Marc D. Binder - US grants

neuromuscular function; motor neurons; stretch receptors; stretch reflex; neural recruitment; neural information processing; evoked potentials; synapses; afferent nerve; gastrocnemius muscle; electromyography;

motor neurons; spinal nerves; neural information processing; synapses; interneurons; innervation; afferent nerve; gastrocnemius muscle; cats;

DESCRIPTION (provided by applicant): The program described in this training grant renewal application provides support for predoctoral (Ph.D.) students in neurobiology at the University of Washington. Seventy-two University of Washington faculty members from the Graduate Program in Neurobiology and Behavior serve as training grant faculty. All of the training faculty direct active, externally-funded research programs and are committed to training graduate students, postdoctoral fellows and visiting scientists. The extensive publication records of the training grant faculty are detailed in their biographical sketches. The training grant faculty provide a breadth of neuroscience research areas extending from molecular biology to behavioral neurobiology. Further, this is a highly collaborative faculty. The large number of training grant faculty provides the opportunity for trainees to learn many different techniques and approaches to research through their lab rotations, journal clubs, seminar series and course work. All trainees are required to complete a course in the neurobiology of disease. Trainees also receive training in the responsible conduct of research, proper treatment of laboratory animals, and lab safety. Trainees receive extensive career guidance and are encouraged to participate in the student outreach program. Four trainees are selected each year from the large pool of graduate students (n=100-125) at the University of Washington pursuing doctoral research in neurobiology. Appointment to the training grant is based on a formal application to the Training Grant Steering Committee following the successful completion of at least one year of graduate studies and the selection of a dissertation advisor. Appointments to the training grant are made on an annual basis and can be renewed for two additional years based on an annual progress report. PUBLIC HEALTH RELEVANCE: This institutional training grant provides support for predoctoral students in neurobiology at the University of Washington. The training program exposes the students to a wide range of neuroscience research areas extending from molecular biology and genetics to behavioral neurobiology. Trainees also receive instruction in the neurobiology of human disease and emerge from the program prepared to conduct independent research.

"Nonlinear Systems Analysis of Spike Encoding in Montoneurons"

Individual nerve cells (neurons) transform the chemical and electrical signals they receive from other neurons into a series of electrical impulses or spikes. The frequency and pattern of these spikes forms the "neural code" by which information is transmitted throughout a network or system of neurons. Thus far, descriptions of the basic input-output transform of neurons, called spike encoding, have been largely limited to steady-state conditions in which the input signals that the cell receives are held constant. The objective of this proposed research program is to derive a general, quantitative description of spike encoding that will apply to both steady-state and dynamic conditions in which the input signals vary as they do under normal physiological conditions.

In the proposed experiments, the responses of mammalian neurons to brief injected current transients will be measured. The injected current transients are constructed to mimic real inputs as they appear in the cell body of a neuron. Non-linear systems identification procedures originally developed for electrical engineering applications will be used to characterize how these input signals affect the generation of spikes by the neuron. The advantage of this approach is that it yields a basic input-output function that is not as computationally complex as those derived from more detailed neuron models, but still accurately reproduces a wide range of neural behaviors. This compact input-output function can be then incorporated into the neural elements used in models operating at the network and systems levels, increasing the degree to which such models can accurately represent their biological counterparts.

