BRAIN EAGER: Tuning the Intrinsic Computational Properties of Neurons to Changing Circuit Outputs during Early Brain Development

University Of Washington, Seattle WA

Investigators

Abstract

Neurons that are being formed in the brain of a developing animal send out electrical signals that spread like waves over large parts of the brain. The waves are essential for normal brain development. The goal of this project is to find out how this spontaneous electrical activity controls brain development. Recently, a specific type of neuron has been identified as being the pacemaker, or trigger, for these waves. This project will study how these neurons trigger the spontaneous waves. The project will take advantage of a mouse that allows these neurons to be stimulated using light. The responses of the neurons to these stimuli will be monitored, and the results will be used to make computer models of the neurons. These models will reveal the properties of these neurons that allow them to produce the waves. The project will offer opportunities for undergraduate and graduate students to be trained in interdisciplinary research that involves both theoretical and experimental biology, under the guidance of two collaborating principal investigators with unique expertise in these areas. Emphasis will be placed on actively recruiting women into full participation in the computational aspects of the project. This project investigates how the intrinsic electrical properties of developing GABAergic interneurons in the cerebral cortex allow them to initiate spontaneous waves of electrical activity during early development. Previous genetic and pharmacological data indicate that these neurons, which are excitatory during early development, are the primary pacemakers for waves of spontaneous activity in the mouse cortex between embryonic day 18 and and postnatal day 3. The detailed input:output relations of GABAergic neurons will be determined by using calibrated optical stimulation in a dlx5/6 channel-rhodopsin mouse and by recording the outputs of the neurons with extracellular electrode arrays. Conductance-based models of the neurons will be constructed that reflect the diversity of intrinsic properties that are encountered in the population. The model neurons will be connected into synaptic circuits to determine whether the measured properties lead to pacemaking activity in the circuit. By systematically varying the intrinsic properties in the model, aspects of the intrinsic properties that are critical for pacemaking function will be determined. If successful, this project will provide a new high-throughput method for determining how the intrinsic properties of neurons determine circuit output in the brain.