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1.
Nat Commun ; 11(1): 4395, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879322

RESUMO

The formation and maintenance of spatial representations within hippocampal cell assemblies is strongly dictated by patterns of inhibition from diverse interneuron populations. Although it is known that inhibitory synaptic strength is malleable, induction of long-term plasticity at distinct inhibitory synapses and its regulation of hippocampal network activity is not well understood. Here, we show that inhibitory synapses from parvalbumin and somatostatin expressing interneurons undergo long-term depression and potentiation respectively (PV-iLTD and SST-iLTP) during physiological activity patterns. Both forms of plasticity rely on T-type calcium channel activation to confer synapse specificity but otherwise employ distinct mechanisms. Since parvalbumin and somatostatin interneurons preferentially target perisomatic and distal dendritic regions respectively of CA1 pyramidal cells, PV-iLTD and SST-iLTP coordinate a reprioritisation of excitatory inputs from entorhinal cortex and CA3. Furthermore, circuit-level modelling reveals that PV-iLTD and SST-iLTP cooperate to stabilise place cells while facilitating representation of multiple unique environments within the hippocampal network.


Assuntos
Hipocampo/fisiologia , Interneurônios/metabolismo , Células Piramidais/fisiologia , Potenciais de Ação , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Canais de Cálcio Tipo T/metabolismo , Channelrhodopsins/metabolismo , Hipocampo/citologia , Camundongos , Optogenética/métodos , Parvalbuminas/metabolismo , Técnicas de Patch-Clamp , Transdução de Sinais , Somatostatina/metabolismo , Sinapses/metabolismo
2.
Nature ; 583(7818): 813-818, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32699410

RESUMO

Most sensory information destined for the neocortex is relayed through the thalamus, where considerable transformation occurs1,2. One means of transformation involves interactions between excitatory thalamocortical neurons that carry data to the cortex and inhibitory neurons of the thalamic reticular nucleus (TRN) that regulate the flow of those data3-6. Although the importance of the TRN has long been recognised7-9, understanding of its cell types, their organization and their functional properties has lagged behind that of the thalamocortical systems they control. Here we address this by investigating the somatosensory and visual circuits of the TRN in mice. In the somatosensory TRN we observed two groups of genetically defined neurons that are topographically segregated and physiologically distinct, and that connect reciprocally with independent thalamocortical nuclei through dynamically divergent synapses. Calbindin-expressing cells-located in the central core-connect with the ventral posterior nucleus, the primary somatosensory thalamocortical relay. By contrast, somatostatin-expressing cells-which reside along the surrounding edges of the TRN-synapse with the posterior medial thalamic nucleus, a higher-order structure that carries both top-down and bottom-up information10-12. The two TRN cell groups process their inputs in pathway-specific ways. Synapses from the ventral posterior nucleus to central TRN cells transmit rapid excitatory currents that depress deeply during repetitive activity, driving phasic spike output. Synapses from the posterior medial thalamic nucleus to edge TRN cells evoke slower, less depressing excitatory currents that drive more persistent spiking. Differences in the intrinsic physiology of TRN cell types, including state-dependent bursting, contribute to these output dynamics. The processing specializations of these two somatosensory TRN subcircuits therefore appear to be tuned to the signals they carry-a primary central subcircuit tuned to discrete sensory events, and a higher-order edge subcircuit tuned to temporally distributed signals integrated from multiple sources. The structure and function of visual TRN subcircuits closely resemble those of the somatosensory TRN. These results provide insights into how subnetworks of TRN neurons may differentially process distinct classes of thalamic information.


Assuntos
Vias Neurais , Núcleos Talâmicos/citologia , Núcleos Talâmicos/fisiologia , Potenciais de Ação , Animais , Calbindinas/metabolismo , Potenciais Somatossensoriais Evocados , Potenciais Evocados Visuais , Feminino , Cinética , Masculino , Camundongos , Inibição Neural , Neurônios/metabolismo , Somatostatina/metabolismo , Sinapses/metabolismo
3.
Artigo em Chinês | MEDLINE | ID: mdl-32629567

