Daniel J. Denman, Ph.D. - US grants

Project Summary/Abstract The mammalian brain builds and transforms representations of the outside world through the concerted activity of populations of neurons, but the extent to which spike times or spike counts are coordinated within these ensembles beyond pairs is not clear. Models of neural encoding predict variable frequencies of spike pattern occurrence, and models of decoding delineate requirements for spike time precision within the population response. While considerable effort has been made toward the development and refinement of the theoretical basis of such neural coding schemes, and predictions have been tested against single cell and pairwise data, there has been relatively little experimental data beyond pairs able to differentiate between competing hypotheses of population coding. The proposed career development plan aims to marry large-scale electrophysiology in primary visual cortex with analysis of specific predictions derived from computational and theoretical neuroscience work for spike time coordination beyond pairwise interactions. The candidate has a deep background in in vivo experimental techniques and proposes to receive training in the high-dimensional computational techniques and to use experimental data collected to validate specific theoretical predictions. This training will establish the skills necessary for a successful independent research career studying the mechanisms of information representation and transfer in visual cortex, bridging the gap between experimental and computational neuroscience. The candidate will carry out the mentored phase under the guidance of Dr. Clay Reid, a world expert in multiple aspects of mammalian central visual processing including anatomy, physiology, and computation. Additional advising from Dr. Eric Shea- Brown and Dr. Christof Koch will provide guidance in the theoretical and applied mathematical approaches required to implement and assess advanced models of neural encoding and decoding. The training will utilize the strengths of the Allen Institute for Brain Science in collecting large-scale data and the didactic opportunities at the University of Washington. In the independent phase the candidate will use the newly acquired analytical and modeling skills in combination with his previous training in optogenetic techniques to better constrain population measurements. This work will help establish a unique independent research program to elucidate the mechanisms underlying cortical representation.

Project Summary Intracranial electrical brain stimulation (EBS) remains a central method in the clinic as well as for research in several animal model systems. However, little is actually known about the ensembles of neurons activated by typical and clinical intracranial EBS protocols. These stimulation protocols often require a trial-and-error learning period (during and after invasive neurosurgery) to determine what stimulation parameters are effective, if any at all are effective. It remains mysterious why some stimulation patterns work in the clinic while others do not, and what underlying ensembles are activated by various stimulation patterns. It is known that focal electrical microstimulation activates nearby excitable membranes, including neural somas, dendrites, and axons. It is also known that the recruited ensemble of neurons may be locally non- homogenous and that clinical effects may rely more on axons of passage than somatic stimulation. Efforts to model EBS cannot overcome our current gaps in knowledge about the homogeneity of local propagation and brain-wide extent of activation. This ambiguity demands a more detailed understanding of local electric field propagation, particularly in the in vivo mammalian brain. Utilizing recent technological advances, we propose to fill these gaps empirically with high density electrophysiological monitoring and temporally precise fluorescent labeling methods, to quantify clinically relevant activation patterns with high spatial resolution and cell-type specificity. Here we propose an experimental study in mice, based on a biophysically realistic model of mouse cerebral cortex, of the spatial and temporal propagation of activation via focal EBS. The study will test the hypothesis that local electrical stimulation is non-isotropic and cell-type specific. We propose to measure EBS stimulation with more than 1000 electrodes arranges in three dimensions around a site of stimulation, in combination with genetic cell type identity through optotagging (Aim 1). To agnostically isolate brain-wide ensembled activated by EBS, we couple a fluorescent reporter to electrical stimulation for ex vivo whole-brain tissue clearing and light sheet imaging (Aim 2).