Gidon Felsen - US grants

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to understand the neural mechanisms underlying the control of motor output under normal and pathological conditions. The central hypothesis is that brainstem cholinergic systems contribute to motor preparation in much the same way that they are thought to contribute to sensory attention: by modulating activity in motor structures such that the movements most in line with behavioral goals are more likely to be executed. We examine this hypothesis in a robust anatomical projection of an advantageous animal model system: The cholinergic input from the brainstem pedunculopontine tegmental nucleus (PPT) to the intermediate gray layer of the superior colliculus (SC) in the mouse. The project goals will be achieved by recording and manipulating (using pharmacology and optogenetics) neural activity in freely-moving wild-type and transgenic mice performing behavioral tasks that require preparing and generating orienting movements. Aim 1 will examine how cholinergic input modulates SC activity and SC-dependent behavioral output. Aim 2 will focus directly on the activity of cholinergic PPT neurons during behavior. If successful, our proposal will elucidate, in a genetically accessible mouse model, key neural substrates underlying motor control. In addition to testing the specific hypotheses proposed here, the model we develop will make possible future research into how other genetically-defined networks of neurons contribute to motor output. Ultimately, understanding normal motor output can contribute to improving therapies for movement disorders, such as Parkinson's disease. PUBLIC HEALTH RELEVANCE: This proposal will examine how activity in specific brain regions controls movements. Understanding this activity under normal conditions, and how it is altered under pathological conditions, can contribute to improving treatments for movement disorders such as Parkinson's disease.

Core A ? Optogenetics and Neural Engineering: Project Summary (Abstract) The overall goal of the Optogenetics and Neural Engineering (ONE) Core is to enhance existing neuroscience research programs on the University of Colorado Anschutz Medical Campus (UC-AMC) by providing support for experiments and quantitative analysis. Specifically, the ONE Core will facilitate the adoption and optimization of optogenetic techniques in users' research by providing optical equipment and technical expertise (Aim 1), reducing the significant upfront costs required to leverage the advantages of optogenetics. Proof-of-principle for executing this Aim of the ONE Core is provided by the UC School of Medicine-supported Optogenetics Pilot Program, which has confirmed both the need for, and impact of, supporting optogenetic approaches at UC-AMC. In addition, the ONE Core will provide support for quantitative analysis and the development of experimental equipment (Aim 2). By achieving these Aims, the ONE Core will enhance a broad range of strong neuroscience research at UC-AMC consistent with the mission of the NINDS to obtain basic information about nervous system function and ultimately decrease the burden of neurological disease.

PROJECT SUMMARY (ABSTRACT) The long-term goal of the proposed research is to understand the neural mechanisms underlying the control of motor output under normal and pathological conditions. We examine here how functional circuitry in the superior colliculus (SC), a bilateral midbrain structure known to be important for orienting behaviors, contributes to decisions about movements. The central hypothesis is that competition between spatial targets represented in the two SCs is mediated by commissural SC neurons that engage local inhibition. We test this hypothesis by recording and manipulating the activity of specific classes of neurons in freely-moving transgenic mice performing olfactory-cued spatial choice tasks. Aim 1 will examine how the activity within one SC of excitatory and inhibitory SC neurons, examined in separate sets of mice, underlies spatial choice. Aim 2 will examine how this activity, and the influence of inhibition on excitatory SC activity within the same SC, is modulated by competition between spatial targets represented by the two SCs. Aim 3 will examine the role of commissural SC neurons in mediating this competition between spatial targets. If successful, the overall impact of our proposal will be the elucidation of how excitatory and inhibitory SC neurons interact ? within one SC and between the two SCs ? to mediate spatial choice, an important form of decision making. In addition to testing the specific hypotheses proposed here, the model we develop will make possible future research into how other genetically-defined networks of neurons contribute to decisions about movements. Ultimately, understanding normal motor control can contribute to improving therapies for movement disorders, such as Parkinson's disease.