Activity-dependent modification of electrical synapse strength

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DESCRIPTION (provided by applicant): The human process of attention is vital to basic survival and higher learning, yet its basic neurological mechanisms remain poorly understood. During certain stages of sleep and types of epilepsy, the brain is unresponsive to sensory input. The brain center responsible for focusing the neural "searchlight" of attention and for generation spindles during sleep is the thalamic reticular nucleus (TRN), where electrical synapses are a major source of connectivity between neurons in the nucleus. Neurons in the TRN spike in two behaviorally distinct modes - burst and tonic firing - and are densely connected by electrical synapses formed by gap junctions. Gap junctions are a unique type of inter-neuronal connection that physically link membranes of neighboring neurons with small pores, allowing charged ions and small molecules to pass between neurons. These synapses are expressed widely throughout the mammalian brain and are thought to synchronize neuronal activity among coupled neighboring neurons. The strength of electrical synapses, in general, directly affects the synchrony or coherence of connected neurons, and in particular, it modulates the afferent output of the TRN. However, the effect of neuronal activity on electrical synaptic strength has been largely unexplored. We propose two aims that address the fundamental question of how the TRN gates attention by evaluating the role of specific neuronal activity patterns in modifying the strength of electrical synapses in the TRN. In Aim 1, we will record and induce pairings of naturalistic TRN activity patterns - burst and tonic firing - in coupled neurons to determine whether coordinated spiking activity induces changes in electrical synapses. In Aim 2, we will begin to dissect the mechanisms underlying electrical synaptic plasticity by testing whether sodium-based spiking is necessary to induce electrical synaptic modification and by examining the contributions from the prominent low-threshold calcium current in these neurons. Because electrical synapses are widespread throughout the brain, the results of this research will open a promising new field of study and a new perspective on the dynamics of networks that include electrical synapses.