizing mouse genetic strategies, we elucidate the pivotal role of precise changes in FoxG1 expression levels during interneuron specification and migration. Our findings underscore the gene dosage-dependent function of FoxG1, aligning with clinical observations of FOXG1 haploinsufficiency and duplication in syndromic forms of autism spectrum disorders. In conclusion, our results reveal the finely tuned developmental clock governing cortical interneuron development, driven by temporal dynamics and the dose-dependent actions of FoxG1.
Assuntos
Córtex Cerebral , Neocórtex , Camundongos , Animais , Córtex Cerebral/metabolismo , Movimento Celular/fisiologia , Neurogênese/fisiologia , Interneurônios/fisiologia , Biomarcadores/metabolismo , Neurônios GABAérgicos/fisiologiaRESUMO
Unilateral spatial neglect (USN) results from impaired attentional networks and can affect various sensory modalities, such as visual and somatosensory. The rodent medial agranular cortex (AGm), located in the medial part of the forebrain from rostral to caudal direction, is considered a region associated with spatial attention. The AGm selectively receives multisensory input with the rostral AGm receiving somatosensory input and caudal part receiving visual input. Our previous study showed slower recovery from neglect with anterior AGm lesion using the somatosensory neglect assessment. Conversely, the functional differences in spatial attention across the entire AGm locations (anterior, intermediate, and posterior parts) are unknown. Here, we investigated the relationship between the severity of neglect and various locations across the entire AGm in a mouse stroke model using a newly developed program-based analysis method that does not require human intervention. Among various positions of the lesions, the recovery from USN during recovery periods (postoperative day; POD 10-18) tended to be slower in cases with more rostral lesions in the AGm (r = - 0.302; p = 0.028). Moreover, the total number of arm entries and maximum moving speed did not significantly differ between before and after AGm infarction. According to these results, the anterior lesions may slowly recover from USN-like behavior, and there may be a weak association between the AGm infarct site and recovery rate. In addition, all unilateral focal infarctions in the AGm induced USN-like behavior without motor deficits.
Assuntos
Modelos Animais de Doenças , Transtornos da Percepção , Animais , Transtornos da Percepção/fisiopatologia , Transtornos da Percepção/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Lateralidade Funcional/fisiologia , Percepção Espacial/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/complicações , Córtex Cerebral/fisiopatologiaRESUMO
For neuronal circuits in the brain to mature, necessary synapses must be maintained and redundant synapses eliminated through experience-dependent mechanisms. However, the functional differentiation of these synapse types during the refinement process remains elusive. Here, we addressed this issue by distinct labeling and direct recordings of presynaptic terminals fated for survival and for elimination in the somatosensory thalamus. At surviving terminals, the number of total releasable vesicles was first enlarged, and then calcium channels and fast-releasing synaptic vesicles were tightly coupled in an experience-dependent manner. By contrast, transmitter release mechanisms did not mature at terminals fated for elimination, irrespective of sensory experience. Nonetheless, terminals fated for survival and for elimination both exhibited developmental shortening of action potential waveforms that was experience independent. Thus, we dissected experience-dependent and -independent developmental maturation processes of surviving and eliminated presynaptic terminals during neuronal circuit refinement.
Assuntos
Terminações Pré-Sinápticas/fisiologia , Potenciais de Ação , Vias Aferentes/fisiologia , Animais , Canais de Cálcio/metabolismo , Camundongos , Rede Nervosa/fisiologia , Neurotransmissores/metabolismo , Vesículas Sinápticas/metabolismo , Núcleos do Trigêmeo/fisiologia , Núcleos Ventrais do Tálamo/fisiologia , Vibrissas/inervação , Vibrissas/fisiologiaRESUMO
Purpose: To compare the diagnostic performance of virtual monoenergetic imaging (VMI), computed tomography (CT), and magnetic resonance imaging (MRI) in patients with endometrial cancer (EC). Material and methods: This retrospective study analysed 45 EC patients (mean age: 62 years, range: 44-84 years) undergoing contrast-enhanced CT with dual-energy CT (DECT) and MRI between September 2021 and October 2022. Dual-energy CT generated conventional CT (C-CT) and 40 keV VMI. Quantitative analysis compared contrast-to-noise ratio (CNR) of tumour to myometrium between C-CT and VMI. Qualitative assessment by 5 radiologists compared C-CT, VMI, and MRI for myometrial invasion (MI), cervical invasion, and lymph node metastasis. Sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC) were calculated and compared for each diagnostic parameter. Results: Virtual monoenergetic imaging showed significantly higher CNR than C-CT (p < 0.001) and a higher sensitivity for MI than C-CT (p = 0.027) and MRI (p = 0.011) but lower specificity than MRI (p = 0.018). C-CT had a higher sensitivity and AUC for cervical invasion than MRI (p = 0.018 and 0.004, respectively). Conclusions: The study found no significant superiority of MRI over CT across all diagnostic parameters. VMI demonstrated heightened sensitivity for MI, and C-CT showed greater sensitivity and AUC for cervical invasion than MRI. This suggests that combining VMI with C-CT holds promise as a comprehensive preoperative staging tool for EC when MRI cannot be performed.
