Donald J. Woodward - US grants

A program of studies will examine the action of ethanol on motor performance. Rats will be used as experimental models to examine basic principles of sensory and motor integration. One concept to be explored is that ethanol disrupts sensor1-motor integration by impairing the capacity of motor centers to regulate or "gate" sensory transmission. Acute and chronic doses of ethanol will be administered. Experimental observation will be made of: video based recordings of steady locomotor and random movements, footfall events detected electronically on a treadmill, and single unit recordings in sensory and motor cerebral cortex, cerebellum and striatum. Iontophoresis of putative transmitters in awake animals will be done to examine actions of ethanol on components of synaptic systems. The uptake of 14C-2deoxyglucose will be assayed by computer based analysis of autoradiographs. Regional brain variations will be imaged under conditions of acute and chronic ethanol administration. These studies will characterize regional and global changes in brain actively which may be the basis for actions of ethanol on "attentional" mechanisms and other processes which regulate motor performance.

A program of studies will investigate the neurophysiological basis of noradrenergic actions in neuronal circuits in the central nervous system. The aim will be to establish a basis for the examination of the potential interactions between the noradrenergic system and three drugs of abuse: Amphetamine; cocaine and morphine. Function of the noradrenergic system will be examined in the cerebellum and cerebral cortex by employing microiontophoresis of drugs, stimulation of the locus corruleus, and physiological activation of somatosensory and visual afferent pathways. A new hypothesis will be explored which proposes that norepinephrine exerts a modulatory influence on synaptic efficacy in neuronal circuits. Specific studies on amphetamine will test for enhancement of noradrenergic synaptic function due to a combination of enhanced release of endogenous norepinephrine and direct agonist effects. Assays of noradrenergic NE action will also allow tests of the concept that cocaine in the central nervous system blocks norepinephrine release and reuptake processes. The improved criteria for identifying altered noradrenergic function will also be used to test whether morphine lowers tonic physiological noradrenergic activity by acting at terminals or within the locus coeruleus. Overall, the proposed research will contribute to a basic understanding of noradrenergic function, in parallel with tests to clarify the modes of action of drugs of abuse.

The proposed research will continue ongoing studies of the physiological actions of the monoamines DA (dopamine) and NE (norepinephrine), on the function of neural circuits in the CNS. In this phase of research, we aim to study the activity of neural circuits in dorsal and ventral neostriatum during behaviors leading to cocaine self-administration. Newly developed methodology will allow arrays of (multiple microwires to be implanted in dorsal and ventral neostriatum to obtain long-term recordings of ensembles of single neuron spike trains. Rats will be trained to press a bar for cocaine IV self-administration under a variety of experimental conditions. Rats will also locomote after cocaine administration and recordings of the same ensemble of neurons across different behavioral states. Nucleus accumbens neurons will be studied in selected cases across free behaviors during a 24-hour cycle. The anatomical distribution of behaviorally specific activity will be mapped in detail in n. accumbens and caudate-putamen in relation to the topography of afferents, efferents and the patch-matrix organization as defined by naloxone binding sites. Ensemble recording will be carried out in SI-MI cerebral cortex and dorsolateral neostriatum to determine influences of cocaine on the cerebrostriatal system. A search will be made in medial prefrontal cortex and other regions afferent to n. accumbens for the origin of anticipatory activity found to precede bar press for drug selfadministration. Chronic recordings also will be made in anterior lobe and ventral paraflocculus of cerebellum to assess possible cocaine actions via facilitation of the cerebellum NE-system. Correlations will be made between results obtained the known modulatory actions of cocaine, DA, and NE as revealed in previous cellular studies and also in future parallel studies of modulatory actions of these monoamines.

