New Project for 2008:

Interdisciplinary experimental and modeling research project in computational neuroscience for Michigan-SUBMERGE

Mentors: Victoria Booth (Depts of Mathematics and Anesthesiology) and Gina Poe (Depts of Anesthesiology and Molecular & Integrative Physiology)

The broad theme for the project pairs the primary interests of the Poe Lab, namely the investigation of the role of sleep, particularly rapid-eye movement (REM) sleep, in learning with biomathematical modeling in neuroscience. The project will focus on investigating changes in neuronal firing patterns in the rat hippocampus during waking and REM sleep that occur over several days as the animal learns a spatial environment. The modeling component will focus on developing biophysical models of hippocampal neurons to investigate the neuronal mechanisms responsible for generating the observed firing changes. Poes and Booths NIH-funded collaborative work has successfully partnered extracellular recordings of hippocampal activity with biophysical single cell neuronal modeling to understand how the hippocampal theta rhythm and the distinct synaptic inputs to CA1 pyramidal neurons interact to generate observed changes in spike timing during REM sleep (Booth and Poe, 2006). The student team will contribute to our on-going investigations on the role of the sleep-related neurotransmitters, such as serotonin and norepinephrine, in neuronal activity during REM sleep and their effect on learning. As the project involves the current working hypotheses of the lab and represents cutting-edge research into the function of sleep, we expect an outcome of the student project to be presentation of their results at national mathematical and sleep research meetings and the preparation of a manuscript for journal publication.

Experimental Component: The experiments in the Poe Lab involve recordings of multiple, single neuron activity through chronically implanted tetrodes in the hippocampal region CA1. Neuronal activity is recorded while the animal explores a rectangular maze and learns the location of food rewards. Hippocampal neurons, called place cells, display place specific firing patterns that are thought to encode the animals location and relevant contextual cues. Recording is continued for 4 hours after maze exploration to capture the replay firing of hippocampal place cells that occurs during REM sleep. The effects of the sleep-related neurotransmitters will be investigated by altering their levels in the hippocampus, through hippocampal injection of appropriate agonists and antagonists, from the naturally occurring cyclic-variation over waking and REM sleep. These experiments are sufficiently complicated and technical that the undergraduate team will not be able to perform and conduct an entire experiment single-handedly. In fact, in the lab it takes a team of technicians, graduate students and undergraduates to obtain these neural recordings. However, there are many aspects of the experiment where undergraduate research assistants routinely contribute. These aspects include: pre- and post-surgical training of the animal to habituate it to the learning task, fabrication of the recording tetrodes, and assistance in collecting data during the maze running and sleep portions of the experiment. In addition, once the data is collected the undergraduate team will be responsible for all aspects of data analysis, including discrimination of single neuron activity from the extracelluar recordings, identification of cells with place-specific firing patterns, analysis of firing patterns with respect to the hippocampal theta rhythm and statistical analyses of results.

Modeling Component: The students will develop biophysical models of CA1 pyramidal neurons with accurate dendritic morphology and the full complement of identified active ionic currents present in these cells. As a starting point, previously developed neural models that are publicly available on the ModelDB database and implemented in the software package NEURON can be used. The students will modify these models to incorporate other influences on the cell that are present in the intact animal during the different behavioral states of waking and sleep. In addition, effects on cell properties of the sleep-related neurotransmitters will be simulated by modification of appropriate model parameters. In order to allow mathematical analysis of model results, reduced models will be developed that would involve reductions in dendritic structure or reductions in active currents included. Using these reduced models, mathematical techniques of dimensional reduction, geometric singular perturbation theory and dynamical systems can be applied to analyze the key features of the model responsible for the experimentally observed behavior.

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