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1.
Nat Commun ; 11(1): 4929, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004789

RESUMO

Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier's cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry.


Assuntos
Barreira Hematoencefálica/metabolismo , Encefalopatias/tratamento farmacológico , Portadores de Fármacos/efeitos da radiação , Agonistas de Receptores de GABA-A/administração & dosagem , Ultrassonografia de Intervenção/métodos , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/efeitos da radiação , Relação Dose-Resposta à Radiação , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Feminino , Agonistas de Receptores de GABA-A/farmacocinética , Humanos , Imagem por Ressonância Magnética , Modelos Animais , Muscimol/administração & dosagem , Muscimol/farmacocinética , Ratos , Técnicas Estereotáxicas , Ondas Ultrassônicas
2.
J Vis Exp ; (162)2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32925887

RESUMO

In vivo real-time monitoring of neuronal activities in freely moving animals is one of key approaches to link neuronal activity to behavior. For this purpose, an in vivo imaging technique that detects calcium transients in neurons using genetically encoded calcium indicators (GECIs), a miniaturized fluorescence microscope, and a gradient refractive index (GRIN) lens has been developed and successfully applied to many brain structures1 , 2 , 3 , 4 , 5 , 6. This imaging technique is particularly powerful because it enables chronic simultaneous imaging of genetically defined cell populations for a long-term period up to several weeks. Although useful, this imaging technique has not been easily applied to brain structures that locate deep within the brain such as amygdala, an essential brain structure for emotional processing and associative fear memory7. There are several factors that make it difficult to apply the imaging technique to the amygdala. For instance, motion artifacts usually occur more frequently during the imaging conducted in the deeper brain regions because a head-mount microscope implanted deep in the brain is relatively unstable. Another problem is that the lateral ventricle is positioned close to the implanted GRIN lens and its movement during respiration may cause highly irregular motion artifacts that cannot be easily corrected, which makes it difficult to form a stable imaging view. Furthermore, because cells in the amygdala are usually quiet at a resting or anesthetized state, it is hard to find and focus the target cells expressing GECI in the amygdala during baseplating procedure for later imaging. This protocol provides a helpful guideline for how to efficiently target cells expressing GECI in the amygdala with head-mount miniaturized microscope for successful in vivo calcium imaging in such a deeper brain region. It is noted that this protocol is based on a particular system (e.g., Inscopix) but not restricted to it.


Assuntos
Tonsila do Cerebelo/diagnóstico por imagem , Comportamento Animal/fisiologia , Cálcio/metabolismo , Microscopia/instrumentação , Miniaturização/instrumentação , Estimulação Acústica , Animais , Artefatos , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Cabeça , Lentes , Camundongos Endogâmicos C57BL , Movimento , Neuroimagem , Neurônios/metabolismo , Refratometria , Reprodutibilidade dos Testes , Técnicas Estereotáxicas
3.
Nat Commun ; 11(1): 4458, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895383

RESUMO

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.


Assuntos
Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fator 1 de Crescimento de Fibroblastos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Hipotálamo/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteína Relacionada com Agouti/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Glicemia/análise , Comunicação Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/administração & dosagem , Sacarose na Dieta/efeitos adversos , Humanos , Hipotálamo/citologia , Hipotálamo/patologia , Injeções Intraventriculares , Leptina/genética , Masculino , Melanocortinas/metabolismo , Hormônios Estimuladores de Melanócitos/administração & dosagem , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , RNA-Seq , Receptor Tipo 4 de Melanocortina/genética , Receptores de Melanocortina/antagonistas & inibidores , Receptores de Melanocortina/metabolismo , Indução de Remissão/métodos , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Técnicas Estereotáxicas , Transcriptoma/efeitos dos fármacos
4.
Nat Commun ; 11(1): 4550, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917862

RESUMO

Place cells exhibit spatially selective firing fields that collectively map the continuum of positions in environments; how such activity pattern develops with experience is largely unknown. Here, we record putative granule cells (GCs) and mossy cells (MCs) from the dentate gyrus (DG) over 27 days as mice repetitively run through a sequence of objects fixed onto a treadmill belt. We observe a progressive transformation of GC spatial representations, from a sparse encoding of object locations and spatial patterns to increasingly more single, evenly dispersed place fields, while MCs show little transformation and preferentially encode object locations. A competitive learning model of the DG reproduces GC transformations via the progressive integration of landmark-vector cells and spatial inputs and requires MC-mediated feedforward inhibition to evenly distribute GC representations, suggesting that GCs slowly encode conjunctions of objects and spatial information via competitive learning, while MCs help homogenize GC spatial representations.


