David McLean - US grants

9309757 Marsh An option included in current seismic retrofit programs of poorly confined reinforced concrete columns in older bridges is to leave the plastic hinging region just above the foundation of multiple column bents unretrofitted. It is based on the assumption that the flexural strength of such columns will degrade quickly in response to inelastic demands and thus will not transmit much moment to the foundation. It is also assumed that the shear capacity at the plastic hinge region will not be lost. However, the state of knowledge regarding the mechanism of shear strength loss is poor. The purpose of the proposed research is to assess the shear transfer capacity of such columns. The proposed work involves the testing of 10 reduced scale reinforced concrete columns. A range of potential configurations would be tested so that the specific conditions under both the flexural and shear capacities are lost could be identified. The proposed work would provide essential information regarding the performance of unretrofitted, seismically deficient bridge elements, and would help in the rational prioritization of resource allotment for seismic retrofitting of poorly designed bridges. ***

9973034
Davis

The goal of this project is to synthesize and institutionalize an outcomes-based engineering design education model across a region to achieve desired educational responsiveness, student transfer, and resource sharing. Five universities and community colleges in Washington will lead efforts of educators and industry throughout the Pacific Northwest to establish effective processes for improving engineering design education. Through regional workshops, they will define educational objectives and achievement standards suitable for the region, refine and facilitate implementation of assessments for engineering design, and prepare others to implement effective design education practices. Resulting improvements to teaching of design will increase student, learning of competencies important to the region and will increase retention and success of qualified students, especially women and minorities.

This project includes research to evaluate and improve design assessments and training to support institutionalization of effective practices and materials. Proposed design assessments will be tested in two ways: (a) through comparative analysis of design team actions, their design products, and their design perceptions and (b) through comparisons of assessment results to responses on alumni/employer surveys. A web-based survey will be developed to obtain alumni/employer feedback for assessment of program achievement on a regional scale. Faculty trainers will be prepared and assisted to lead local workshops patterned after regional workshops. These workshops will empower faculty to implement and continue improvement of design education materials, methods, and assessments for their local needs.

The regional design education model will be synthesized from resources developed in Washington through the NSF-funded Transferable Integrated Design Engineering Education (TTDEE) project:
- Proven TTIDEE collaborative learning models for teaching and learning of engineering design
- Definitions of learning outcomes for engineering design at mid-program and end-of-program points
- Pilot-tested and proposed instruments for mid-program and end-of-program design assessments
- Workshop facilitation expertise for team-based engineering design education and assessment
- Extensive collaborative efforts across the state on engineering design education
- Affiliations with institutions and organizations across the region and nation for extended impact

Previous Abstract still valid

DESCRIPTION (provided by applicant): Neuromodulation is extremely important as it can govern the way neurons interact with one another. This is true from the simplest to the most complex neural processes, be it locomotion or emotion. Investigations into vertebrate neuromodulation to date have primarily used pharmacological tools, where drugs are bath applied and their cellular and synaptic consequences are monitored electrophysiologically. However, these studies provide no direct information about the activity patterns of the cells that contain these chemicals or what the real behavioral consequences of that activity may be. This research project plans to gain unprecedented access to neuromodulation in a vertebrate preparation using the elegant imaging and genetic tools available in the zebrafish, Danio rerio. The zebrafish is poised to become a powerful model system in all aspects of motor control and its development and this project intends to capitalize on its advantages by focusing on the role of descending modulatory centers. Thus, the aim of this proposal is three-fold: 1) to identify and catalogue the development of three potential neuromodulators, serotonin, dopamine and noradrenaline, 2) to visualize the activity of their respective neurons during elicited axial motor behaviors, and 3) to perturb the activity of these neurons in vivo and monitor the behavioral consequences.

DESCRIPTION (provided by applicant): Networks of rhythmically active neurons in the spinal cord are responsible for producing locomotor movements. In developing vertebrates, ventral spinal cord can be sub-divided into five zones, four of which are responsible for producing the interneurons that drive rhythmic motoneuron activity (V0-V3). Critically, interneurons that emerge from these zones are labeled by the same transcription factors and have similar morphologies and functions in different vertebrates. This has made it even easier to compare features of circuit organization in simpler model systems, like fishes and frogs, to more complex ones, like chicks and mice. What is unclear, however, is how only four progenitor zones can yield the diverse array of functionally distinct interneurons that are known to exist. Our plan is to explore the contribution of development to the functional elaboration of spinal circuitry, by studying a genetically identified population of spinal interneurons in zebrafish. Our work suggests that interneurons labeled by the transcription factor alx in zebrafish are not functionally identical and contribute to different speeds of movement. However, it is not clear how differences in the morphology, connectivity and the excitability of alx interneurons may be related to their function and whether developmental programs shape these features. The remarkable conservation of developmental mechanisms leads us to think that the patterns we find will be present broadly among vertebrates, including mammals. By doing so, we hope to better explain and treat disorders that affect the speed and coordination of movements, like Parkinson's disease or spinal injury. PUBLIC HEALTH RELEVANCE: Networks of neurons in the spinal cord generate movements, but we understand very little about their organization. We will investigate the contribution of development to the functional diversification of spinal networks using zebrafish as a model.