RESUMO
Mutations in the gene encoding the chromatin remodeler CHD8 are strongly associated with autism spectrum disorder (ASD). CHD8 haploinsufficiency also results in autistic phenotypes in humans and mice. Although myelination defects have been observed in individuals with ASD, whether oligodendrocyte dysfunction is responsible for autistic phenotypes has remained unknown. Here we show that reduced expression of CHD8 in oligodendrocytes gives rise to abnormal behavioral phenotypes in mice. CHD8 was found to regulate the expression of many myelination-related genes and to be required for oligodendrocyte maturation and myelination. Ablation of Chd8 specifically in oligodendrocytes of mice impaired myelination, slowed action potential propagation and resulted in behavioral deficits including increased social interaction and anxiety-like behavior, with similar effects being apparent in Chd8 heterozygous mutant mice. Our results thus indicate that CHD8 is essential for myelination and that dysfunction of oligodendrocytes as a result of CHD8 haploinsufficiency gives rise to several neuropsychiatric phenotypes.
Assuntos
Transtorno do Espectro Autista/genética , Proteínas de Ligação a DNA/genética , Neurogênese/genética , Fatores de Transcrição/genética , Animais , Transtorno do Espectro Autista/patologia , Montagem e Desmontagem da Cromatina/genética , Modelos Animais de Doenças , Haploinsuficiência/genética , Heterozigoto , Humanos , Camundongos , Mutação/genética , Oligodendroglia/metabolismo , Oligodendroglia/patologia , FenótipoRESUMO
PURPOSE: The "babysitter" procedure is a reconstruction technique for facial nerve complete paralysis and uses the movement source from the healthy facial nerve with a cross-nerve graft. First, an end-to-side neurorrhaphy is performed between the affected facial nerve trunk and hypoglossal nerve for continuously delivering stimuli to the mimetic muscles for preventing the atrophy of mimetic muscles. Despite favorable clinical results, histological and physiological mechanisms remain unknown. This study attempted to establish a model for the "babysitter" procedure and find its efficacy in rats with facial nerve complete paralysis. MATERIALS AND METHODS: A total of 16 Lewis rats were used and divided into 2 groups; cross nerve graft (n = 8) and babysitter groups (n = 8). The facial nerve trunk was transected in both groups. Babysitter group underwent a two-stage procedure. Cross nerve graft group underwent only the transfer of nerve graft from the healthy side to affected side. The animals were assessed physiologically by compound muscle action potential (CMAP), and the regenerated nerve tissues were evaluated histopathologically at 13 weeks after surgery. RESULTS: Facial nucleus stained with retrograde tracers proved the re-innervation of affected facial muscle by the babysitter procedure. In CMAP, the amplitude of babysitter group was significantly higher than that of the cross-facial nerve graft group (p < .05). Histological examination found a significant difference in myelin g-ratio between two groups (p < .05). CONCLUSION: This study investigated the "babysitter" procedure for rat facial nerve palsy. Babysitter procedure shortened the denervation period without mimic muscle atrophy.