Assuntos
Fibras Musgosas Hipocampais/fisiologia , Células de Lugar/fisiologia , Aprendizagem Espacial/fisiologia , Potenciais de Ação/fisiologia , Animais , Eletrodos Implantados , Eletroencefalografia/instrumentação , Masculino , Camundongos , Modelos Animais , Técnicas Estereotáxicas/instrumentação
5.
Nat Commun ; 11(1): 4686, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943633

RESUMO

Electrophysiology provides a direct readout of neuronal activity at a temporal precision only limited by the sampling rate. However, interrogating deep brain structures, implanting multiple targets or aiming at unusual angles still poses significant challenges for operators, and errors are only discovered by post-hoc histological reconstruction. Here, we propose a method combining the high-resolution information about bone landmarks provided by micro-CT scanning with the soft tissue contrast of the MRI, which allowed us to precisely localize electrodes and optic fibers in mice in vivo. This enables arbitrating the success of implantation directly after surgery with a precision comparable to gold standard histology. Adjustment of the recording depth with micro-drives or early termination of unsuccessful experiments saves many working hours, and fast 3-dimensional feedback helps surgeons avoid systematic errors. Increased aiming precision enables more precise targeting of small or deep brain nuclei and multiple targeting of specific cortical or hippocampal layers.


Assuntos
Encéfalo/diagnóstico por imagem , Eletrodos Implantados , Processamento de Imagem Assistida por Computador/métodos , Fibras Ópticas , Microtomografia por Raio-X/métodos , Animais , Comportamento Animal , Encéfalo/patologia , Mapeamento Encefálico , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Hipocampo/cirurgia , Técnicas Histológicas/métodos , Imagem por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Silício , Técnicas Estereotáxicas
6.
PLoS Biol ; 18(8): e3000851, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32822389

RESUMO

High levels of the amyloid-beta (Aß) peptide have been shown to disrupt neuronal function and induce hyperexcitability, but it is unclear what effects Aß-associated hyperexcitability may have on tauopathy pathogenesis or propagation in vivo. Using a novel transgenic mouse line to model the impact of human APP (hAPP)/Aß accumulation on tauopathy in the entorhinal cortex-hippocampal (EC-HIPP) network, we demonstrate that hAPP overexpression aggravates EC-Tau aggregation and accelerates pathological tau spread into the hippocampus. In vivo recordings revealed a strong role for hAPP/Aß, but not tau, in the emergence of EC neuronal hyperactivity and impaired theta rhythmicity. Chronic chemogenetic attenuation of EC neuronal hyperactivity led to reduced hAPP/Aß accumulation and reduced pathological tau spread into downstream hippocampus. These data strongly support the hypothesis that in Alzheimer's disease (AD), Aß-associated hyperactivity accelerates the progression of pathological tau along vulnerable neuronal circuits, and demonstrates the utility of chronic, neuromodulatory approaches in ameliorating AD pathology in vivo.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Córtex Entorrinal/metabolismo , Tauopatias/genética , Proteínas tau/genética , Potenciais de Ação/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animais de Doenças , Eletrodos Implantados , Córtex Entorrinal/patologia , Feminino , Regulação da Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Agregados Proteicos , Técnicas Estereotáxicas , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/terapia , Ritmo Teta/fisiologia , Transdução Genética , Transgenes , Proteínas tau/metabolismo
7.
Nat Commun ; 11(1): 3688, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703948