1066575
Patankar

Summary description: Deciphering the logic behind how neural circuits generate behavior is a fundamental question in neuroscience. Locomotion offers a unique opportunity to probe issues of neuronal organization because motor circuitry generates a measurable product ? movement. Thus, studies of neural circuits for movement can not only help understand how the nervous system functions in general, but can also help to repair the motor circuitry after it has been disrupted, either by injury or disease. To fully grasp how to address the clinical challenges of overcoming neuronal disease or injury, it is informative to look for solutions in natural processes. This proposal is focused on the fundamental science underlying this transformational vision. The NU team will concentrate on discovering and understanding the function of spinal motor circuitry of a model system: the zebrafish.

Intellectual merit: A major drawback of modern computational models is considered to be that the patterns of connectivity among spinal neurons are largely assumed. With a large parameter space, the assumed neural circuitry in the computational models, that mimic natural behavior, may not be the actual circuitry in organisms. The NU team has designed a research approach based on the hypothesis that information about the required muscle forcing for movement can be used to discover the actual neural circuitry. Hence, instead of assuming any neural circuitry, they propose a novel inverse paradigm in which they will first identify the muscle forcing required to produce the observed swimming kinematics. Second, they will construct possible neural circuits that could lead to the predicted muscle forcing. Finally, they will use transgenic zebrafish lines to hunt for classes of neurons predicted by the modeling, but as yet unidentified.
Transformational impact: This project will lead to the discovery of new classes of neurons and the related circuitry, and to a fundamental understanding of how neuronal activation leads to a sequence of events in which the muscle energy is focused and transformed into the translational kinetic energy of movement. These fundamental discoveries and insights will not be restricted to the zebrafish model system but will conceptually apply in general to vertebrates whose movements range from swimming to limbed locomotion.

Broader impact: The PIs will develop new interdisciplinary courses. The work done in this proposal will be a crucial application example that will be introduced in a book on computational methods that the PI is writing. The PI is also developing a novel approach based on computer animation to teach the fundamental principles in his research field. These educational videos will be broadly distributed through the internet by using YouTube.

The decision to approach or avoid is a fundamental aspect of animal behavior. How this decision is made by networks of motor neurons that are located in the brainstem and spinal cord, and which trigger muscle cell contraction, is still unclear. This project will investigate the neural and mechanical basis of innate decision-making in vertebrates. Studies will be carried out using zebrafish larvae because they undergo a change in their innate decision-making ability during the first few days after hatching. Immediately after hatching, zebrafish larvae have the ability to generate escape behavior in response to threats. Three days later, they add the ability to not only avoid, but to approach and attack small objects. The goal of this project will be to determine how the neural circuitry supporting the decision to escape or approach visually detected objects is organized during development. Graduate students will be trained in the use of cutting-edge electrophysiological, imaging, computational and behavioral techniques uniquely applied in the zebrafish model system. In addition, an outreach program will be designed and implemented to introduce local high school students to basic neurobiological concepts addressed in this project. The program will involve intuitive and interactive experiments using simple robots with circuits that can be modified to create the approach or avoidance behaviors observed in fish.

The investigators will pursue several hypotheses regarding the development of approach and avoidance behaviors in larval zebrafish. Aim 1 will use high-speed videography and automated body tracking to evaluate the hypothesis that the circuitry for approach is not in place until later on in development. The expectation is that only the older larvae will be able to generate kinematically-distinct responses to attractive visual stimuli. Aim 2 will distinguish between two leading possibilities for how reticular circuitry mediates approach and avoidance, either via the addition of new components or the modification of pre-existing ones. In vivo dye labeling combined with functional calcium imaging approaches will assess changes in the morphologies and responses to visual stimuli of readily identifiable reticular neurons during development. In vivo patch clamp recordings will also be used to confirm outputs to spinal circuitry. Aim 3 will examine the likelihood that newly developed approach circuitry in the spinal cord is either overpowered or shut off by reticulospinal drive during avoidance maneuvers. The predictable read-outs of either scenario will be assessed using electrophysiological recordings of motor output, advanced computational fluids and body modeling, and targeted laser ablations followed by kinematic analysis.

Project Summary The recovery of function after damage is an important, yet elusive goal in motor control. Spinal motor neurons are particularly vulnerable to damage thanks to long axons that innervate peripheral muscles. Motor neurons also have central axon collaterals that impact motor output, but we know little of their response to injury. This is important because changes in motor neuron excitability accompany spinal injury, contributing to short-term spasticity and long-term recovery. The goal of this exploratory R21 proposal is to develop a new model system to understand how central spinal circuits reorganize after injury, beginning with an overlooked motor neuron response to injury. Like all vertebrates, zebrafish have slow, intermediate and fast types of spinal motor units defined by their target musculature and each type exhibits central axon collaterals. However, unlike all other vertebrates it is possible to track the same spinal motor neurons and their central and peripheral connections before and after injury in living, growing zebrafish. In pilot experiments using two-photon axotomies, we found that some motor neurons regrow and successfully re-innervate target musculature, while others fail to exit spinal cord and instead grow elaborate central axons and form synapses. This mirrors a phenomenon also observed in axotomized spinal motor neurons of adult cats. These observations suggest that some axotomized motor neurons are creating ectopic circuits that could impact motor control. But what conditions predict peripheral versus central regeneration and do ectopic central motor axons integrate into functional circuits? In Aim 1, we will assess the relative contribution of time of development and motor unit identity to axotomy responses. In Aim 2, we will determine if axotomized motor neurons are recruited and connected to other spinal neurons. These aims will characterize the capacity for motor neurons to form ectopic recurrent circuits and will inform studies exploring maladaptive and adaptive changes in spinal circuit structure following injury.