Neurons of the velocity storage neural integrator store a 'short-term memory' of head velocity that provides a central representation of head and body orientation in space, allowing animals to navigate with respect to an inertial reference frame. Much effort has been focused on modeling vestibular integrators at the systems level and by recurrent feedback networks, however the biophysical mechanisms that subserve neural integration remain unknown. Individual integrator neurons exhibit a corresponding variability in integrator storage capacity and dendritic branching structure, but to date no studies have attempted to relate these. This is primarily due to technical difficulties in obtaining the requisite structure/function to begin biophysical modeling in mammals, and lack of computational and analytic techniques to perform precise geometric modeling. A multidisciplinary approach combining mathematical, experimental and imaging expertise will address these inadequacies in the well-developed goldfish model, in which integrator neurons are easily identified, and finite in number for realistic modeling and structure-function experiments. Our central hypothesis, that spatially-extended single cell properties including dendritic topology and its interaction with active membrane and synaptic properties are essential elements of neural integration, will be tested by (1) characterizing the diversity in integrator neurons and its role in oculomotor behavior and plasticity; (2) parametrising 3-D dendritic branching structure with novel imaging, image analysis and geometric techniques; (3) verifying the relationships determined between function in Aim 1 and morphology in Aim 2 by compartment modeling of high-resolution morphologic data, and evaluation of circuit models containing reduced versions of biophysically realistic neuron models. Development of new mathematical techniques for relating neural dynamics to local and global properties of dendritic structures is a unique feature of this project. In the long term, we want to understand the contributions of cellular properties and interactions between realistic neurons to the persistent neural activity that underlies vestibular neural integrators specifically, and fundamental mechanisms of short-term or working memory in multiple areas of neuroscience. A mechanistic understanding of neural integration will yield basic information leading to rational strategies for prevention, treatment and reversal of balance and equilibrium dysfunction, and for understanding the structural determinants of disorders and loss of short-term memory. ? ?
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