Regulation of Dendritic Compartmentalization Features

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The brain is made of billions of microscopic cells called neurons, which are interconnected in dense, complex networks. Neurons have large branches called dendrites that resemble the branches on a tree, which are studded with specialized connections called synapses, where neurons communicate with one another. Neurons sum-up synaptic inputs in real-time and, when enough synapses are activated, fire `spikes' to transmit signals to their partners downstream. Since every single neuron may carry more than ten thousand synapses, the number of computations that a neuron potentially performs is staggering. Remarkable insights into these operations have been made in recent decades, together outlining fundamental mechanisms for information processing at single neurons. One key finding is that individual branches of a neuron's dendritic tree can powerfully boost synaptic inputs and drive neuronal spiking, which enable neurons to be more efficient at information processing. In this way, neurons are thought to be divided into multiple functional `subunits' or `compartments', represented by individual branches of the dendritic tree. In recent years, our laboratory has applied cutting-edge laser scanning microscopy and electrophysiology to study in live neurons the maturation of synapses along these dendritic subunits during brain development. We have discovered a novel mode of calcium signaling that takes place at developing dendritic compartments, shedding light on how neural circuits are formed. In this research proposal, we aim to extend these findings to better understand how information processing is controlled at individual dendritic compartments. In our first Objective, we will characterize how developing dendrites respond to different patterns of synaptic input. These experiments are a natural extension of the work we have accomplished to date, and will provide a firm foundation for understanding how synaptic activity is processed during neural circuit formation. In the second and third Objectives, we will directly investigate how specific neuromodulators in the brain, specifically endocannabinoids and serotonin, affect the function of individual dendrites. Endocannabinoids are natural chemicals in the body that resemble the active drug in cannabis, and serotonin is classically involved in the regulation of mood, appetite and sexual behavior. Although these neurochemicals are well-known to alter neuron function, current understanding of these processes is rudimentary, and significantly lags behind modern models of neural computation. The experiments we propose will expand on recent discoveries about dendritic subunit function, and are therefore suited to push forward our understanding of neuromodulation in the brain. This research program will make use of sophisticated technologies and analyses to uncover the complex cellular mechanisms that underlie brain function.