RESUMO

Objective: To investigate the protective effect of somatostatin (SS) on acute kidney injury (AKI) of paraquat (PQ) poisoned mice and its mechanism. Methods: From December 2017 to April 2018, a total of 48 SPF male BALB/C mice were selected and randomly divided into 4 groups, with 12 mice in each group: Control group, SS group (20 mg/kg SS was injected 1 hour before and 3 hours after gavage with normal saline) , PQ group (2% PQ 60 mg/kg by gavage) and PQ+SS group (Intragastric administration was performed with 2% PQ solution of 60 mg/kg, and 20 mg/kg SS was administered 1 h before and 3 h after intragastric administration) , 12 mice in each group were observed for the general situation and behavioral effects. After 24 hours of modeling, mice were sacrificed.Then blood was extracted after eyeball was removed, and both kidneys were removed by laparotomy. Serum IL-6, TNF-α and MPO levels were determined by ELISA. The characteristic pathological changes of toxic renal tubular injury were observed under light microscope and scored accordingly. The changes of NF-κB expression were detected by Western-Blot, SOD, Caspase-3 and malondialdehyde (MDA) were detected by chemical colorimetry. Results: Mice in Control group and SS group showed normal general conditions and behaviors; Mice in PQ group were significantly worse than those in Control group, showing decreased feeding and activity, dry fur, hair shedding and listless spirit; The above symptoms in the mice of PQ+SS group were alleviated compared with the PQ group. Under the light microscope, the renal tissue structure of PQ group was obviously disordered and severely damaged, and the nephropathy score was (6.14±0.72) . The performance of PQ+SS group under light microscope was improved compared with PQ group, and nephropathy score (4.36±0.42) decreased (P<0.05) . Compared with the Control group, serum TNF-α (39.89±3.32) pg/ml, IL-6 (77.29±4.77) pg/ml, renal NF-κB (2.29±0.097) , MPO (0.31±0.017) µg/ml, MDA (0.91±0.03) mmol/mg prot, and Caspase-3 (376.51±8.24) % levels were significantly increased in the PQ group, while the level of renal SOD (2.36±0.73) U/mg prot was significantly decreased (P<0.05) . Compared with the PQ group, serum TNF-α (33.82±1.57) pg/ml, IL-6 (58.49±5.89) pg/ml, renal NF-κB (0.84±0.05) , MPO (0.22±0.01) µg/ml, MDA (0.72±0.05) mmol/mg prot, Caspase-3 (327.32±21.93) % decreased significantly, and renal SOD (4.90±0.81) U/mg prot increased significantly in the PQ+SS group (P<0.05) . Conclusion: PQ poisoning can lead to AKI in mice, while SS can reduce AKI caused by PQ poisoning, improve the general survival state of PQ poisoned mice, and play a certain protective role in kidney injury caused by PQ poisoning, which may be achieved by inhibiting oxidative stress response, inflammatory response and apoptosis caused by poisoning.


Assuntos
Paraquat/toxicidade , Somatostatina/metabolismo , Animais , Rim , Pulmão , Masculino , Camundongos , Camundongos Endogâmicos BALB C
4.
Nat Commun ; 11(1): 2889, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32514083

RESUMO

Inhibitory interneurons orchestrate information flow across the cortex and are implicated in psychiatric illness. Although interneuron classes have unique functional properties and spatial distributions, the influence of interneuron subtypes on brain function, cortical specialization, and illness risk remains elusive. Here, we demonstrate stereotyped negative correlation of somatostatin and parvalbumin transcripts within human and non-human primates. Cortical distributions of somatostatin and parvalbumin cell gene markers are strongly coupled to regional differences in functional MRI variability. In the general population (n = 9,713), parvalbumin-linked genes account for an enriched proportion of heritable variance in in-vivo functional MRI signal amplitude. Single-marker and polygenic cell deconvolution establish that this relationship is spatially dependent, following the topography of parvalbumin expression in post-mortem brain tissue. Finally, schizophrenia genetic risk is enriched among interneuron-linked genes and predicts cortical signal amplitude in parvalbumin-biased regions. These data indicate that the molecular-genetic basis of brain function is shaped by interneuron-related transcripts and may capture individual differences in schizophrenia risk.


Assuntos
Encéfalo/metabolismo , Perfilação da Expressão Gênica/métodos , Interneurônios/metabolismo , Parvalbuminas/genética , Esquizofrenia/genética , Somatostatina/genética , Adulto , Animais , Encéfalo/citologia , Encéfalo/diagnóstico por imagem , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Interneurônios/citologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Parvalbuminas/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Esquizofrenia/diagnóstico , Esquizofrenia/metabolismo , Análise de Célula Única/métodos , Somatostatina/metabolismo , Adulto Jovem
5.
Nat Commun ; 11(1): 2388, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404907

RESUMO

Deep brain stimulation (DBS) of the subthalamic nucleus is a symptomatic treatment of Parkinson's disease but benefits only to a minority of patients due to stringent eligibility criteria. To investigate new targets for less invasive therapies, we aimed at elucidating key mechanisms supporting deep brain stimulation efficiency. Here, using in vivo electrophysiology, optogenetics, behavioral tasks and mathematical modeling, we found that subthalamic stimulation normalizes pathological hyperactivity of motor cortex pyramidal cells, while concurrently activating somatostatin and inhibiting parvalbumin interneurons. In vivo opto-activation of cortical somatostatin interneurons alleviates motor symptoms in a parkinsonian mouse model. A computational model highlights that a decrease in pyramidal neuron activity induced by DBS or by a stimulation of cortical somatostatin interneurons can restore information processing capabilities. Overall, these results demonstrate that activation of cortical somatostatin interneurons may constitute a less invasive alternative than subthalamic stimulation.