Assuntos
Paralisia Facial , Transferência de Nervo , Animais , Nervo Facial/cirurgia , Paralisia Facial/cirurgia , Nervo Hipoglosso/cirurgia , Atrofia Muscular/etiologia , Atrofia Muscular/prevenção & controle , Atrofia Muscular/cirurgia , Regeneração Nervosa , Ratos , Ratos Endogâmicos LewRESUMO
In the neocortex, both layer 2/3 and layer 5 contain corticocortical pyramidal cells projecting to other cortices. We previously found that among L5 pyramidal cells of the secondary motor cortex (M2), not only intratelencephalic projection cells but also pyramidal tract cells innervate ipsilateral cortices and that the two subtypes are different in corticocortical projection diversity and axonal laminar distributions. Layer 2/3 houses intratelencephalically projecting pyramidal cells that also innervate multiple ipsilateral and contralateral cortices. However, it remained unclear whether layer 2/3 pyramidal cells can be divided into projection subtypes each with distinct innervation to specific targets. In the present study we show that layer 2 pyramidal cells are organized into subcircuits on the basis of corticocortical projection targets. Layer 2 corticocortical cells of the same projection subtype were monosynaptically connected. Between the contralaterally and ipsilaterally projecting corticocortical cells, the monosynaptic connection was more common from the former to the latter. We also found that ipsilaterally and contralaterally projecting corticocortical cell subtypes differed in their morphological and physiological characteristics. Our results suggest that layer 2 transfers separate outputs from M2 to individual cortices and that its subcircuits are hierarchically organized to form the discrete corticocortical outputs.NEW & NOTEWORTHY Pyramidal cell subtypes and their dependent subcircuits are well characterized in cortical layer 5, but much less is understood for layer 2/3. We demonstrate that in layer 2 of the rat secondary motor cortex, ipsilaterally and contralaterally projecting corticocortical cells are largely segregated. These layer 2 cell subtypes differ in dendrite morphological and intrinsic electrophysiological properties, and form subtype-dependent connections. Our results suggest that layer 2 pyramidal cells form distinct subcircuits to provide discrete corticocortical outputs.
Assuntos
Córtex Motor/fisiologia , Neocórtex/fisiologia , Células Piramidais/classificação , Animais , Feminino , Masculino , Córtex Motor/citologia , Neocórtex/citologia , Vias Neurais/citologia , Vias Neurais/fisiologia , Células Piramidais/fisiologia , Ratos , Ratos Wistar , Sinapses/fisiologiaRESUMO
PURPOSE: This study investigated the potential of collagen-coated polyglycolic acid (PGA) tube with interpositional jump graft (IPJG) in rat. MATERIALS AND METHODS: A total of 16 Lewis rats were used in this study. Facial nerve paralysis was created by ligating facial nerve trunk with a ligature clip. The rats were divided into 3 groups. Nerve conduit group (n = 6) were treated by IPJG with collagen-coated PGA tubes between the facial nerve trunks and the hypoglossal nerves. Autograft group (n = 6) were treated by IPJG with the greater auricular nerves. As the control group (n = 4), non-treated-model rats with facial nerve paralysis were used. The number of myelinated fibers, fiber diameter, axon diameter, myelin thickness, and g-ratio, were analyzed histologically at 13 weeks after surgery. Compound muscle action potential (CMAP) and retrograde tracing were measured. RESULT: Although the number of myelinated fibers in autograft group (1957 ± 775) had significantly higher than that of nerve conduit group (90 ± 41, P < .05), the nerve conduit group showed the regeneration of myelinated nerve axons. CMAP amplitude values of the autograft (4706 ± 1154 µV) and the nerve conduit groups (4119 ± 1397 µV) were significantly higher than that of the control group (915 ± 789 µV, P < .05). Retrograde tracing confirmed the double innervation of mimetic muscles by the facial and hypoglossal nucleus in both groups. CONCLUSION: This study showed histologically and physiologically the superior effectiveness of performing IPJG with a collagen-coated PGA conduit in a rat model.
Assuntos
Nervo Facial/cirurgia , Paralisia Facial/cirurgia , Procedimentos Neurocirúrgicos/métodos , Ácido Poliglicólico , Anastomose Cirúrgica , Animais , Modelos Animais de Doenças , Nervo Hipoglosso/cirurgia , Ratos , Ratos Endogâmicos LewRESUMO
Adipose-derived stem cells (ADSCs) and the stromal vascular fraction (SVF) promote nerve regeneration. Biodegradable nerve conduits are used to treat peripheral nerve injuries, but their efficiencies are lower than those of autologous nerve grafts. This study developed biodegradable nerve conduits containing ADSCs and SVF and evaluated their facial nerve regenerating abilities in a rat model with a 7-mm nerve defect. SVF and ADSCs were individually poured into nerve conduits with polyglycolic acid-type I collagen as a scaffold (ADSCs and SVF groups). The conduits were grafted on to the nerve defects. As the control, the defect was bridged with polyglycolic acid-collagen nerve conduits without cells. At 13 weeks, after transplantation, the regenerated nerves were evaluated physiologically and histologically. The compound muscle action potential of the SVF group was significantly higher in amplitude than that of the control group. Electron microscopy showed that the axon diameter of the SVF group was the largest, followed by the ADSC group and control group with significant differences among them. The SVF group had the largest fiber diameter, followed by the ADSC group and control group with significant differences among them. The ADSC group had the highest myelin thickness, followed by the SVF group and control group with significant differences among them. Identical excellent promoting effects on nerve regeneration were observed in both the ADSC and SVF groups. Using SVF in conduits was more practical than using ADSCs because only the enzymatic process was required to prepare SVF, indicating that SVF could be more suitable to induce nerve regeneration.