[unreadable] DESCRIPTION (provided by applicant): This application seeks financial support for developing a course in the neurobiology of disease for graduate students receiving basic neuroscience training at the University of Washington under the auspices of the Institutional Grant for Neurobiology (T32 GM007108-31). The course will introduce basic science graduate students to the principles and practices of pathophysiology, translational research and clinical research in neurological disease. The course will also serve clinical fellows in neurology. The course will be designed, and the course materials developed, by a faculty group at the University of Washington from multiple clinical and basic science departments. Included in the course development plan is a web-based video archive of patient interviews and examinations to illustrate the spectrum of nervous system diseases to be discussed in the course. A web-based syllabus of educational materials related to this course will also be produced. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Each motoneuron drives the muscle fibers it innervates in a one-to-one fashion, thus forming a motor unit. Because muscle fiber action potentials are relatively easy to measure, motoneurons are the only CNS cells whose firing patterns can be readily quantified in human subjects. Thus, the motoneuron potentially provides a unique window on CNS function in both normal and disease states. The cellular mechanisms that drive motoneuron firing patterns, however, can only be measured via intracellular studies in animal preparations. Thus, the design of our meeting is inherently cross-disciplinary: to bring together specialists investigating motor unit firing patterns in human subjects with specialists focusing on cellular mechanisms underlying motoneuron electrical behavior. To facilitate interactions between labs, each session consists of an introduction for non-specialists, short presentations, and extended time for discussion. Each session will have at least one presentation by a post-doctoral fellow or a graduate student. The meeting will begin with cellular presentations and proceed to human data, with the transition focusing on recent developments in high speed, biologically realistic computer simulations that potentially provide a platform for quantitatively relating these two types of data. The issue at the heart of the meeting is, to what degree the present state-of-the- art results and simulations allow identification of the cellular mechanisms of plastic changes that take place in motor unit firing patterns both in normal function (fatigue, exercise) and in disease states (spinal injury, hemiparetic stroke, and ALS). The meeting will end with an entire session devoted to discussion of this fundamental question. The abstracts submitted by each invited speaker will be posted on a publicized website. We anticipate that this meeting will generate new ideas and approaches for investigation of plasticity in the motor system as well as creation of new therapeutic strategies for spasticity in spinal injury and stroke and motoneuron degeneration in ALS. PUBLIC HEALTH RELEVANCE: This application seeks support for international meeting on mechanisms of plasticity and disease in motoneurons. The 3.5 day conference will bring together specialists investigating motor unit firing patterns in human subjects with specialists focusing on cellular mechanisms underlying motoneuron electrical behavior. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): We are seeking financial support for PIs, post-doctoral fellows and graduate students working in US laboratories planning to participate in the 8th Meeting of the International Motoneuron Society scheduled for July 2012. The goal of these highly successful, international meetings is to bring investigators working on motoneurons and motor units in animal models together with those performing analogous studies on human subjects. A major emphasis of the discussions is on translating basic science advances into clinical therapies. This field is unusually international, with the key laboratories scattered throughout North America, Europe and Australia. Thus, these meetings have been essential for maintaining communication and progress in the field, and they have fostered a number of important collaborative projects. NINDS has generously supported several of the prior meetings in this series (Boulder, 2000; Boulder, 2004; Seattle, 2006 and Paris, 2008). To facilitate interactions between the participating labs at the meeting, each session consists of an introduction for non-specialists, short presentations, and extended time for discussion. Each session will have at least one presentation by a post-doctoral fellow or a graduate student. Sessions on cellular physiology from animal models are interspersed with related studies on human subjects throughout the meeting. We also include discussions of recent developments in high-speed, biologically realistic computer simulations that potentially provide a platform for quantitatively relating these two types of data. The issue at the heart of the meeting is how can the experimental results and computer simulations be best integrated to resolve the cellular mechanisms underlying motor-unit firing-patterns both in normal function (fatigue, exercise) and in disease states (spinal injury, hemiparetic stroke, and ALS). We also plan to invite one or more experts from cognate fields to provide keynote addresses on new developments in techniques (e.g., optogenetics, brain-machine interfaces) and therapeutic approaches to motor pathologies. The abstracts submitted by each invited speaker will be posted on a publicized website. Following the meeting, video recordings of the talks and discussion sessions will be uploaded to the expanded website. We anticipate that this will generate new ideas and approaches for investigation of motor system as well as creation of new therapeutic strategies for spasticity in spinal injury and stroke and motoneuron degeneration in ALS.) PUBLIC HEALTH RELEVANCE: This application seeks support for the 8th International Meeting on Motoneurons and Motor Units. The 4.5 day conference will bring together specialists investigating the normal and pathological behavior of motor units in humans with specialists focusing on cellular mechanisms underlying motoneuron behavior in both normal animals and those designed as models for human motor pathologies including ALS, spinal cord injury, Parkinson's disease and stroke.)