Assuntos
Estimulação Encefálica Profunda/métodos , Levodopa/uso terapêutico , Transtornos Parkinsonianos/terapia , Somatostatina/metabolismo , Algoritmos , Animais , Antiparkinsonianos/uso terapêutico , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Córtex Motor/efeitos dos fármacos , Córtex Motor/metabolismo , Córtex Motor/fisiopatologia , Optogenética/métodos , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Núcleo Subtalâmico/efeitos dos fármacos , Núcleo Subtalâmico/metabolismo , Núcleo Subtalâmico/fisiopatologia
6.
Nat Commun ; 11(1): 1896, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312960

RESUMO

Glucagon is released from pancreatic α-cells to activate pathways that raise blood glucose. Its secretion is regulated by α-cell-intrinsic glucose sensing and paracrine control through insulin and somatostatin. To understand the inadequately high glucagon levels that contribute to hyperglycemia in type-2 diabetes (T2D), we analyzed granule behavior, exocytosis and membrane excitability in α-cells of 68 non-diabetic and 21 T2D human donors. We report that exocytosis is moderately reduced in α-cells of T2D donors, without changes in voltage-dependent ion currents or granule trafficking. Dispersed α-cells have a non-physiological V-shaped dose response to glucose, with maximal exocytosis at hyperglycemia. Within intact islets, hyperglycemia instead inhibits α-cell exocytosis, but not in T2D or when paracrine inhibition by insulin or somatostatin is blocked. Surface expression of somatostatin-receptor-2 is reduced in T2D, suggesting a mechanism for the observed somatostatin resistance. Thus, elevated glucagon in human T2D may reflect α-cell insensitivity to paracrine inhibition at hyperglycemia.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Exocitose/fisiologia , Células Secretoras de Glucagon/metabolismo , Glucagon/metabolismo , Células Secretoras de Glucagon/patologia , Glucose/metabolismo , Humanos , Hiperglicemia/metabolismo , Insulina/metabolismo , Imagem Óptica , Receptores de Somatostatina/metabolismo , Somatostatina/metabolismo
7.
Proc Natl Acad Sci U S A ; 117(11): 6189-6195, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123116

RESUMO

Neurofibromatosis 1 (NF1) is caused by mutations in the NF1 gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouse Nf1 from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Nf1 loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss of Nf1, without changes in somatostatin (SST)-positive CINs. We discovered that loss of Nf1 results in a dose-dependent decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone.


Assuntos
Córtex Cerebral/patologia , Neurônios GABAérgicos/patologia , Interneurônios/patologia , Proteínas com Homeodomínio LIM/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurofibromatose 1/patologia , Neurofibromina 1/genética , Fatores de Transcrição/metabolismo , Aminoacetonitrila/administração & dosagem , Aminoacetonitrila/análogos & derivados , Animais , Células Cultivadas , Córtex Cerebral/citologia , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Neurônios GABAérgicos/metabolismo , Humanos , Interneurônios/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Eminência Mediana/citologia , Camundongos , Camundongos Knockout , Neurofibromatose 1/genética , Neurofibromina 1/metabolismo , Neuroglia/citologia , Parvalbuminas/metabolismo , Cultura Primária de Células , Somatostatina/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo
8.
Proc Natl Acad Sci U S A ; 117(14): 8126-8134, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32205443

