Identifying Electrically Coupled Networks in vitro

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Summary We plan to explore the functional topography of electrical synapses in the thalamic reticular nucleus (TRN), a central brain region that controls cortical attention to the sensory surround by gating thalamocortical interactions. During slow-wave of sleep and absence epilepsy, the brain is unresponsive to sensory input; the TRN is thought to focus this neural “searchlight” of attention, and to generate the rhythms that appear as spindles during sleep and sharp-wave discharges in epilepsy. Neuronal communication in the TRN is dominated by the electrical synapses that are formed by connexin36 gap junctions amongst its GABAergic neurons. Our best understanding of electrical synapses is limited by current techniques to pairs of neurons and a single electrical synapse. Here, we will leverage modern optogenetic and focal photostimulation techniques to map electrically coupled networks in molecularly defined populations of GABAergic neurons of the live TRN. Our central hypothesis is that the electrically coupled networks within the TRN link neurons across molecular identity, sensory modality and higher-order and primary relay channels, and thereby regulate thalamocortical transmission. We will test the hypothesis that activity-dependent electrical synaptic depression, which is induced by bursting patterns that are prominent during slow-wave sleep, is global for all synaptic coupling to a strongly bursting neuron, due to its dependence on pan-neuronal T currents. Finally, we will model and experimentally validate how plastic electrically coupled networks finely control the inhibition that TRN neurons deliver to thalamocortical relay cells, and thereby gate thalamocortical communication. Because these synapses are both widespread and underappreciated for their power throughout the mammalian brain, it is crucial to understand the molecular and functional topography and the dynamics of their networks. The significance of this proposal lies in its potential to, for the first time, identify and characterize electrically coupled networks in vitro, both in the TRN and eventually, throughout the brain. This research will make great strides in our understanding of the physiological function and plasticity of electrical synapses, and provide insight into how the TRN controls thalamocortical information processing.