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In addition to the research projects funded by grants to individual members of the Institute, several collaborative research projects are supported by program and center grants administered within the Brain Research Institute. These interdisciplinary research programs involve BRI members and scientific staff from different departments who have joined together for common objectives.

UCLA MORRIS K. UDALL CENTER OF EXCELLENCE FOR THE STUDY OF PARKINSON’S DISEASE

The National Institute for Neurological Disease and Stroke has awarded a Morris K. Udall Center of Excellence for Parkinson's Disease Research to UCLA under the direction of Marie-Françoise Chesselet, M.D., Ph.D. UCLA has the distinction of being named the only Udall Center of Excellence west of the Mississippi. (UCLA research on Parkinson's disease is also supported through its funding as an Advanced Center for Parkinson's Disease Research by the American Parkinson's Disease Association as well as individual research awards.)

Parkinson's disease is a neurodegenerative condition caused by the death of neurons in the brain responsible for manufacturing a key neurotransmitter called dopamine. Although important advances have been made, current treatments have limitations and do not prevent the progressive worsening of the disease as neurons continue to die.

The NIH-supported Udall Center is part of a large multidisciplinary effort in which scientists, clinicians and neurosurgeons team together at UCLA to advance treatment and therapies for Parkinson's disease. The Center is seeking to understand the long-term effects of the loss of dopaminergic neurons and of the current treatments for Parkinson's disease in order to improve therapeutic approaches.

In the Udall Center, scientists at the David Geffen School of Medicine at UCLA collaborate with bioengineers at the UCLA School of Engineering to develop microscopic stimulators that can be placed in deep brain structures to modify brain activity as a means of controlling abnormal movements.

Only about ten percent of patients inherit Parkinson's disease. Researchers at UCLA seek to understand if some patients may carry "susceptibility genes" that interact with environmental toxins to cause this degenerative condition in order to develop new strategies for treatment. Research is also performed on the role stem cells may play in new therapies for Parkinson's disease as well as how deep brain stimulation and growth factors may protect dopaminergic cells. In coordination with the Ahmanson/Lovelace Brain Mapping Center at UCLA, scientists are using functionally-activated brain MRI scans to discover and localize abnormal activity of Parkinson's patients during learning. Clinical trials with pharmacological therapeutic agents are also being conducted at UCLA to determine if these drugs can improve cognitive and behavioral functions of Parkinson's disease patients.

The Center uses an integrated multidisciplinary approach to elucidate the effects of nigrostraital lesions and treatment of Parkinson’s disease on the molecular and cellular characteristics of the subthalamic nucleus. This region of the basal ganglia has recently emerged as an important focus for the development of novel therapeutic strategies for the disease. One goal of the Center is to identify new molecular targets of non-invasive pharmacological treatments of Parkinson’s disease.

Interactions between the Center and clinical investigators in the Movement Disorders Program at UCLA provide an ideal conduit for the rapid translation of research findings into clinical applications. The Center provides a dynamic training environment that expands the research capabilities of scientists at all career levels and also their trainees. The Center facilitates the participation of new investigators across the UCLA campus in research on Parkinson’s disease and reinforces the existing interactions between basic and clinical research on Parkinson’s disease at UCLA.

                          PLASTICITY OF GABA RECEPTORS

In this program project a group of five independent faculty have combined expertise in electrophysiology, neuroanatomy, biochemistry, behavior, and molecular biology to approach important questions in basic neurobiology, that would be difficult for any one individual.  The theme chosen for collaborative research is "Plasticity of GABA Receptors."  Program Director Richard Olsen has assembled, like the structure of GABAA receptors themselves, a "heteropentamer" of scientists.  Olsen's component project is "Mechanisms of Ligand-Induced GABAA Receptor Plasticity." Tom Otis' component is "Molecular Determinants of Extrasynaptic GABA Receptor Function on Cerebellar Granule Cells." Carolyn Houser's project is "Plasticity of GABAA Receptor Subunits in Epilepsy," and involves a pilocarpine rat model of chronic epilepsy. Istvan Mody's component is "Inhibitory Mechanisms in Homeostatic Neuronal Plasticity," and Michael Fanselow's component is  "GABA Receptors and Pavlovian Conditioning."
           
In addition, the group is working together on characterizing knockout mice for GABAA receptors, correlating plastic changes that take place with respect to GABA receptors and other synaptic gene products in relationship to the anatomy, physiology, pharmacology, and behavior of these mice. All projects focus on GABAA receptors, the major postsynaptic receptors involved in rapid inhibitory neurotransmission.  These receptors, and "plastic" alterations in them that occur in response to a variety of extraordinary experiences, are implicated in many neurological and psychiatric disorders. The wide variety of employed techniques promises a level of investigation aimed at understanding the assembly, functioning, and plasticity of GABAA receptors in the mammalian nervous system.  It is both hoped and expected that these studies will serve as a leading inquisitive collaboration to unveil the short and long-term control of inhibition in the mammalian brain. The studies deal with the nature of the alterations in the molecular structure and function of GABAA receptors that contribute to chronic changes in excitability of neurons, or to the mechanism of tolerance and withdrawal from chronic drug exposure.  Ultimately, therapeutic strategies could be based on our studies, aimed rationally at preventing the unwanted or pathological alterations in GABAA receptors characteristic of several neurological and psychiatric disorders.