RESUMO

We recently reported that social choice-induced voluntary abstinence prevents incubation of methamphetamine craving in rats. This inhibitory effect was associated with activation of protein kinase-Cδ (PKCδ)-expressing neurons in central amygdala lateral division (CeL). In contrast, incubation of craving after forced abstinence was associated with activation of CeL-expressing somatostatin (SOM) neurons. Here we determined the causal role of CeL PKCδ and SOM in incubation using short-hairpin RNAs against PKCδ or SOM that we developed and validated. We injected two groups with shPKCδ or shCtrlPKCδ into CeL and trained them to lever press for social interaction (6 d) and then for methamphetamine infusions (12 d). We injected two other groups with shSOM or shCtrlSOM into CeL and trained them to lever press for methamphetamine infusions (12 d). We then assessed relapse to methamphetamine seeking after 1 and 15 abstinence days. Between tests, the rats underwent either social choice-induced abstinence (shPKCδ groups) or homecage forced abstinence (shSOM groups). After test day 15, we assessed PKCδ and SOM, Fos, and double-labeled expression in CeL and central amygdala medial division (CeM). shPKCδ CeL injections decreased Fos in CeL PKCδ-expressing neurons, increased Fos in CeM output neurons, and reversed the inhibitory effect of social choice-induced abstinence on incubated drug seeking on day 15. In contrast, shSOM CeL injections decreased Fos in CeL SOM-expressing neurons, decreased Fos in CeM output neurons, and decreased incubated drug seeking after 15 forced abstinence days. Our results identify dissociable central amygdala mechanisms of abstinence-dependent expression or inhibition of incubation of craving.


Assuntos
Núcleo Central da Amígdala/fisiologia , Fissura/fisiologia , Comportamento de Procura de Droga/fisiologia , Relações Interpessoais , Animais , Comportamento Animal , Modelos Animais de Doenças , Humanos , Masculino , Metanfetamina/administração & dosagem , Metanfetamina/efeitos adversos , Neurônios/metabolismo , Proteína Quinase C-delta/genética , Proteína Quinase C-delta/metabolismo , RNA Interferente Pequeno/administração & dosagem , Ratos , Ratos Sprague-Dawley , Autoadministração , Somatostatina/genética , Somatostatina/metabolismo
9.
Endocrinology ; 161(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32067028

RESUMO

Elevated and sustained estradiol concentrations cause a gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) surge that is necessary for ovulation. In sheep, several different neural systems have been implicated in this stimulatory action of estradiol and this study focused on somatostatin (SST) neurons in the ventral lateral region of the ventral medial nucleus (vlVMN) which express c-Fos during the surge. First, we determined if increased activity of SST neurons could be related to elevated GnRH secretion by assessing SST synapses onto GnRH neurons and neurons coexpressing kisspeptin, neurokinin B, dynorphin (KNDy). We found that the percentage of preoptic area GnRH neurons that receive SST input increased during the surge compared with other phases of the cycle. However, since SST is generally inhibitory, and pharmacological manipulation of SST signaling did not alter the LH surge in sheep, we hypothesized that nitric oxide (NO) was also produced by these neurons to account for their activation during the surge. In support of this hypothesis we found that (1) the majority of SST cells in the vlVMN (>80%) contained neuronal nitric oxide synthase (nNOS); (2) the expression of c-Fos in dual-labeled SST-nNOS cells, but not in single-labeled cells, increased during the surge compared with other phases of the cycle; and (3) intracerebroventricular (ICV) infusion of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester, completely blocked the estrogen-induced LH surge. These data support the hypothesis that the population of SST-nNOS cells in the vlVMN are a source of NO that is critical for the LH surge, and we propose that they are an important site of estradiol positive feedback in sheep.


Assuntos
Hormônio Luteinizante/sangue , Óxido Nítrico/metabolismo , Ovulação , Ovinos/sangue , Núcleo Hipotalâmico Ventromedial/enzimologia , Animais , Feminino , Óxido Nítrico Sintase Tipo I/metabolismo , Somatostatina/metabolismo
10.
Nat Commun ; 11(1): 1017, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32094367

RESUMO

Individuals with autism spectrum disorder (ASD) have social interaction deficits and difficulty filtering information. Inhibitory interneurons filter information at pyramidal neurons of the anterior cingulate cortex (ACC), an integration hub for higher-order thalamic inputs important for social interaction. Humans with deletions including LMO4, an endogenous inhibitor of PTP1B, display intellectual disabilities and occasionally autism. PV-Lmo4KO mice ablate Lmo4 in PV interneurons and display ASD-like repetitive behaviors and social interaction deficits. Surprisingly, increased PV neuron-mediated peri-somatic feedforward inhibition to the pyramidal neurons causes a compensatory reduction in (somatostatin neuron-mediated) dendritic inhibition. These homeostatic changes increase filtering of mediodorsal-thalamocortical inputs but reduce filtering of cortico-cortical inputs and narrow the range of stimuli ACC pyramidal neurons can distinguish. Simultaneous ablation of PTP1B in PV-Lmo4KO neurons prevents these deficits, indicating that PTP1B activation in PV interneurons contributes to ASD-like characteristics and homeostatic maladaptation of inhibitory circuits may contribute to deficient information filtering in ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Giro do Cíngulo/fisiopatologia , Rede Nervosa/metabolismo , Parvalbuminas/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Potenciais de Ação/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Técnicas de Observação do Comportamento , Comportamento Animal/fisiologia , Dendritos/fisiologia , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Feminino , Giro do Cíngulo/citologia , Giro do Cíngulo/patologia , Humanos , Interneurônios/metabolismo , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Masculino , Camundongos , Camundongos Knockout , Inibição Neural/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Células Piramidais/metabolismo , Somatostatina/metabolismo , Técnicas Estereotáxicas , Tálamo/citologia , Tálamo/metabolismo
11.
Sci Rep ; 10(1): 1982, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029751