RESUMO

Zeta inhibitory peptide (ZIP), a PKMζ inhibitor, is widely used to interfere with the maintenance of acquired memories. ZIP is able to erase memory even in the absence of PKMζ, via an unknown mechanism. We found that ZIP induces redistribution of the AMPARGluA1 in HEK293 cells and primary cortical neurons, and decreases AMPAR-mediated currents in the nucleus accumbens (NAc). These effects were mimicked by free arginine or by a modified ZIP in which all but the arginine residues were replaced by alanine. Redistribution was blocked by a peptidase-resistant version of ZIP and by treatment with the nitric oxide (NO)-synthase inhibitor L-NAME. ZIP increased GluA1-S831 phosphorylation and ZIP-induced redistribution was blocked by nitrosyl-mutant GluA1-C875S or serine-mutant GluA1-S831A. Introducing the cleavable arginine-alanine peptide into the NAc attenuated expression of cocaine-conditioned reward. Together, these results suggest that ZIP may act as an arginine donor, facilitating NO-dependent downregulation of AMPARs, thereby attenuating learning and memory.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Lipopeptídeos/farmacologia , Memória de Longo Prazo/efeitos dos fármacos , Óxido Nítrico/metabolismo , Receptores de AMPA/metabolismo , Animais , Cocaína/administração & dosagem , Regulação para Baixo , Endocitose/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Células HEK293 , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Modelos Animais , NG-Nitroarginina Metil Éster/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Óxido Nítrico/antagonistas & inibidores , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Fosforilação , Cultura Primária de Células , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Ratos , Receptores de AMPA/genética , Recompensa , Técnicas Estereotáxicas
8.
World Neurosurg ; 139: 775-788, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32689698

RESUMO

Technical limitations and clinical challenges have historically limited the diagnostic tools and treatment methods available for surgical approaches to the management of epilepsy. By contrast, recent technological innovations in several areas hold significant promise in improving outcomes and decreasing morbidity. We review innovations in the neurosurgical management of epilepsy in several areas, including wireless recording and stimulation systems (particularly responsive neurostimulation [NeuroPace]), conformal electrodes for high-resolution electrocorticography, robot-assisted stereotactic surgery, optogenetics and optical imaging methods, novel positron emission tomography ligands, and new applications of focused ultrasonography. Investigation into genetic causes of and susceptibilities to epilepsy has introduced a new era of precision medicine, enabling the understanding of cell signaling mechanisms underlying epileptic activity as well as patient-specific molecularly targeted treatment options. We discuss the emerging path to individualized treatment plans, predicted outcomes, and improved selection of effective interventions, on the basis of these developments.


Assuntos
Epilepsia Resistente a Medicamentos/cirurgia , Invenções , Procedimentos Neurocirúrgicos , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/terapia , Eletrocorticografia , Ablação por Ultrassom Focalizado de Alta Intensidade , Humanos , Neuroestimuladores Implantáveis , Imagem Óptica , Optogenética , Tomografia por Emissão de Pósitrons , Medicina de Precisão , Implantação de Prótese , Procedimentos Cirúrgicos Robóticos , Técnicas Estereotáxicas , Tecnologia sem Fio
9.
Nat Commun ; 11(1): 3764, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724058

RESUMO

Context can influence reactions to environmental cues and this elemental process has implications for substance use disorder. Using an animal model, we show that an alcohol-associated context elevates entry into a fluid port triggered by a conditioned stimulus (CS) that predicted alcohol (CS-triggered alcohol-seeking). This effect persists across multiple sessions and, after it diminishes in extinction, the alcohol context retains the capacity to augment reinstatement. Systemically administered eticlopride and chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons reduce CS-triggered alcohol-seeking. Chemogenetically silencing VTA dopamine terminals in the nucleus accumbens (NAc) core reduces CS-triggered alcohol-seeking, irrespective of context, whereas silencing VTA dopamine terminals in the NAc shell selectively reduces the elevation of CS-triggered alcohol-seeking in an alcohol context. This dissociation reveals new roles for divergent mesolimbic dopamine circuits in the control of responding to a discrete cue for alcohol and in the amplification of this behaviour in an alcohol context.