The goal of this technology development program is to create a resource for fabrication and development of multichannel voltage and chemical sensor systems for the Neurosciences. The aim is to address the need to take advantage of new microcircuit fabrication techniques that have been recently developed within the Center for High Density Electronics at the U. Arkansas under direction of Dr. S. Ang. The plan is to work on four major aims in parallel. The first aim is to fabricate a new generation of small silicon-based multisite microprobes with sites specialized for either or both voltage or electrochemical sensing. Evaluation and study of sensor site properties will be conducted by Drs. I Fritsch (U. Ark.), D. Woodward (Wake Forest U.), and R.M. Wightman (U.N. Carolina). A second aim is to integrate the silicon probe into flexible polyimide cable system. New technologies for fabrication and coating of such materials will be adapted for in vivo Neuroscience applications. A third aim is to design and fabricate multichannel VLSI microchip headstage devices to amplify and transmit information from the voltage and electrochemcal sensor sites. The chip design will include the capacity to microstimulate through the voltage sensor sites or to apply polarization voltages at the electrochemical sites. Prototype designs already in progress will be developed further. The VLSI microcircuit will be integrated into the probe design to achieve higher desensity integration. A multiple probe configuration will be developed as the basic module is perfected. A wireless transmission system with an integrated DSP will be developed to digitize and transmit multichannel information at high rates to a host computer. A dual processor host PC workstation with the Windows NT Operating System will be further developed with software enhancements to manage the multichannel data flow and analysis. Education of students and training of users will be continued and expanded. As has been done previously, interactions with small businesses will be developed to disseminate utility of the technology development. This project will provide technology critical for ongoing research and therapeutic needs in Neuroscience of many NIH Institutes, including NIDA, NIA, NIAAA, NINDS, and NIMH.

DESCRIPTION (provided by applicant): The mesolimbic regions including the medial and lateral prefrontal cortices, the nucleus accumbens, and ventral tegmental area (VTA) are thought to mediate the neural signals that regulate reward-seeking behaviors. This research program will study the neurophysiology of the influence of ethanol on the reward and learning functions of the mesolimbic system. Advanced methods for simultaneous recording of spike train activity of large scale populations of neurons in different mesolimbic regions over many sessions across days will be applied to obtain information on the circuit functions related to actions of ethanol over different time scales. An initial aim is to determine the progress of changes in the mesolimbic system in rats at all stages of acquisition of self-administration of ethanol by a procedure of fading from a high percent sucrose to a high percent ethanol concentration. Normal Long Evans rats will be compared with the inbred P (ethanol-preferring) rats to be obtained from the Center for Ethanol Research at U. Indiana. A second aim will characterize change in responses as tone cues are conditioned to provide information about the reward to be obtained at a spout. A third aim will study neuronal activity in mesolimbic regions on the pattern of operant responses progressive ratio nose poke responding for ethanol in the P rats that exhibit persistent responding during extinction, and enhanced responding during the Alcohol Deprivation Effect. We hypothesize that the nucleus accumbens will reveal the most heterogeneous responses characteristic of central integration; orbital frontal cortex will mediate taste and reward valuation t mediate future behavioral choice selection, medial prefrontal cortex will exhibit neural coding of response selection and that VTA dopamine neurons will track information of cues predictive of future reward. A unifying concept is that ethanol will exert widespread influences by induction of an inflexibility of control over conditioned cue responding for reward seeking behavior.

The goal of this project is to characterize the neurophysiological changes induced during the recovery of function in awake behaving rat by the depletion of dopamine in striatum by the unilateral administration of 6-hydroxydopamine as a model for Parkinson's disease. Preliminary studies have shown that depletion of dopamine results in an elevation of resting firing rates of neurons in the neostriatum. This effect is maximum of the depleted side but is nearly equally apparent on the intact side with no depletion of DA. Activation of rotation activates reciprocal changes in neighboring neurons on both sides with no net changes in means rates, thus indicating the presence of an effective synaptic input to both intact and DA depleted striatum. An interpretation is that absence of dopamine induces a motor dysfunction directly on the affected side. This in turn activates a widespread motor recovery adaptive mechanism that engages both sides of the cortical striatal nigral thalamic system. Forced use of the limb on the DA depleted side by application of a cast to restrict use of the unaffected limb, specifically in the first 7 days after 6-OHDA, has recently been found to offer neuroprotection against 6-OHDA, and thus raised the possibility that the widespread bilateral elevation of activity may play both a neuroprotective as well as a compensatory role. An aim of this project is to record activity of populations of neurons recorded simultaneously from 64 microwires implanted bilaterally in striatum, substantia nigra reticulata/compacta, and forelimb sensorimotor cortex. These advanced recording procedures developed in this laboratory will determine activity of populations over the two weeks after 6-OHDA administration. Casting to restrict limb use will be done on both the DA depleted and intact side to compare effects of restriction of movement and to determine the neural signals during movements during tests of motor impairment. Casting will be done prior to 6-OHDA to test whether elevation of activity appears during the early period of motor reorganization and may serve to activate neuroprotection. Recordings made from dopamine neurons will test the emerging concept of a role in motor learning and reorganization. A prediction is that the novel movement patterns during forced use will produce many signals in striatum and cortex correlated with movement that are not present in over-trained circuits.