Assuntos
Tecido Adiposo/citologia , Colágeno/farmacologia , Nervo Facial/fisiopatologia , Regeneração Nervosa/fisiologia , Doenças do Sistema Nervoso Periférico/terapia , Ácido Poliglicólico/farmacologia , Células-Tronco/citologia , Adipócitos/citologia , Adipócitos/transplante , Tecido Adiposo/transplante , Animais , Modelos Animais de Doenças , Regeneração Nervosa/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/fisiopatologia , Ratos , Recuperação de Função Fisiológica/fisiologia , Células-Tronco/efeitos dos fármacosRESUMO
PURPOSE: Interpositional jump-graft (IPJG) technique with the hypoglossal nerve for supercharging can be applied in a facial nerve paresis case. In IPJG, an autologous nerve is required, and the donor site morbidity is unavoidable. Biodegradable nerve conduits are made from polyglycolic acid (PGA) and used recently without donor site complications after providing autologous grafts. Hybrid artificial nerve conduits with adipose-derived stem cells (ASCs) also attract attention as a nerve-regeneration enhancing agent. This study examined the effect of hybrid artificial nerve conduit on IPJG. MATERIALS AND METHODS: A total of 34 Lewis rats were used and divided into 4 groups by the bridge materials: autograft (n = 8), PGA nerve conduit (n = 8), hybrid PGA nerve conduit with ASCs (n = 8), and the nontreated control groups (n = 8). ASCs were collected from 2 rats and cultured. The animals were assessed physiologically and histopathologically at 13 weeks after surgery. RESULTS: In compound muscle action potential, the amplitude of hybrid PGA group (3,222 ± 1,779 µV) was significantly higher than that of PGA group (1,961 ± 445 µV, P < .05), and no significant difference between hybrid PGA and autograft group. All treated groups showed a myelinated nerve regeneration with double innervation in hypoglossal and facial nerve nuclei for vibrissal muscle. CONCLUSION: This study showed the effectiveness of IPJG with a hybrid PGA conduit especially in physiological examination.
Assuntos
Paralisia Facial/cirurgia , Regeneração Tecidual Guiada/métodos , Regeneração Nervosa , Alicerces Teciduais , Adipócitos , Animais , Modelos Animais de Doenças , Masculino , Ácido Poliglicólico , Ratos , Ratos Endogâmicos Lew , Células-TroncoRESUMO
Functional synapse elimination and strengthening are crucial developmental processes in the formation of precise neuronal circuits in the somatosensory system, but the underlying alterations in topographical organization are not yet fully understood. To address this issue, we generated transgenic mice in which afferent fibers originating from the whisker-related brain region, called the maxillary principal trigeminal nucleus (PrV2), were selectively visualized with genetically expressed fluorescent protein. We found that functional synapse elimination drove and established large-scale somatotopic refinement even after the thalamic barreloid architecture was formed. Before functional synapse elimination, the whisker sensory thalamus was innervated by afferent fibers not only from the PrV2, but also from the brainstem nuclei representing other body parts. Most notably, only afferent fibers from PrV2 onto a whisker sensory thalamic neuron selectively survived and were strengthened, whereas other afferent fibers were preferentially eliminated via their functional synapse elimination. This large-scale somatotopic refinement was at least partially dependent on somatosensory experience. These novel results uncovered a previously unrecognized role of developmental synapse elimination in the large-scale, instead of the fine-scale, somatotopic refinement even after the initial segregation of the barreloid map.