Assuntos
Transtornos Relacionados ao Uso de Álcool/psicologia , Dopamina/metabolismo , Etanol/administração & dosagem , Extinção Psicológica/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Sinais (Psicologia) , Modelos Animais de Doenças , Antagonistas de Dopamina/administração & dosagem , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Extinção Psicológica/efeitos dos fármacos , Feminino , Humanos , Masculino , Ratos , Salicilamidas/administração & dosagem , Técnicas Estereotáxicas , Área Tegmentar Ventral/citologia
10.
Neurocirugía (Soc. Luso-Esp. Neurocir.) ; 31(3): 119-131, mayo-jun. 2020. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-192416

RESUMO

El objetivo principal del tratamiento en las metástasis espinales es el control local de la enfermedad, el alivio del dolor y el mantenimiento de la deambulación. Clásicamente, se ha recomendado una resección quirúrgica del tumor lo más amplia posible seguida de radioterapia o quimioterapia adyuvante. En la actualidad, la radioterapia estereotáxica corporal (SBRT) en dosis única o hipofraccionada proporciona tasas globales de control local al año superiores al 95% con mínima morbilidad, incluso en histologías que suelen considerarse radiorresistentes. Por otro lado, mediante cirugía de descompresión circunferencial posterolateral y estabilización de la columna es factible crear un espacio de 2-3 mm entre el borde tumoral y la duramadre (separation surgery) suficiente para permitir administrar de forma segura SBRT a dosis ablativas. Dado que con frecuencia se trata de pacientes frágiles, dicha cirugía puede realizarse mediante técnicas mínimamente invasivas, que reducen la agresividad quirúrgica y ayudan a minimizar el retraso de eventuales tratamientos sistémicos


The main goal of treatment in spinal metastatic patients is local control of the disease, pain relief and the maintenance of ambulation. Traditionally, wide surgical resection of the tumour followed by adjuvant radiation and/or chemotherapy has been recommended. Currently, single-fraction or hypofractionated stereotactic body radiation therapy (SBRT) yields a one-year local control rate of over 95% with minimum morbidity, even for tumours previously considered radioresistant. In addition, by posterolateral and circumferential decompression and stabilisation of the spinal cord, it is feasible to create a 2 to 3 mm epidural margin between the dura mater and the tumour (separation surgery), enough to deliver safe and ablative doses of SBRT to the vertebrae. As these patients tend to be frail, such interventions should ideally be minimally invasive, thereby reducing surgical aggressiveness and helping to minimise the delay of any systemic therapies


Assuntos
Humanos , Feminino , Adulto , Idoso , Técnicas Estereotáxicas/instrumentação , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Neoplasias da Medula Espinal/cirurgia , Metástase Neoplásica , Manejo da Dor , Transtornos Neurológicos da Marcha/terapia , Qualidade de Vida , Algoritmos , Radiocirurgia/efeitos adversos , Compressão da Medula Espinal/diagnóstico por imagem , Compressão da Medula Espinal/cirurgia , Cifose/diagnóstico por imagem , Imunoterapia
11.
Turk Neurosurg ; 30(4): 595-603, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530481

RESUMO

AIM: To share our clinical experience with surgical and adjuvant treatment strategies followed during the treatment of midline gliomas. MATERIAL AND METHODS: Pediatric patients with midline gliomas who underwent surgery in our clinic between March 2016 and November 2019 were included. Tissue samples were obtained through surgical excision, open biopsy, or stereotactic biopsy. All samples were analyzed for ATRX, BRAFV600E, IDH1/2, H3K27M, and H3G34R mutations, EGFR and PGFRA amplifications, and PTEN loss. RESULTS: There were 7 (43.8%) female and 9 (56.2%) male pediatric patients in the study. Eight patients had thalamic, 5 patients had pontine, 2 patients had medulla oblongata and one patient had brachium pontis tumors. Presenting symptoms were headache, disequilibrium, ophthalmoplegia, and panic attack. Eleven tumors showed H3K27M mutation and were diagnosed as diffuse midline gliomas. BRAFV600E, ATRX mutations, PTEN loss, and EGFR amplifications were other molecular alterations detected within tumor samples. Patients with H3K27M mutant tumors had a shorter life span. Five patients were enrolled in an ONC201 trial. CONCLUSION: Although most midline gliomas are not amenable to gross total excision, obtaining tissue samples is mandatory for determining patients? exact diagnoses, tailored treatment plans, and eligibility for clinical trials. Stereotactic biopsy for midline gliomas is a safe and effective method.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Glioma/genética , Glioma/cirurgia , Mutação/genética , Adolescente , Biópsia/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Seguimentos , Glioma/diagnóstico por imagem , Histonas/genética , Humanos , Masculino , Estudos Retrospectivos , Técnicas Estereotáxicas
12.
Epilepsia ; 61(7): 1406-1416, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32533794