RESUMO

People with schizophrenia exhibit deficits in inhibitory neurons and cognition. The timing of maternal immune activation (MIA) may present distinct schizophrenia-like phenotypes in progeny. We investigated whether early gestation [gestational day (GD) 10] or late gestation (GD19) MIA, via viral mimetic polyI:C, produces deficits in inhibitory neuron indices (GAD1, PVALB, SST, SSTR2 mRNAs) within cortical, striatal, and hippocampal subregions of male adult rat offspring. In situ hybridisation revealed that polyI:C offspring had: (1) SST mRNA reductions in the cingulate cortex and nucleus accumbens shell, regardless of MIA timing; (2) SSTR2 mRNA reductions in the cortex and striatum of GD19, but not GD10, MIA; (3) no alterations in cortical or striatal GAD1 mRNA of polyI:C offspring, but an expected reduction of PVALB mRNA in the infralimbic cortex, and; (4) no alterations in inhibitory markers in hippocampus. Maternal IL-6 response negatively correlated with adult offspring SST mRNA in cortex and striatum, but not hippocampus. These results show lasting inhibitory-related deficits in cortex and striatum in adult offspring from MIA. SST downregulation in specific cortical and striatal subregions, with additional deficits in somatostatin-related signalling through SSTR2, may contribute to some of the adult behavioural changes resulting from MIA and its timing.


Assuntos
Inibição Neural/imunologia , Complicações Infecciosas na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Esquizofrenia/imunologia , Animais , Comportamento Animal , Biomarcadores/análise , Biomarcadores/metabolismo , Córtex Cerebral/patologia , Corpo Estriado/patologia , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Feminino , Glutamato Descarboxilase/análise , Glutamato Descarboxilase/metabolismo , Hipocampo/patologia , Humanos , Interleucina-6/análise , Interleucina-6/metabolismo , Interneurônios/imunologia , Interneurônios/metabolismo , Interneurônios/patologia , Masculino , Poli I-C/imunologia , Gravidez , Ratos , Receptores de Somatostatina/análise , Receptores de Somatostatina/metabolismo , Esquizofrenia/patologia , Fatores Sexuais , Transdução de Sinais/imunologia , Somatostatina/análise , Somatostatina/metabolismo , Fatores de Tempo
12.
Biomed Res Int ; 2020: 7103053, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32051828

RESUMO

Mesenchymal stem cells (MSCs) can be differentiated in vitro to form insulin-producing cells (IPCs). However, the proportion of induced cells is modest. Extracts from injured pancreata of rodents promoted this differentiation, and three upregulated proteins were identified in these extracts. The aim of this study was to evaluate the potential benefits of adding these proteins to the differentiation medium alone or in combination. Our results indicate that the proportion of IPCs among the protein(s)-supplemented samples was significantly higher than that in the samples with no added proteins. The yield from samples supplemented with PRDX6 alone was 4-fold higher than that from samples without added protein. These findings were also supported by the results of fluorophotometry. Gene expression profiles revealed higher levels among protein-supplemented samples. Significantly higher levels of GGT, SST, Glut-2, and MafB expression were noted among PRDX6-treated samples. There was a stepwise increase in the release of insulin and c-peptide, as a function of increasing glucose concentrations, indicating that the differentiated cells were glucose sensitive and insulin responsive. PRDX6 exerts its beneficial effects as a result of its biological antioxidant properties. Considering its ease of use as a single protein, PRDX6 is now routinely used in our differentiation protocols.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Insulina/biossíntese , Células-Tronco Mesenquimais/metabolismo , Peroxirredoxina VI/metabolismo , Peroxirredoxina VI/farmacologia , Peptídeo C/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Humanos , Fator de Transcrição MafB/metabolismo , Peroxirredoxina VI/genética , Somatostatina/metabolismo , Transcriptoma , gama-Glutamiltransferase/metabolismo
13.
Epilepsia ; 61(2): 310-318, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31958887