Assuntos
Neurogênese/fisiologia , Sinapses/fisiologia , Tálamo/crescimento & desenvolvimento , Tálamo/ultraestrutura , Animais , Potenciais Pós-Sinápticos Excitadores , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Técnicas de Patch-Clamp , Sinapses/ultraestruturaRESUMO
The metabotropic glutamate receptor subtype 1 (mGluR1, Grm1) in cerebellar Purkinje cells (PCs) is essential for motor coordination and motor learning. At the synaptic level, mGluR1 has a critical role in long-term synaptic depression (LTD) at parallel fiber (PF)-PC synapses, and in developmental elimination of climbing fiber (CF)-PC synapses. mGluR1a, a predominant splice variant in PCs, has a long carboxyl (C)-terminal domain that interacts with Homer scaffolding proteins. Cerebellar roles of the C-terminal domain at both synaptic and behavior levels remain poorly understood. To address this question, we introduced a short variant, mGluR1b, which lacks this domain into PCs of mGluR1-knock-out (KO) mice (mGluR1b-rescue mice). In mGluR1b-rescue mice, mGluR1b showed dispersed perisynaptic distribution in PC spines. Importantly, mGluR1b-rescue mice exhibited impairments in inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca(2+) release, CF synapse elimination, LTD induction, and delay eyeblink conditioning: they showed normal transient receptor potential canonical (TRPC) currents and normal motor coordination. In contrast, PC-specific rescue of mGluR1a restored all cerebellar defects of mGluR1-KO mice. We conclude that the long C-terminal domain of mGluR1a is required for the proper perisynaptic targeting of mGluR1, IP3R-mediated Ca(2+) release, CF synapse elimination, LTD, and motor learning, but not for TRPC currents and motor coordination.
Assuntos
Plasticidade Neuronal/fisiologia , Células de Purkinje/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Sinapses/metabolismo , Animais , Cerebelo/metabolismo , Imunofluorescência , Imuno-Histoquímica , Imunoprecipitação , Hibridização In Situ , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Patch-Clamp , Estrutura Terciária de Proteína , Desempenho Psicomotor/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Histological and physiological basis of the therapeutic efficacy of the vascularized autologous nerve graft in facial nerve regeneration remains poorly understood because of no established rat model. The left median nerve and median artery/vein of Lewis rats were collectively ligated, and harvested as a vascularized island median nerve, which was transplanted to a 7-mm gap in the left buccal branch of facial nerve. Nerve regeneration was investigated. The numbers of myelinated fibers, axon diameter, and myelin thickness were significantly higher in the vascularized nerve graft group than in the nonvascularized nerve graft group. Compound muscle action potential measurement showed that the parameters of vascularized group were similar to those in the intact control group. A vascularized median nerve graft resulted in better facial nerve regeneration outcomes.
Assuntos
Traumatismos do Nervo Facial/patologia , Mucosa Bucal/patologia , Fibras Nervosas Mielinizadas/patologia , Regeneração Nervosa , Procedimentos de Cirurgia Plástica/métodos , Retalhos Cirúrgicos/irrigação sanguínea , Animais , Nervo Facial/patologia , Fáscia/irrigação sanguínea , Nervo Mediano/patologia , Modelos Animais , Mucosa Bucal/irrigação sanguínea , Ratos , Ratos Endogâmicos Lew , Recuperação de Função FisiológicaRESUMO
Developmental synapse elimination is crucial for shaping mature neural circuits. In the neonatal mouse cerebellum, Purkinje cells (PCs) receive excitatory synaptic inputs from multiple climbing fibers (CFs) and synapses from all but one CF are eliminated by around postnatal day 20. Heterosynaptic interaction between CFs and parallel fibers (PFs), the axons of cerebellar granule cells (GCs) forming excitatory synapses onto PCs and molecular layer interneurons (MLIs), is crucial for CF synapse elimination. However, mechanisms for this heterosynaptic interaction are largely unknown. Here we show that deletion of AMPA-type glutamate receptor functions in GCs impairs CF synapse elimination mediated by metabotropic glutamate receptor 1 (mGlu1) signaling in PCs. Furthermore, CF synapse elimination is impaired by deleting NMDA-type glutamate receptors from MLIs. We propose that PF activity is crucial for CF synapse elimination by directly activating mGlu1 in PCs and indirectly enhancing the inhibition of PCs through activating NMDA receptors in MLIs.