RESUMO

OBJECTIVE: This retrospective, cross-sectional study evaluated the feasibility and potential benefits of incorporating deep-learning on structural magnetic resonance imaging (MRI) into planning stereoelectroencephalography (sEEG) implantation in pediatric patients with diagnostically complex drug-resistant epilepsy. This study aimed to assess the degree of colocalization between automated lesion detection and the seizure onset zone (SOZ) as assessed by sEEG. METHODS: A neural network classifier was applied to cortical features from MRI data from three cohorts. (1) The network was trained and cross-validated using 34 patients with visible focal cortical dysplasias (FCDs). (2) Specificity was assessed in 20 pediatric healthy controls. (3) Feasibility of incorporation into sEEG implantation plans was evaluated in 34 sEEG patients. Coordinates of sEEG contacts were coregistered with classifier-predicted lesions. sEEG contacts in seizure onset and irritative tissue were identified by clinical neurophysiologists. A distance of <10 mm between SOZ contacts and classifier-predicted lesions was considered colocalization. RESULTS: In patients with radiologically defined lesions, classifier sensitivity was 74% (25/34 lesions detected). No clusters were detected in the controls (specificity = 100%). Of the total 34 sEEG patients, 21 patients had a focal cortical SOZ, of whom eight were histopathologically confirmed as having an FCD. The algorithm correctly detected seven of eight of these FCDs (86%). In patients with histopathologically heterogeneous focal cortical lesions, there was colocalization between classifier output and SOZ contacts in 62%. In three patients, the electroclinical profile was indicative of focal epilepsy, but no SOZ was localized on sEEG. In these patients, the classifier identified additional abnormalities that had not been implanted. SIGNIFICANCE: There was a high degree of colocalization between automated lesion detection and sEEG. We have created a framework for incorporation of deep-learning-based MRI lesion detection into sEEG implantation planning. Our findings support the prospective evaluation of automated MRI analysis to plan optimal electrode trajectories.


Assuntos
Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletroencefalografia/métodos , Técnicas Estereotáxicas , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Estudos de Viabilidade , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Estudos Retrospectivos
13.
Nat Commun ; 11(1): 2847, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504036

RESUMO

The browning of white adipose tissue (WAT) has got much attention for its potential beneficial effects on metabolic disorders, however, the nutritional factors and neuronal signals involved remain largely unknown. We sought to investigate whether WAT browning is stimulated by leucine deprivation, and whether the amino acid sensor, general control non-derepressible 2 (GCN2), in amygdalar protein kinase C-δ (PKC-δ) neurons contributes to this regulation. Our results show that leucine deficiency can induce WAT browning, which is unlikely to be caused by food intake, but is largely blocked by PKC-δ neuronal inhibition and amygdalar GCN2 deletion. Furthermore, GCN2 knockdown in amygdalar PKC-δ neurons blocks WAT browning, which is reversed by over-expression of amino acid responsive gene activating transcription factor 4 (ATF4), and is mediated by the activities of amygdalar PKC-δ neurons and the sympathetic nervous system. Our data demonstrate that GCN2/ATF4 can regulate WAT browning in amygdalar PKC-δ neurons under leucine deprivation.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Tecido Adiposo Branco/fisiologia , Tonsila do Cerebelo/fisiologia , Leucina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/inervação , Tonsila do Cerebelo/citologia , Animais , Técnicas de Silenciamento de Genes , Lipólise/fisiologia , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Proteína Quinase C-delta/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/fisiologia , Técnicas Estereotáxicas , Sistema Nervoso Simpático/fisiologia , Termogênese/fisiologia
14.
Nat Commun ; 11(1): 3143, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561719

