RESUMEN
Lysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.
Asunto(s)
Trastorno del Espectro Autista/metabolismo , Dopamina/metabolismo , Heparitina Sulfato/metabolismo , Enfermedades por Almacenamiento Lisosomal/metabolismo , Animales , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/patología , Benzazepinas/uso terapéutico , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Antagonistas de Dopamina/uso terapéutico , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Heparitina Sulfato/farmacología , Enfermedades por Almacenamiento Lisosomal/tratamiento farmacológico , Enfermedades por Almacenamiento Lisosomal/patología , Mesencéfalo/efectos de los fármacos , Mesencéfalo/embriología , Mesencéfalo/patología , Ratones , Mucopolisacaridosis III/tratamiento farmacológico , Mucopolisacaridosis III/metabolismo , Mucopolisacaridosis III/patología , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/metabolismoRESUMEN
Brain-inspired computing paradigms have led to substantial advances in the automation of visual and linguistic tasks by emulating the distributed information processing of biological systems1. The similarity between artificial neural networks (ANNs) and biological systems has inspired ANN implementation in biomedical interfaces including prosthetics2 and brain-machine interfaces3. While promising, these implementations rely on software to run ANN algorithms. Ultimately, it is desirable to build hardware ANNs4,5 that can both directly interface with living tissue and adapt based on biofeedback6,7. The first essential step towards biologically integrated neuromorphic systems is to achieve synaptic conditioning based on biochemical signalling activity. Here, we directly couple an organic neuromorphic device with dopaminergic cells to constitute a biohybrid synapse with neurotransmitter-mediated synaptic plasticity. By mimicking the dopamine recycling machinery of the synaptic cleft, we demonstrate both long-term conditioning and recovery of the synaptic weight, paving the way towards combining artificial neuromorphic systems with biological neural networks.
Asunto(s)
Plasticidad Neuronal , Neurotransmisores/fisiología , Algoritmos , Animales , Redes Neurales de la Computación , Células PC12 , RatasRESUMEN
Neuromorphic computers could overcome efficiency bottlenecks inherent to conventional computing through parallel programming and readout of artificial neural network weights in a crossbar memory array. However, selective and linear weight updates and <10-nanoampere read currents are required for learning that surpasses conventional computing efficiency. We introduce an ionic floating-gate memory array based on a polymer redox transistor connected to a conductive-bridge memory (CBM). Selective and linear programming of a redox transistor array is executed in parallel by overcoming the bridging threshold voltage of the CBMs. Synaptic weight readout with currents <10 nanoamperes is achieved by diluting the conductive polymer with an insulator to decrease the conductance. The redox transistors endure >1 billion write-read operations and support >1-megahertz write-read frequencies.
RESUMEN
We study the cascading failure of networks due to overload, using the betweenness centrality of a node as the measure of its load following the Motter and Lai model. We study the fraction of survived nodes at the end of the cascade p_{f} as a function of the strength of the initial attack, measured by the fraction of nodes p that survive the initial attack for different values of tolerance α in random regular and Erdös-Renyi graphs. We find the existence of a first-order phase-transition line p_{t}(α) on a p-α plane, such that if p