Studies on synaptic plasticity underlying learning and memory have mainly focused on neuronal elements. However, astrocytes, classically considered as merely supportive cells, are emerging as key regulatory elements potentially involved in learning, memory, and neural information processing because they respond to neurotransmitters and modulate neuronal activity and synaptic function through the release of gliotransmitters. While important progress has been made to define the cellular mechanisms underlying astrocyte modulation of synaptic function in certain brain areas, such as hippocampus, retina and cortex, exactly what specific roles astrocytes play in the neural information processing system remains largely unknown. We have recently found that neuronal activity in the dorsal striatum elevates astrocyte Ca2+ levels, which, in turn, impact striatal neuronal activity and synaptic transmission. Yet, fundamental questions remain unknown, such as the astrocyte contribution to synaptic plasticity, to neural network information processing, and to the consequences on animal behavior. The present proposal aims to define the impact of striatal astrocyte activity on corticostriatal synaptic transmission and plasticity, striatal neural network activity and striatum-related behavioral task performance. We hypothesize that astrocyte activity controls synaptic function and plasticity, and influences neural network operation and animal behavior. To test this hypothesis we will combine in situ and in vivo approaches and state-of-the-art techniques, including optogenetics, pharmacogentics (?designer receptors exclusively activated by designer drugs?, DREADD), simultaneous two-photon microscopy Ca2+ imaging and multiple electrophysiological recordings, novel transgenic mice, in vivo electrophysiological recordings, and specific behavior studies. For this purpose, the proposal brings together two laboratories with complimentary expertise ? the Araque lab with expertise in astrocyte-neuron interactions in in vitro slices at cellular level and the Redish lab with expertise in striatal neuronal information processing and behavior at circuit and organism levels, that are already collaborating successfully, including co-advising a graduate student funded by a F30 NIH grant. The expected results will define the role of astrocytes in the striatal function and the consequent animal behavior, which will help to identify novel cellular mechanisms underlying brain function. Defining these roles of astrocytes on synaptic plasticity, network operation and animal behavior will reveal novel mechanisms involved in brain disorders occurring in certain brain diseases, such Parkinsons and Huntington`s diseases, Obsessive Compulsive Disorder, Tourette's syndrome, and addiction, which may serve to identify novel cellular targets to develop future therapeutic strategies.
Accumulating evidence indicates that astrocytes, classically considered to serve passive structural and support roles, may play important functions in learning, memory, and neural information processing by actively modulating neuronal activity and synaptic function. The present proposal aims to the define properties of the bidirectional communication between astrocytes and neurons, the involvement in long-term synaptic plasticity, and the effects on neural network information processing and striatal-related behavioral tasks. Defining the impact of astrocyte-neuron signaling on striatal function may reveal novel mechanisms involved in brain disorders, such as Parkinsons disease or Obsessive Compulsive Disorder.
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