RESUMO

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is typically unwitnessed but can be preceded by seizures in the period prior to death. Peri-ictal respiratory dysfunction is a likely mechanism for some SUDEP, and central apnea has been shown following amygdala stimulation. The amygdala is enriched in neuropeptides that modulate neuronal activity and can be transiently depleted following seizures. In a postmortem SUDEP series, we sought to investigate alterations of neuropeptidergic networks in the amygdala, including cases with recent poor seizure control. METHODS: In 15 SUDEP cases, 12 epilepsy controls, and 10 nonepilepsy controls, we quantified the labeling index (LI) for galanin, neuropeptide Y (NPY), and somatostatin (SST) in the lateral, basal, and accessory basal nuclei and periamygdala cortex with whole slide scanning image analysis. Within the SUDEP group, seven had recent generalized seizures with recovery 24 hours prior to death (SUDEP-R). RESULTS: Galanin, NPY, and SST LIs were significantly lower in all amygdala regions in SUDEP cases compared to epilepsy controls (P < .05 to P < .0005), and galanin LI was lower in the lateral nucleus compared to nonepilepsy controls (P < .05). There was no difference in the LI in the SUDEP-R group compared to other SUDEP. Higher LI was noted in epilepsy controls than nonepilepsy controls; this was significant for NPY in lateral and basal nuclei (P < .005 and P < .05). SIGNIFICANCE: A reduction in galanin in the lateral nucleus in SUDEP could represent acute depletion, relevant to postictal amygdala dysfunction. In addition, increased amygdala neuropeptides in epilepsy controls support their seizure-induced modulation, which is relatively deficient in SUDEP; this could represent a vulnerability factor for amygdala dysfunction in the postictal period.


Assuntos
Tonsila do Cerebelo/metabolismo , Neuropeptídeos/metabolismo , Morte Súbita Inesperada na Epilepsia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cadáver , Causas de Morte , Epilepsia/metabolismo , Feminino , Galanina/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/metabolismo , Neuropeptídeo Y/metabolismo , Somatostatina/metabolismo , Bancos de Tecidos , Adulto Jovem
14.
BMC Biol ; 18(1): 7, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31937327

RESUMO

BACKGROUND: Abnormal accumulation of amyloid ß1-42 oligomers (AßO1-42), a hallmark of Alzheimer's disease, impairs hippocampal theta-nested gamma oscillations and long-term potentiation (LTP) that are believed to underlie learning and memory. Parvalbumin-positive (PV) and somatostatin-positive (SST) interneurons are critically involved in theta-nested gamma oscillogenesis and LTP induction. However, how AßO1-42 affects PV and SST interneuron circuits is unclear. Through optogenetic manipulation of PV and SST interneurons and computational modeling of the hippocampal neural circuits, we dissected the contributions of PV and SST interneuron circuit dysfunctions on AßO1-42-induced impairments of hippocampal theta-nested gamma oscillations and oscillation-induced LTP. RESULTS: Targeted whole-cell patch-clamp recordings and optogenetic manipulations of PV and SST interneurons during in vivo-like, optogenetically induced theta-nested gamma oscillations in vitro revealed that AßO1-42 causes synapse-specific dysfunction in PV and SST interneurons. AßO1-42 selectively disrupted CA1 pyramidal cells (PC)-to-PV interneuron and PV-to-PC synapses to impair theta-nested gamma oscillogenesis. In contrast, while having no effect on PC-to-SST or SST-to-PC synapses, AßO1-42 selectively disrupted SST interneuron-mediated disinhibition to CA1 PC to impair theta-nested gamma oscillation-induced spike timing-dependent LTP (tLTP). Such AßO1-42-induced impairments of gamma oscillogenesis and oscillation-induced tLTP were fully restored by optogenetic activation of PV and SST interneurons, respectively, further supporting synapse-specific dysfunctions in PV and SST interneurons. Finally, computational modeling of hippocampal neural circuits including CA1 PC, PV, and SST interneurons confirmed the experimental observations and further revealed distinct functional roles of PV and SST interneurons in theta-nested gamma oscillations and tLTP induction. CONCLUSIONS: Our results reveal that AßO1-42 causes synapse-specific dysfunctions in PV and SST interneurons and that optogenetic modulations of these interneurons present potential therapeutic targets for restoring hippocampal network oscillations and synaptic plasticity impairments in Alzheimer's disease.