DESCRIPTION (provided by applicant): We are seeking financial support for PIs, post-doctoral fellows and graduate students working in US laboratories planning to participate in the 9th Meeting of the International Motoneuron Society scheduled for June 2014. The goal of these highly successful, international meetings is to bring investigators working on motoneurons and motor units in animal models together with those performing analogous studies on human subjects. A major emphasis of the discussions is on translating basic science advances into clinical therapies. This field is unusually international, with the key laboratories scattered throughout North America, Europe and Australia. Thus, these meetings have been essential for maintaining communication and progress in the field, and they have fostered a number of important collaborative projects. NINDS has generously supported several of the prior meetings in this series (Boulder, 2000; Boulder, 2004; Seattle, 2008, Paris, 2010 and Sydney, 2012). To facilitate interactions between the participating labs at the meeting, each session consists of an introduction for non-specialists, short presentations, and extended time for discussion. Each session will have at least one presentation by a post-doctoral fellow or a graduate student. Sessions on cellular physiology from animal models are interspersed with related studies on human subjects throughout the meeting. We also include discussions of recent developments in high speed, biologically realistic computer simulations that potentially provide a platform for quantitatively relating these two types of data. The issue at the heart of the meeting is how can the experimental results and computer simulations be best integrated to resolve the cellular mechanisms underlying motor unit firing patterns both in normal function (fatigue, exercise) and in disease states (spinal injury, hemiparetic stroke, ALS and SMA). A new addition at this meeting will be the inclusion of clinician-scientists who will address therapeutic approaches to motor pathologies. The abstracts submitted by each invited speaker will be posted on a publicized website. Following the meeting, video recordings of the talks and discussion sessions will be uploaded to the expanded website. We anticipate that this will generate new ideas and approaches for investigation of motor systems as well as creation of new therapeutic strategies for spasticity in spinal injury and stroke and motoneuron degeneration in ALS and SMA.

Multiple mechanisms has been proposed for the selective vulnerability of motoneurons in neurodegenerative diseases. In reflecting on the prior work from our laboratories, as well as that of our colleagues around the world, we have developed a synthetic hypothesis that accounts for a vast majority of the reported findings. We propose that the net response of mouse motoneurons to the presence of mutant proteins is a disregulation of homeostatic plasticity. This manifests as an increased `gain' of both the up- and down-regulation of compensatory mechanisms designed to control the level of motoneuronal activity. The toxic increase of gain function leads to overcompensation and a dramatic cascade of homeostatic oscillations that increases motoneuron morbidity. Further, we propose that size-scaling of these compensatory mechanisms leads to the observed greater vulnerability of the largest motoneurons. The goal of this project is to provide rigorous testing of this novel disregulation hypothesis using mutant SOD1 mice as a model system for neurodegenerative diseases that disproportionately target motoneurons. The proposed experiments rest heavily on our recent technical breakthroughs that enable us to perform intracellular recordings of mouse motoneurons throughout disease progression, from neonate through adult, using both in vivo and in vitro preparations, as well as our expertise in assessing the density and spatial distributions of membrane channels in motoneurons. Our approach entails presenting a series of `homeostatic challenges' to motoneuron excitability and comparing the compensatory responses of mSOD1 motoneurons to those of wild-type controls. If our hypothesis is correct, we expect to observe that mSOD1 motoneurons exhibit consistently greater responses to each of the challenges than do wild-types and that these mSOD1 responses scale with motoneuron size. There are three specific aims: to assess the responses of mSOD1 and control motoneurons to drug perturbations that alter the intrinsic electrical properties of motoneurons (Aim 1), the synaptic inputs to motoneurons (Aim 2) and the neuromodulatory inputs to motoneurons (Aim 3). The resulting data will provide a strong impetus for pursuing radical, novel therapeutic strategies as well as for elucidating the specific signal transduction cascades underlying the different homeostatic mechanisms.