NEUROMUSCULAR PLASTICITY

The overall objectives of the UCLA Laboratory of Neuromuscular Plasticity are:

· to determine the degree of neuromuscular plasticity after spinal cord injury or prolonged weightlessness
·
to identify physiological and molecular mechanisms which will induce neuromuscular plasticity after spinal cord injury or prolonged weightlessness
·
to define optimal procedures to maximize functional recovery
·
 to develop and test preventive and rehabilitative strategies which will benefit people who suffer from spinal cord or neuromuscular system injury or disease

Major research in this laboratory is carried out under the auspices of the Program Project Grant (PPG) "Neuromuscular Plasticity: Functional Recovery After Spinalization," awarded by the National Institute of Neurological Disorders and Stroke. The PPG director is Dr. V. Reggie Edgerton and the co-director is Dr. Roland R. Roy.

As part of this PPG, investigators are developing robotic-assistive devices for use in quantifying limb movements following spinal cord injury. These efforts include neural and mechanical control modeling of locomotion and are conducted in cooperation with the Jet Propulsion Laboratory.

Neuromuscular plasticity also is being studied in response to the microgravity environment involved in spaceflight, with a focus on questions related to the physiological signals that regulate muscle mass, selected muscle proteins, and the size and metabolic properties of spinal cord and dorsal root ganglion cells. The effects of prolonged weightlessness on the control of movement is also being investigated.

This PPG has been funded since 1980, and consists of five individual and three core projects.

The primary objective of Project I (Roland R. Roy, PI) is to determine the contribution of neural (activity-independent neurotrophic) and mechanical (tension) factors as independent and as interactive factors in maintaining the functional, structural and metabolic integrity of skeletal muscles in adult rats that have been subjected to complete inactivity. This project consists of a series of experiments designed to identify and determine the relative importance of critical variables for regulating muscle fiber phenotype and size.  Dr. Ken Baldwin at UCI has a subcontract with this grant and is identifying at the molecular level the principal regulators involved in maintaining muscle mass and phenotype.   The efficacy of short, daily periods of programmed mechanical stimulation as a preventive and/or rehabilitative tool for subjects with spinal and neuromuscular maladies is being studied.

In Project II (V. Reggie Edgerton, PI), the ability of the spinal cord to generate a corrective kinematic response and whether these adaptive events are mediated by molecular mechanisms similar to those associated with learning in the brain are studied. These experiments will characterize the kinematic and physiological adaptations to swing phase force field induced learning by the lumbar spinal cord in spinal cord transected rats. Selective neural substrates and specific pathways associated with the adaptive responses are examined using pharmacological, anatomical and biochemical approaches to gain insight into the physiological and molecular mechanisms to which these learning and memory events can be attributed. These studies allow us to identify physiological and cellular events that may underlie spinal motor learning, and provide a framework around which strategies for use-dependent therapeutic procedures following neural injury in human patients can be developed.

In Project III (L.A. Havton, P.I.), we study in the rat the effects of a neonatal spinal cord transection injury and locomotor training upon the synaptic inputs to muscle specific motoneurons. Retrogradely labeled hind-limb motoneurons are identified in the spinal cord and studied in the electron microscope. Excitatory and inhibotory inputs to these neurons are quantified. This project will provide a better understanding of the plasticity of spinal cord circuitries involved in motor function following a spinal cord injury and a training intervention.

The primary objective of Project IV (Michael V. Sofroniew, PI) is to examine the contribution of different descending spinal pathways to the control of stepping and determine how lesions of different pathways may influence neuromuscular plasticity after spinal cord and step training in mice. These studies will take advantage of recently developed, robot-assisted evaluation of stepping, and combine this with video analysis and electromyographic recordings in adult mice. After characterization of non-transgenic mice, we will examine transgenic mice in which the glial and inflammatory response to spinal cord injury has been modified. Results from the present study will establish a framework for quantitative evaluation of the neuromuscular control of stepping in transgenic mice with spinal cord injury.

Project V (Susan Harkema, PI) consists of a subcontract with the University of Louisville in Kentucky.  Project V focuses on how the human lumbosacral spinal cord, after a clinically complete injury, responds to and learns from sensory inputs associated with 1) limb loading (kinetics), 2) joint positions and movements (kinematics), and 3) the combined effects of the kinetics and kinematics of both limbs, during stepping with body weight support on a moving treadmill.  These studies are a continuation of clinical studies designed to determine the feasibility of entraining neurally impaired patients to regain significant locomotor capability by practicing stepping on a treadmill belt daily with the body receiving minimum weight support from a suspension system. The results suggest that repetitively performing a motor task can facilitate the development of the motor skill that is practiced.  The efficacy of these rehabilitative strategies for optimizing the recovery of mobility following spinal cord injury are now being tested.

 

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