RESUMO

Topoisomerase 3ß (Top3ß) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3ß mutations have been linked to schizophrenia, autism, epilepsy, and cognitive impairment. Here we show that Top3ß knockout mice exhibit behavioural phenotypes related to psychiatric disorders and cognitive impairment. The mice also display impairments in hippocampal neurogenesis and synaptic plasticity. Notably, the brains of the mutant mice exhibit impaired global neuronal activity-dependent transcription in response to fear conditioning stress, and the affected genes include many with known neuronal functions. Our data suggest that Top3ß is essential for normal brain function, and that defective neuronal activity-dependent transcription may be a mechanism by which Top3ß deletion causes cognitive impairment and psychiatric disorders.


Assuntos
Disfunção Cognitiva/genética , DNA Topoisomerases Tipo I/genética , Transtornos Mentais/genética , Neurogênese/genética , Plasticidade Neuronal/genética , Animais , Técnicas de Observação do Comportamento , Comportamento Animal , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Feminino , Hipocampo/citologia , Hipocampo/diagnóstico por imagem , Hipocampo/crescimento & desenvolvimento , Hipocampo/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/patologia , Camundongos , Camundongos Knockout , Neurônios/patologia , Técnicas Estereotáxicas , Potenciais Sinápticos/genética , Transcrição Genética/fisiologia
15.
Proc Natl Acad Sci U S A ; 117(25): 14473-14481, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513737

RESUMO

Hypothalamic tanycytes are chemosensitive glial cells that contact the cerebrospinal fluid in the third ventricle and send processes into the hypothalamic parenchyma. To test whether they can activate neurons of the arcuate nucleus, we targeted expression of a Ca2+-permeable channelrhodopsin (CatCh) specifically to tanycytes. Activation of tanycytes ex vivo depolarized orexigenic (neuropeptide Y/agouti-related protein; NPY/AgRP) and anorexigenic (proopiomelanocortin; POMC) neurons via an ATP-dependent mechanism. In vivo, activation of tanycytes triggered acute hyperphagia only in the fed state during the inactive phase of the light-dark cycle.


Assuntos
Núcleo Arqueado do Hipotálamo/fisiopatologia , Células Ependimogliais/fisiologia , Hiperfagia/fisiopatologia , Neurônios/fisiologia , Proteína Relacionada com Agouti/metabolismo , Animais , Apetite/fisiologia , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/diagnóstico por imagem , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Metabolismo Energético/fisiologia , Comportamento Alimentar/fisiologia , Feminino , Genes Reporter , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Rede Nervosa/fisiologia , Neuropeptídeo Y/metabolismo , Imagem Óptica , Optogenética , Técnicas de Patch-Clamp , Pró-Opiomelanocortina/metabolismo , Técnicas Estereotáxicas
16.
J Vis Exp ; (160)2020 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-32568247

RESUMO

Metastatic spread of cancer is an unfortunate consequence of disease progression, aggressive cancer subtypes, and/or late diagnosis. Brain metastases are particularly devastating, difficult to treat, and confer a poor prognosis. While the precise incidence of brain metastases in the United States remains hard to estimate, it is likely to increase as extracranial therapies continue to become more efficacious in treating cancer. Thus, it is necessary to identify and develop novel therapeutic approaches to treat metastasis at this site. To this end, intracranial injection of cancer cells has become a well-established method in which to model brain metastasis. Previously, the inability to directly measure tumor growth has been a technical hindrance to this model; however, increasing availability and quality of small animal imaging modalities, such as magnetic resonance imaging (MRI), are vastly improving the ability to monitor tumor growth over time and infer changes within the brain during the experimental period. Herein, intracranial injection of murine mammary tumor cells into immunocompetent mice followed by MRI is demonstrated. The presented injection approach utilizes isoflurane anesthesia and a stereotactic setup with a digitally controlled, automated drill and needle injection to enhance precision, and reduce technical error. MRI is measured over time using a 9.4 Tesla instrument in The Ohio State University James Comprehensive Cancer Center Small Animal Imaging Shared Resource. Tumor volume measurements are demonstrated at each time point through use of ImageJ. Overall, this intracranial injection approach allows for precise injection, day-to-day monitoring, and accurate tumor volume measurements, which combined greatly enhance the utility of this model system to test novel hypotheses on the drivers of brain metastases.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/secundário , Injeções , Imagem por Ressonância Magnética , Anestesia , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Neoplasias da Mama/patologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Camundongos , Técnicas Estereotáxicas , Carga Tumoral
17.
J Vis Exp ; (160)2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32597878

