Complex biological systems are composed of diverse units, a feature which is exemplified throughout the brain. This diversity is evident at each scale from animal behavior, to distinct brain regions, to local circuit responses, to distinct cell types and their unique morphologies, to the diverse protein expression patterns and subcellular localization of those proteins. Reductionist theory suggests that understanding the diversity of the most basic building blocks will ultimately inform our understanding of differences in animal behavior. However, linking knowledge of diversity in protein expression to diverse behavior is challenging. Here we propose an experimental and computational approach to linking mechanisms of diversity between cells to how a given cell performs a computation - particularly to how that cell encodes specific features of a stimulus. We will use the mammalian olfactory bulb as a model system to probe how sensory information is encoded by its two main projection neuron types, mitral cells (MCs) and tufted cells (TCs). Our lab has previously demonstrated that cell-to-cell diversity of physiological properties within MCs increases the information transferred by a population of MCs, enhances its range of stimulus encoding, and limits its neural synchronization. However, the mechanisms that underlie the diversity within MCs are poorly understood. Whereas our lab and others have demonstrated diverse ion channel expression within MCs, the relationship between diverse ion channel expression and differential sensitivity to specific stimulus features has not been established. Importantly, understanding of this link is not established in any cell type across the brain. Yet, this link is essential to comprehend how the collection of ion channels in a cell create the emergent property of single neuron computation. Here we propose to test our central hypothesis that differences in functional ion channel expression within and between MCs and TCs govern the differential sensitivity to specific stimulus features across these cells.
In Aim 1, we will determine the mechanisms of diversity within and between MCs and TCs. We will measure diversity across cells using a recently developed experimental and computational approach to creating biophysical models. We predict that levels of functional ion channel expression will covary across cells.
In Aim 2, we will determine the role of the diversity of ion channel expression in stimulus encoding. We will use statistical approaches to determine how diverse functional ion channel expression relates to encoding of specific stimulus features and test novel hypotheses with recordings from MCs and TCs.
The goal of this proposal is to identify the specific mechanisms that cause neurons of the same type to respond differently to the same sensory input. We propose to develop a novel combination of experimental and computational techniques that will be applicable to answering similar questions across the brain. Our approach can serve as a basis to translate knowledge about the proteins such as ion channels and signaling molecules into information about their role in behavior of single cells, of populations of cells, and of whole animals under normal conditions and in disease states.
| Glasgow, Nathan G; Wilcox, Madeleine R; Johnson, Jon W (2018) Effects of Mg2+ on recovery of NMDA receptors from inhibition by memantine and ketamine reveal properties of a second site. Neuropharmacology 137:344-358 |