Assuntos
Cerebelo , Receptores de Glutamato Metabotrópico , Sinapses , Animais , Cerebelo/metabolismo , Cerebelo/fisiologia , Cerebelo/citologia , Sinapses/fisiologia , Sinapses/metabolismo , Camundongos , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/genética , Células de Purkinje/metabolismo , Células de Purkinje/fisiologia , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Interneurônios/metabolismo , Interneurônios/fisiologia , Camundongos Knockout , Camundongos Endogâmicos C57BLRESUMO
DNA methylation is crucial for chromatin structure and gene expression and its aberrancies, including the global "hypomethylator phenotype", are associated with cancer. Here we show that an underlying mechanism for this phenotype in the large proportion of the highly lethal brain tumor glioblastoma (GBM) carrying receptor tyrosine kinase gene mutations, involves the mechanistic target of rapamycin complex 2 (mTORC2), that is critical for growth factor signaling. In this scenario, mTORC2 suppresses the expression of the de novo DNA methyltransferase (DNMT3A) thereby inducing genome-wide DNA hypomethylation. Mechanistically, mTORC2 facilitates a redistribution of EZH2 histone methyltransferase into the promoter region of DNMT3A, and epigenetically represses the expression of DNA methyltransferase. Integrated analyses in both orthotopic mouse models and clinical GBM samples indicate that the DNA hypomethylator phenotype consistently reprograms a glutamate metabolism network, eventually driving GBM cell invasion and survival. These results nominate mTORC2 as a novel regulator of DNA hypomethylation in cancer and an exploitable target against cancer-promoting epigenetics.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Camundongos , Animais , Glioblastoma/patologia , Linhagem Celular Tumoral , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Metilação de DNA , Fenótipo , Neoplasias Encefálicas/patologia , DNA/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Proteínas Tirosina Quinases/genéticaRESUMO
The remodeling of neural circuitry and changes in synaptic efficacy after peripheral sensory nerve injury are considered the basis for functional reorganization in the brain, including changes in receptive fields. However, when or how the remodeling occurs is largely unknown. Here we show the rapid rewiring of afferent fibers in the mature ventral posteromedial thalamic nucleus of mice after transection of the peripheral whisker sensory nerve, using the whole-cell voltage-clamp technique. Transection induced the recruitment of afferent fibers to a thalamic relay neuron within 5-6 d of injury. The rewiring was pathway specific, but not sensory experience dependent or peripheral nerve activity dependent. The newly recruited fibers mediated small EPSCs, and postsynaptic GluA2-containing AMPA receptors were selectively upregulated at the new synapses. This rapid and pathway-specific remodeling of thalamic circuitry may be an initial step in the massive axonal reorganization at supraspinal levels, which occurs months or years after peripheral sensory nerve injury.
Assuntos
Vias Aferentes/fisiopatologia , Regeneração Nervosa/fisiologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Receptores de AMPA/biossíntese , Núcleos Ventrais do Tálamo/fisiopatologia , Animais , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/fisiologia , Fatores de Tempo , Regulação para Cima , Núcleos Ventrais do Tálamo/citologia , Vibrissas/inervação , Vibrissas/fisiologiaRESUMO
The somatosensory system organizes the topographic representation of body maps, termed somatotopy, at all levels of an ascending hierarchy. Postnatal maturation of somatotopy establishes optimal somatosensation, whereas deafferentation in adults reorganizes somatotopy, which underlies pathological somatosensation, such as phantom pain and complex regional pain syndrome. Here, we focus on the mouse whisker somatosensory thalamus to study how sensory experience shapes the fine topography of afferent connectivity during the critical period and what mechanisms remodel it and drive a large-scale somatotopic reorganization after peripheral nerve injury. We will review our findings that, following peripheral nerve injury in adults, lemniscal afferent synapses onto thalamic neurons are remodeled back to immature configuration, as if the critical period reopens. The remodeling process is initiated with local activation of microglia in the brainstem somatosensory nucleus downstream to injured nerves and heterosynaptically controlled by input from GABAergic and cortical neurons to thalamic neurons. These fruits of thalamic studies complement well-studied cortical mechanisms of somatotopic organization and reorganization and unveil potential intervention points in treating pathological somatosensation.