Assuntos
Potenciais de Ação/fisiologia , Peptídeos beta-Amiloides/efeitos adversos , Hipocampo , Interneurônios/fisiologia , Potenciação de Longa Duração/fisiologia , Parvalbuminas/metabolismo , Fragmentos de Peptídeos/efeitos adversos , Somatostatina/metabolismo , Animais , Camundongos , Optogenética
15.
Neuron ; 105(1): 93-105.e4, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31780328

RESUMO

The developmental journey of cortical interneurons encounters several activity-dependent milestones. During the early postnatal period in developing mice, GABAergic neurons are transient preferential recipients of thalamic inputs and undergo activity-dependent migration arrest, wiring, and programmed cell-death. Despite their importance for the emergence of sensory experience and the role of activity in their integration into cortical networks, the collective dynamics of GABAergic neurons during that neonatal period remain unknown. Here, we study coordinated activity in GABAergic cells of the mouse barrel cortex using in vivo calcium imaging. We uncover a transient structure in GABAergic population dynamics that disappears in a sensory-dependent process. Its building blocks are anatomically clustered GABAergic assemblies mostly composed by prospective parvalbumin-expressing cells. These progressively widen their territories until forming a uniform perisomatic GABAergic network. Such transient patterning of GABAergic activity is a functional scaffold that links the cortex to the external world prior to active exploration. VIDEO ABSTRACT.


Assuntos
Neurônios GABAérgicos/fisiologia , Interneurônios/fisiologia , Córtex Somatossensorial/crescimento & desenvolvimento , Córtex Somatossensorial/fisiologia , Tálamo/fisiologia , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Feminino , Glutamato Descarboxilase/genética , Masculino , Camundongos , Camundongos Transgênicos , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/fisiologia , Neuroimagem , Parvalbuminas/metabolismo , Privação Sensorial/fisiologia , Córtex Somatossensorial/metabolismo , Somatostatina/metabolismo , Vibrissas/patologia
16.
Neuron ; 105(1): 75-92.e5, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31780329

RESUMO

During neonatal development, sensory cortices generate spontaneous activity patterns shaped by both sensory experience and intrinsic influences. How these patterns contribute to the assembly of neuronal circuits is not clearly understood. Using longitudinal in vivo calcium imaging in un-anesthetized mouse pups, we show that spatially segregated functional assemblies composed of interneurons and pyramidal cells are prominent in the somatosensory cortex by postnatal day (P) 7. Both reduction of GABA release and synaptic inputs onto pyramidal cells erode the emergence of functional topography, leading to increased network synchrony. This aberrant pattern effectively blocks interneuron apoptosis, causing increased survival of parvalbumin and somatostatin interneurons. Furthermore, the effect of GABA on apoptosis is mediated by inputs from medial ganglionic eminence (MGE)-derived but not caudal ganglionic eminence (CGE)-derived interneurons. These findings indicate that immature MGE interneurons are fundamental for shaping GABA-driven activity patterns that balance the number of interneurons integrating into maturing cortical networks.


Assuntos
Neurônios GABAérgicos/fisiologia , Interneurônios/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Apoptose/fisiologia , Sobrevivência Celular/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Neurônios GABAérgicos/metabolismo , Potenciais Pós-Sinápticos Inibidores/fisiologia , Interneurônios/metabolismo , Masculino , Eminência Mediana/fisiologia , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Transgênicos , Vias Neurais/fisiologia , Neurogênese/fisiologia , Parvalbuminas/metabolismo , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Córtex Somatossensorial/crescimento & desenvolvimento , Somatostatina/metabolismo , Potenciais Sinápticos/fisiologia , Ácido gama-Aminobutírico/metabolismo
17.
J Cell Biol ; 219(1)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31676717

RESUMO

Although the role of transcription factors in fate specification of cortical interneurons is well established, how these interact with extracellular signals to regulate interneuron development is poorly understood. Here we show that the activin receptor ALK4 is a key regulator of the specification of somatostatin interneurons. Mice lacking ALK4 in GABAergic neurons of the medial ganglionic eminence (MGE) showed marked deficits in distinct subpopulations of somatostatin interneurons from early postnatal stages of cortical development. Specific losses were observed among distinct subtypes of somatostatin+/Reelin+ double-positive cells, including Hpse+ layer IV cells targeting parvalbumin+ interneurons, leading to quantitative alterations in the inhibitory circuitry of this layer. Activin-mediated ALK4 signaling in MGE cells induced interaction of Smad2 with SATB1, a transcription factor critical for somatostatin interneuron development, and promoted SATB1 nuclear translocation and repositioning within the somatostatin gene promoter. These results indicate that intrinsic transcriptional programs interact with extracellular signals present in the environment of MGE cells to regulate cortical interneuron specification.