RESUMO

Cerebral contusion is a severe medical problem affecting millions of people worldwide each year. There is an urgent need to understand the pathophysiological mechanism and to develop effective therapeutic strategy for this devastating neurological disorder. Intraparenchymal hemorrhage and post-traumatic inflammatory response induced by initial physical impact can aggravate microglia/macrophage activation and neuroinflammation which subsequently worsen brain pathology. We provide here a controlled cortical impact (CCI) protocol that can reproduce experimental cortical contusion in mice by using a pneumatic impactor system to deliver mechanical force with controllable magnitude and velocity onto the dural surface. This preclinical model allows researchers to induce moderately severe focal cerebral contusion in mice and to investigate a wide range of post-traumatic pathological progressions including hemorrhage contusion, microglia/macrophage activation, iron toxicity, axonal injury, as well as short-term and long-term neurobehavioral deficits. The present protocol can be useful for exploring the long-term effects of and potential interventions for cerebral contusion.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Córtex Cerebral/patologia , Contusões/complicações , Contusões/patologia , Hemorragia/complicações , Hemorragia/patologia , Inflamação/patologia , Animais , Lesões Encefálicas Traumáticas/patologia , Craniotomia , Modelos Animais de Doenças , Inflamação/complicações , Masculino , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Técnicas Estereotáxicas
18.
World Neurosurg ; 139: e784-e791, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32371080

RESUMO

OBJECTIVE: We sought to determine the location of kinesthetic cell clusters within the subthalamic nucleus (STN) on magnetic resonance imaging, adjusted for interindividual anatomic variability by employing the medial STN border as a reference point. METHODS: We retrospectively localized microelectrode recording-defined kinesthetic cells on 3-Tesla T2-weighted and susceptibility-weighted images in patients who underwent STN deep brain stimulation for Parkinson disease and averaged the stereotactic coordinates. These locations were calculated relative to the nonindividualized midcommissural point (MCP) and, in order to account for interindividual anatomic variability, also calculated relative to the patient-specific intersection of Bejjani line with the medial STN border. Two example patients were selected in order to visualize the discrepancies between the adjusted and nonadjusted theoretic kinesthetic cell clusters on magnetic resonance imaging. RESULTS: Relative to the MCP, average kinesthetic cell coordinates were 12.3 ± 1.2 mm lateral, 1.7 ± 1.4 mm posterior, and 2.3 ± 1.5 mm inferior. Relative to the medial STN border, mean coordinates were 3.4 ± 1.0 mm lateral, 1.0 ± 1.4 mm anterior, and 1.7 ± 1.5 mm superior on T2-sequences, and on susceptibility-weighted images mean coordinates were 3.2 ± 1.1 mm lateral, 0.8 ± 1.5 mm anterior, and 2.1 ± 1.5 mm superior. The theoretic kinesthetic cell clusters may appear outside the sensorimotor STN when using the MCP, whereas these clusters fall well within the sensorimotor STN when employing the medial STN border as a reference point. CONCLUSIONS: By using the medial STN border as a patient-specific anatomic reference point in STN deep brain stimulation for Parkinson disease, we accounted for interindividual anatomic variability and provided accurate insight in the clustering of kinesthetic cells within the dorsolateral STN.