Assuntos
Traumatismos dos Nervos Periféricos , Camundongos , Animais , Tálamo , Neurônios/fisiologia , Tronco Encefálico/fisiologia , Sinapses/fisiologia , Córtex Somatossensorial/fisiologiaRESUMO
Mutations of the myosin Va gene cause the neurological diseases Griscelli syndrome type 1 and Elejalde syndrome in humans and dilute phenotypes in rodents. To understand the pathophysiological mechanisms underlying the neurological disorders in myosin Va diseases, we conducted an integrated analysis at the molecular, cellular, electrophysiological, and behavioral levels using the dilute-neurological (d-n) mouse mutant. These mice manifest an ataxic gait and clonic seizures during postnatal development, but the neurological disorders are ameliorated in adulthood. We found that smooth endoplasmic reticulum (SER) rarely extended into the dendritic spines of Purkinje cells (PCs) of young d-n mice, and there were few, if any, IP(3) receptors. Moreover, long-term depression (LTD) at parallel fiber-PC synapses was abolished, consistent with our previous observations in juvenile lethal dilute mutants. Young d-n mice exhibited severe impairment of cerebellum-dependent motor learning. In contrast, adult d-n mice showed restoration of motor learning and LTD, and these neurological changes were associated with accumulation of SER and IP(3) receptors in some PC spines and the expression of myosin Va proteins in the PCs. RNA interference-mediated repression of myosin Va caused a reduction in the number of IP(3) receptor-positive spines in cultured PCs. These findings indicate that myosin Va function is critical for subsequent processes in localization of SER and IP(3) receptors in PC spines, LTD, and motor learning. Interestingly, d-n mice had defects of motor coordination from young to adult ages, suggesting that the role of myosin Va in PC spines is not sufficient for motor coordination.
Assuntos
Cerebelo/fisiologia , Aprendizagem/fisiologia , Atividade Motora/fisiologia , Cadeias Pesadas de Miosina/metabolismo , Miosina Tipo V/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Análise de Variância , Animais , Western Blotting , Condicionamento Clássico/fisiologia , Condicionamento Palpebral/fisiologia , Espinhas Dendríticas/metabolismo , Eletrofisiologia , Retículo Endoplasmático Liso/metabolismo , Imuno-Histoquímica , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Camundongos , Camundongos Mutantes Neurológicos , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Teste de Desempenho do Rota-Rod , Sinapses/fisiologiaRESUMO
Nociception, a somatic discriminative aspect of pain, is, like touch, represented in the primary somatosensory cortex (S1), but the separation and interaction of the two modalities within S1 remain unclear. Here, we show spatially distinct tactile and nociceptive processing in the granular barrel field (BF) and adjacent dysgranular region (Dys) in mouse S1. Simultaneous recordings of the multiunit activity across subregions revealed that Dys neurons are more responsive to noxious input, whereas BF neurons prefer tactile input. At the single neuron level, nociceptive information is represented separately from the tactile information in Dys layer 2/3. In contrast, both modalities seem to converge on individual layer 5 neurons of each region, but to a different extent. Overall, these findings show layer-specific processing of nociceptive and tactile information between Dys and BF. We further demonstrated that Dys activity, but not BF activity, is critically involved in pain-like behavior. These findings provide new insights into the role of pain processing in S1.
Assuntos
Nociceptividade , Percepção do Tato , Animais , Mapeamento Encefálico/métodos , Camundongos , Nociceptividade/fisiologia , Dor , Córtex Somatossensorial/fisiologia , Percepção do Tato/fisiologiaRESUMO
Cyclin-dependent kinase 5 (Cdk5) /p35 is involved in many developmental processes of the central nervous system. Cdk5/p35 is also implicated in synaptic plasticity, learning and memory. Several lines of conditional Cdk5 knockout mice (KO) have been generated and have shown different outcomes for learning and memory. Here, we present our analysis of p35 conditional KO mice (p35cKO) in hippocampal pyramidal neurons or forebrain GABAergic neurons using electrophysiological and behavioral methods. In the fear conditioning task, CamKII-p35cKO mice showed impaired memory retention. Furthermore, NMDAR-dependent long-term depression (LTD) induction by low-frequency stimuli in hippocampal slices from CamkII-p35cKO mice was impaired compared to that in control mice. In contrast, Dlx-p35cKO mice showed no abnormalities in behavioral tasks and electrophysiological analysis in their hippocampal slices. These results indicated that Cdk5/p35 in excitatory neurons is important for the hippocampal synaptic plasticity and associative memory retention.