Assuntos
Receptores de Ativinas Tipo I/fisiologia , Córtex Cerebral/citologia , Neurônios GABAérgicos/citologia , Interneurônios/citologia , Eminência Mediana/citologia , Neurogênese , Somatostatina/metabolismo , Animais , Diferenciação Celular , Linhagem da Célula , Córtex Cerebral/metabolismo , Feminino , Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Masculino , Eminência Mediana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Parvalbuminas/metabolismo , Transdução de Sinais
18.
Ann Neurol ; 87(1): 97-115, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31657482

RESUMO

OBJECTIVE: To investigate the network dynamics mechanisms underlying differential initiation of epileptic interictal spikes and seizures. METHODS: We performed combined in vivo 2-photon calcium imaging from different targeted neuronal subpopulations and extracellular electrophysiological recordings during 4-aminopyridine-induced neocortical spikes and seizures. RESULTS: Both spikes and seizures were associated with intense synchronized activation of excitatory layer 2/3 pyramidal neurons (PNs) and to a lesser degree layer 4 neurons, as well as inhibitory parvalbumin-expressing interneurons (INs). In sharp contrast, layer 5 PNs and somatostatin-expressing INs were gradually and asynchronously recruited into the ictal activity during the course of seizures. Within layer 2/3, the main difference between onset of spikes and seizures lay in the relative recruitment dynamics of excitatory PNs compared to parvalbumin- and somatostatin-expressing inhibitory INs. Whereas spikes exhibited balanced recruitment of PNs and parvalbumin-expressing INs, during seizures IN responses were reduced and less synchronized than in layer 2/3 PNs. Similar imbalance was not observed in layers 4 or 5 of the neocortex. Machine learning-based algorithms we developed were able to distinguish spikes from seizures based solely on activation dynamics of layer 2/3 PNs at discharge onset. INTERPRETATION: During onset of seizures, the recruitment dynamics markedly differed between neuronal subpopulations, with rapid synchronous recruitment of layer 2/3 PNs, layer 4 neurons, and parvalbumin-expressing INs and gradual asynchronous recruitment of layer 5 PNs and somatostatin-expressing INs. Seizures initiated in layer 2/3 due to a dynamic mismatch between local PNs and inhibitory INs, and only later spread to layer 5 by gradually and asynchronously recruiting PNs in this layer. ANN NEUROL 2020;87:97-115.


Assuntos
Interneurônios/fisiologia , Células Piramidais/fisiologia , Recrutamento Neurofisiológico/fisiologia , Convulsões/fisiopatologia , 4-Aminopiridina , Potenciais de Ação/fisiologia , Algoritmos , Animais , Feminino , Interneurônios/metabolismo , Aprendizado de Máquina , Masculino , Camundongos , Convulsões/induzido quimicamente , Somatostatina/metabolismo
19.
Nat Neurosci ; 23(1): 61-74, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31844314

RESUMO

Theories stipulate that memories are encoded within networks of cortical projection neurons. Conversely, GABAergic interneurons are thought to function primarily to inhibit projection neurons and thereby impose network gain control, an important but purely modulatory role. Here we show in male mice that associative fear learning potentiates synaptic transmission and cue-specific activity of medial prefrontal cortex somatostatin (SST) interneurons and that activation of these cells controls both memory encoding and expression. Furthermore, the synaptic organization of SST and parvalbumin interneurons provides a potential circuit basis for SST interneuron-evoked disinhibition of medial prefrontal cortex output neurons and recruitment of remote brain regions associated with defensive behavior. These data suggest that, rather than constrain mnemonic processing, potentiation of SST interneuron activity represents an important causal mechanism for conditioned fear.


Assuntos
Aprendizagem por Associação/fisiologia , Medo/fisiologia , Interneurônios/fisiologia , Memória/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Somatostatina/metabolismo , Transmissão Sináptica/fisiologia
20.
Nat Neurosci ; 23(1): 47-60, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31844317

RESUMO

The prefrontal cortex (PFC) is implicated in processing of the affective state of others through non-verbal communication. This social cognitive function is thought to rely on an intact cortical neuronal excitatory and inhibitory balance. Here combining in vivo electrophysiology with a behavioral task for affective state discrimination in mice, we show a differential activation of medial PFC (mPFC) neurons during social exploration that depends on the affective state of the conspecific. Optogenetic manipulations revealed a double dissociation between the role of interneurons in social cognition. Specifically, inhibition of mPFC somatostatin (SOM+), but not of parvalbumin (PV+) interneurons, abolishes affective state discrimination. Accordingly, synchronized activation of mPFC SOM+ interneurons selectively induces social discrimination. As visualized by in vivo single-cell microendoscopic Ca2+ imaging, an increased synchronous activity of mPFC SOM+ interneurons, guiding inhibition of pyramidal neurons, is associated with affective state discrimination. Our findings provide new insights into the neurobiological mechanisms of affective state discrimination.


Assuntos
Afeto/fisiologia , Interneurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Comportamento Social , Animais , Masculino , Camundongos , Somatostatina/metabolismo
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