RESUMO
The grey matter is a central target of pathological processes in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The grey matter is often also affected in multiple sclerosis, an autoimmune disease of the central nervous system. The mechanisms that underlie grey matter inflammation and degeneration in multiple sclerosis are not well understood. Here we show that, in Lewis rats, T cells directed against the neuronal protein ß-synuclein specifically invade the grey matter and that this is accompanied by the presentation of multifaceted clinical disease. The expression pattern of ß-synuclein induces the local activation of these T cells and, therefore, determined inflammatory priming of the tissue and targeted recruitment of immune cells. The resulting inflammation led to significant changes in the grey matter, which ranged from gliosis and neuronal destruction to brain atrophy. In humans, ß-synuclein-specific T cells were enriched in patients with chronic-progressive multiple sclerosis. These findings reveal a previously unrecognized role of ß-synuclein in provoking T-cell-mediated pathology of the central nervous system.
Assuntos
Substância Cinzenta/imunologia , Substância Cinzenta/patologia , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Crônica Progressiva/patologia , Linfócitos T/imunologia , beta-Sinucleína/imunologia , Animais , Encéfalo/patologia , Movimento Celular/imunologia , Feminino , Regulação da Expressão Gênica , Gliose/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Esclerose Múltipla Crônica Progressiva/sangue , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Ratos , Ratos Endogâmicos Lew , Linfócitos T/metabolismo , Linfócitos T/patologia , beta-Sinucleína/análise , beta-Sinucleína/genética , beta-Sinucleína/metabolismoRESUMO
In this Article, owing to an error during the production process, the y-axis label of Fig. 2c should read "Number of Tß-syn cells" rather than "Number of T1ß-syn cells" and the left and right panels of Fig. 4 should be labelled 'a' and 'b', respectively. These errors have been corrected online.
RESUMO
Channelrhodopsin-2 (ChR2) has provided a breakthrough for the optogenetic control of neuronal activity. In adult Drosophila melanogaster, however, its applications are severely constrained. This limitation in a powerful model system has curtailed unfolding the full potential of ChR2 for behavioral neuroscience. Here, we describe the D156C mutant, termed ChR2-XXL (extra high expression and long open state), which displays increased expression, improved subcellular localization, elevated retinal affinity, an extended open-state lifetime, and photocurrent amplitudes greatly exceeding those of all heretofore published ChR variants. As a result, neuronal activity could be efficiently evoked with ambient light and even without retinal supplementation. We validated the benefits of the variant in intact flies by eliciting simple and complex behaviors. We demonstrate efficient and prolonged photostimulation of monosynaptic transmission at the neuromuscular junction and reliable activation of a gustatory reflex pathway. Innate male courtship was triggered in male and female flies, and olfactory memories were written through light-induced associative training.
Assuntos
Potenciais Evocados Visuais , Mutação de Sentido Incorreto , Neurônios/metabolismo , Rodopsina/metabolismo , Transmissão Sináptica , Substituição de Aminoácidos , Animais , Feminino , Masculino , Rodopsina/genéticaRESUMO
Training can improve the ability to discriminate between similar, confusable stimuli, including odors. One possibility of enhancing behaviorally expressed discrimination (i.e., sensory acuity) relies on differential associative learning, during which animals are forced to detect the differences between similar stimuli. Drosophila represents a key model organism for analyzing neuronal mechanisms underlying both odor processing and olfactory learning. However, the ability of flies to enhance fine discrimination between similar odors through differential associative learning has not been analyzed in detail. We performed associative conditioning experiments using chemically similar odorants that we show to evoke overlapping neuronal activity in the fly's antennal lobes and highly correlated activity in mushroom body lobes. We compared the animals' performance in discriminating between these odors after subjecting them to one of two types of training: either absolute conditioning, in which only one odor is reinforced, or differential conditioning, in which one odor is reinforced and a second odor is explicitly not reinforced. First, we show that differential conditioning decreases behavioral generalization of similar odorants in a choice situation. Second, we demonstrate that this learned enhancement in olfactory acuity relies on both conditioned excitation and conditioned inhibition. Third, inhibitory local interneurons in the antennal lobes are shown to be required for behavioral fine discrimination between the two similar odors. Fourth, differential, but not absolute, training causes decorrelation of odor representations in the mushroom body. In conclusion, differential training with similar odors ultimately induces a behaviorally expressed contrast enhancement between the two similar stimuli that facilitates fine discrimination.