Karen A. Sigvardt - US grants

The goal of the proposed research is to elucidate the neural mechanisms in the spinal cord that underlie the generation of rhythmic locomotory output and to determine, at the cellular level, the role of putative amino acid transmitters in the production and control of spinal locomotion. The study will be done on an in vitro lamprey spinal cord preparation that generates "fictive locomotion", the neuronal correlate of locomotory behavior. The first objective of the proposed study is to identify and describe the interneurons or types of interneurons that may be a part of the locomotory central pattern generator, those neurons with membrane potential oscillations and/or spike activity correlated with the pattern of efferent discharge. The description of each neuron will include physiological properties and morphological characteristics, as revealed by intracellular dye injection. Evidence of synaptic connections between the neuron being characterized and other components of the spinal cord will be gathered and tests to determine the role each neuron plays in the network will be performed. Amino acid transmitter receptor agonists and antagonists have powerful effects on the locomotory motor output generated by the spinal cord. The second objective of the proposed research is to determine the effects of amino acid neurotransmitter receptor agonists and antagonists on the central pattern generator by combining a study of the effects of these pharmacological agents on the activity of individual interneurons during fictive locomotion with a detailed description of each recorded neuron's physiological and morphological characteristics. The results of this study can provide insights into how the spinal network is organized and at what level in the organization of the network these agents operate. Furthermore, any agents found to act specifically to turn on or modulate spinal centers for locomotion may be related to transmitter than function in the control of locomotion by descending systems from the brain, control that is lost following spinal transection.

The over-all goal of the proposed research is to investigate the neural mechanisms in the spinal cord that underlie the generation of locomotor output in vertebrates. The studies are being done on the in vitro lamprey spinal cord preparation that generates "fictive locomotion", the pattern of activity recorded from spinal ventral roots known to correlate with the locomotor behavior. I have chosen this primitive vertebrate for study because it has a central nervous system homologous to the CNS of higher vertebrates but has relatively fewer neurons and a relatively simple locomotor behavior. In particular, the goals are to elucidate the cellular and network mechanisms whereby a small portion of the lamprey spinal cord can generate rhythmic activity and to investigate the ascending and descending coupling mechanisms responsible for intersegmental coordination during locomotion. We have recently developed a theoretical framework for studying intersegmental coordination and discovered general properties of intersegmental coupling that can give rise to the appropriate locomotor pattern. Future progress depends on limiting the number of possible ways that the segmental oscillators might be connected. The first objective of the study is a series of experiments designed to identify and investigate the properties of the neurons of the intersegmental coordinating system using a combined anatomical and physiological approach. The second objective is to characterized the internal structure of the spinal oscillators; to establish, in more detail than is currently available, the characteristics of the neurons that generate the rhythmic activity within the spinal cord and the contribution each makes to the generation of rhythmicity. The results of this work will provide new insights into how the neuronal components of the spinal cord are organized to produce the appropriate locomotor behavior and, more generally, insights into how interactions between oscillating networks of neurons are governed.

DESCRIPTION: (Verbatim from the Applicant's Abstract) Parkinson's Disease (PD) results from the degeneration of dopaminergic neurons in the substantia nigra, yet little is understood about how this loss results in the primary motor symptoms of the disease (rigidity, bradykinesia and tremor). Although a lesion placed in the globus pallidus can relieve rigidity tremor and/or drug-induced dyskinesia, the mechanism underlying this effect is also not understood. Furthermore, the role of the basal ganglia in the control of movement remains to be established. These facts underscore the need for directly studying basal ganglia function in PD patients. The surgical treatment of PD by pallidotomy provides an excellent, and largely unexploited, opportunity for achieving this goal. Our proposed work brings together recent developments in the fields of behavioral science, neurophysiology and clinical neurology to test the hypothesis that specific motor symptoms of PD are the result of specific changes in the spatiotemporal dynamics of the neural activity within the basal ganglia. These properties have received little attention in studies of the human globus pallidus. To establish this relationship, we propose the following specific aims: 1). to determine the severity of the constellation of Parkinsonian motor symptoms in individual patients using a battery of tests that are more quantitative than standard neurological rating scales; 2). to characterize the spatiotemporal dynamics of neural activity in the basal ganglia of individual PD patients who have undergone microelectrode-guided pallidotomy; 3). to determine the neuronal correlates, in the pallidum of the primary motor symptoms of PD by constructing a relational database of the results of the two components of the study. The results of the proposed work should lead to modifications of the current theories of the neural mechanisms underlying the motor symptoms of PD and guide others in their search for the cellular mechanisms which underlie the transformation of the normal striatum and globus pallidus following the loss of striatal dopamine.

psychomotor function; cognition; Parkinson's disease; performance; basal ganglia; clinical research; human subject;