Assuntos
Mapeamento Encefálico/métodos , Estimulação Encefálica Profunda/métodos , Doença de Parkinson/terapia , Núcleo Subtalâmico/diagnóstico por imagem , Núcleo Subtalâmico/fisiologia , Idoso , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Microeletrodos , Pessoa de Meia-Idade , Neurônios/citologia , Técnicas Estereotáxicas , Núcleo Subtalâmico/citologia
19.
Proc Natl Acad Sci U S A ; 117(23): 13066-13077, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32461374

RESUMO

Layer 6 (L6) is the sole purveyor of corticothalamic (CT) feedback to first-order thalamus and also sends projections to higher-order thalamus, yet how it engages the full corticothalamic circuit to contribute to sensory processing in an awake animal remains unknown. We sought to elucidate the functional impact of L6CT projections from the primary visual cortex to the dorsolateral geniculate nucleus (first-order) and pulvinar (higher-order) using optogenetics and extracellular electrophysiology in awake mice. While sustained L6CT photostimulation suppresses activity in both visual thalamic nuclei in vivo, moderate-frequency (10 Hz) stimulation powerfully facilitates thalamic spiking. We show that each stimulation paradigm differentially influences the balance between monosynaptic excitatory and disynaptic inhibitory corticothalamic pathways to the dorsolateral geniculate nucleus and pulvinar, as well as the prevalence of burst versus tonic firing. Altogether, our results support a model in which L6CTs modulate first- and higher-order thalamus through parallel excitatory and inhibitory pathways that are highly dynamic and context-dependent.


Assuntos
Corpos Geniculados/fisiologia , Pulvinar/fisiologia , Córtex Visual/fisiologia , Animais , Estimulação Elétrica , Eletrodos Implantados , Feminino , Masculino , Camundongos , Microeletrodos , Optogenética , Técnicas Estereotáxicas , Vias Visuais
20.
Epilepsia ; 61(6): 1190-1200, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32401350

RESUMO

OBJECTIVE: Corpus callosotomy is an effective palliative treatment for drug-resistant Lennox-Gastaut syndrome (LGS). Laser interstitial thermal therapy has been increasingly used in the treatment of epilepsy. Here, we assess the safety and effectiveness of minimally invasive stereotactic laser anterior corpus callosotomy (SLACC) for drop attacks in LGS. METHODS: We reviewed sequential cases of patients with medically intractable LGS who underwent SLACC using a two-cannula technique between November 2014 and July 2019. Pre- and postoperative magnetic resonance imaging was used to measure the anteroposterior length of callosal ablation (contrast-enhancing lesion) and estimated disconnection (gap in tract projections on diffusion tensor imaging). Patients were followed longitudinally to assess clinical outcomes. RESULTS: Ten patients were included in this study. The median age was 33 (range = 11-52) years, median duration of epilepsy was 26 (range = 10-49) years, and median duration of postoperative follow-up was 19 (range = 6-40) months. In the anteroposterior direction, 53 ± 7% (mean ± SD) of the corpus callosum was ablated and 62 ± 19% of the corpus callosum was estimated to be disconnected. Six (60%) of 10 patients achieved >80% seizure reduction, two (20%) of whom became seizure-free. Eight (80%) patients had >80% reduction in drop attacks, five (50%) of whom became free of drop attacks. Three patients subsequently underwent laser posterior callosotomy with further improvement in drop attacks and/or overall seizure frequency. One patient had an asymptomatic intracerebral hemorrhage along the cannula tract. One patient developed significant aggression after becoming seizure-free. SIGNIFICANCE: Seizure outcomes following SLACC were comparable to previously reported outcomes of open callosotomy, with reasonable safety profile. SLACC appears to be an effective alternative to open anterior corpus callosotomy with minimal postoperative discomfort and a short recovery period.


Assuntos
Corpo Caloso/diagnóstico por imagem , Corpo Caloso/cirurgia , Terapia a Laser/métodos , Síndrome de Lennox Gastaut/diagnóstico por imagem , Síndrome de Lennox Gastaut/cirurgia , Técnicas Estereotáxicas , Adolescente , Adulto , Criança , Corpo Caloso/fisiopatologia , Feminino , Seguimentos , Humanos , Síndrome de Lennox Gastaut/fisiopatologia , Masculino , Pessoa de Meia-Idade , Psicocirurgia/métodos , Estudos Retrospectivos
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