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1.
Neuron ; 110(5): 795-808.e6, 2022 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-34932941

RESUMO

The neural basis of abnormal social behavior in autism spectrum disorders (ASDs) remains incompletely understood. Here we used two complementary but independent brain-wide mapping approaches, mouse resting-state fMRI and c-Fos-iDISCO+ imaging, to construct brain-wide activity and connectivity maps of the Cntnap2 knockout (KO) mouse model of ASD. At the macroscale level, we detected reduced functional coupling across social brain regions despite general patterns of hyperconnectivity across major brain structures. Oxytocin administration, which rescues social deficits in KO mice, strongly stimulated many brain areas and normalized connectivity patterns. Notably, chemogenetically triggered release of endogenous oxytocin strongly stimulated the nucleus accumbens (NAc), a forebrain nucleus implicated in social reward. Furthermore, NAc-targeted approaches to activate local oxytocin receptors sufficiently rescued their social deficits. Our findings establish circuit- and systems-level mechanisms of social deficits in Cntnap2 KO mice and reveal the NAc as a region that can be modulated by oxytocin to promote social interactions.


Assuntos
Transtorno do Espectro Autista , Ocitocina , Animais , Transtorno do Espectro Autista/genética , Encéfalo/metabolismo , Proteínas de Membrana , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Ocitocina/fisiologia , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Comportamento Social
2.
Hum Brain Mapp ; 42(12): 3804-3820, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-33991165

RESUMO

Transcranial magnetic stimulation (TMS) has become one of the major tools for establishing the causal role of specific brain regions in perceptual, motor, and cognitive processes. Nevertheless, a persistent limitation of the technique is the lack of clarity regarding its precise effects on neural activity. Here, we examined the effects of TMS intensity and frequency on concurrently recorded blood-oxygen-level-dependent (BOLD) signals at the site of stimulation. In two experiments, we delivered TMS to the dorsolateral prefrontal cortex in human subjects of both sexes. In Experiment 1, we delivered a series of pulses at high (100% of motor threshold) or low (50% of motor threshold) intensity, whereas, in Experiment 2, we always used high intensity but delivered stimulation at four different frequencies (5, 8.33, 12.5, and 25 Hz). We found that the TMS intensity and frequency could be reliably decoded using multivariate analysis techniques even though TMS had no effect on the overall BOLD activity at the site of stimulation in either experiment. These results provide important insight into the mechanisms through which TMS influences neural activity.


Assuntos
Córtex Pré-Frontal Dorsolateral/fisiologia , Processamento de Imagem Assistida por Computador , Estimulação Magnética Transcraniana , Adulto , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Análise Multivariada , Estimulação Magnética Transcraniana/métodos , Adulto Jovem
3.
Neuropsychopharmacology ; 38(5): 846-53, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23299932

RESUMO

Aberrant activity in brain regions underlying various aspects of executive cognition has been reported in patients with schizophrenia and in their healthy relatives, suggesting an association with genetic liability. The aim of this study was to investigate brain responses to selective aspects of cognitive control in unaffected siblings who are at increased genetic risk of schizophrenia. Altogether, 65 non-affected siblings, 70 patients with schizophrenia spectrum disorders, and 235 normal controls participated in this study. Blood-oxygen-level-dependent functional magnetic resonance imaging was conducted while participants performed a cognitive control task ('flanker task') to identify brain activity and connectivity associated with response inhibition and conflict monitoring, and suppression. Behaviorally, similar to patients with schizophrenia, siblings were less accurate when inhibiting prepotent responses relative to normal controls. During response inhibition, again similar to patients with schizophrenia, siblings showed decreased activity in the anterior cingulate (ACC), along with increased functional coupling with the dorsolateral prefrontal cortex (PFC) when compared to normal controls. Our findings show altered ACC activity and PFC connectivity in unaffected siblings and patients with schizophrenia during response inhibition. These results suggest that such changes in the neural activity underlying aspects of cognitive control may represent a potential intermediate phenotype for the investigation of the genetic basis of schizophrenia.


Assuntos
Córtex Cerebral/fisiopatologia , Transtornos Cognitivos/etiologia , Esquizofrenia/complicações , Esquizofrenia/genética , Adulto , Análise de Variância , Córtex Cerebral/irrigação sanguínea , Distribuição de Qui-Quadrado , Feminino , Humanos , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Oxigênio , Escalas de Graduação Psiquiátrica , Tempo de Reação/fisiologia , Irmãos , Adulto Jovem
4.
Eur J Neurosci ; 36(11): 3559-67, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22909094

RESUMO

A functional decline of brain regions underlying memory processing represents a hallmark of cognitive aging. Although a rich literature documents age-related differences in several memory domains, the effect of aging on networks that underlie multiple memory processes has been relatively unexplored. Here we used functional magnetic resonance imaging during working memory and incidental episodic encoding memory to investigate patterns of age-related differences in activity and functional covariance patterns common across multiple memory domains. Relative to younger subjects, older subjects showed increased activation in left dorso-lateral prefrontal cortex along with decreased deactivation in the posterior cingulate. Older subjects showed greater functional covariance during both memory tasks in a set of regions that included a positive prefronto-parietal-occipital network as well as a negative network that spanned the default mode regions. These findings suggest that the memory process-invariant recruitment of brain regions within prefronto-parietal-occipital network increases with aging. Our results are in line with the dedifferentiation hypothesis of neurocognitive aging, thereby suggesting a decreased specialization of the brain networks supporting different memory networks.


Assuntos
Envelhecimento/fisiologia , Lobo Frontal/fisiologia , Memória Episódica , Memória de Curto Prazo/fisiologia , Rede Nervosa/fisiologia , Lobo Parietal/fisiologia , Adulto , Idoso , Envelhecimento/psicologia , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Occipital/fisiologia
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