Eric J. Lang, M.D./Ph.D. - US grants

DESCRIPTION (from applicant's abstract) The generation of movements is a fundamental function of the nervous system. It is accomplished by a process, termed motor control, involving the interaction of multiple brain regions. The result of this process is motor commands that encode the appropriate muscle combinations and the timing of their activation for carrying out complex movement sequences. The experiments of this proposal will investigate the interaction of two key motor systems (the motor cortex and the olivocerebellar system) in the generation of these motor commands. The ability of the olivocerebellar system to generate rhythmic synchronous discharges suggests that its function is to bind in time the different muscle groups involved in making complex movement sequences. Indeed, damage to the inferior olive produces motor deficits characterized by the loss of precisely timed muscle activation. Thus, to investigate the interaction of the motor cortex and olivocerebellar system in motor control, whisker movements will be evoked by motor cortex stimuli and the influence of olivocerebellar activity on the evoked movements will be determined. The whisker movements will be recorded using either a photodetector device or high speed video taping. Olivocerebellar activity will be monitored with multiple electrode recordings of complex spike (CS) activity from Purkinje cells, the main target of the olivocerebellar system. Multiple electrode recordings allow determination of the spatial patterns of synchronous CS activity. The first goal will be to demonstrate that there is in fact a significant interaction between these two brain systems: that is that synchronous discharges in the olivocerebellar system gate the efficacy of motor cortex activity in producing movement. The next goal will be to investigate whether the rhythmic nature of olivocerebellar activity allows it to function as an internal clock for organizing motor outputs in time. The third goal will be to determine the major brain sites where the interactions between these systems occur. Finally, the question of whether changes in the patterns of synchronous discharge of the olivocerebellar system result in changes in the pattern of coupling of different muscles will be addressed. In sum, these experiments should help to define the role of the olivocerebellar system in motor control as well as the reasons why cerebellar damage results in motor coordination deficits. They thus represent a step toward the more general goal of understanding cerebro-cerebellar interactions in motor control.

DESCRIPTION:(provided by applicant) The generation of movements is a fundamental function of the nervous system. It is accomplished by a process, termed motor control, involving the interaction of multiple brain regions. The result of this process is motor commands that encode the appropriate muscle combinations and the timing of their activation for carrying out complex movement sequences. The experiments of this proposal will investigate the interaction of two key motor systems (the motor cortex and the olivocerebellar system) in the generation of these motor commands. The ability of the olivocerebellar system to generate rhythmic synchronous discharges suggests that its function is to bind in time the different muscle groups involved in making complex movement sequences. Indeed, damage to the inferior olive produces motor deficits characterized by the loss of precisely timed muscle activation. To investigate the interaction of the motor cortex and olivocerebellar system in motor control whisker movements will be evoked by motor cortex stimuli, and the influence of olivocerebellar activity on the evoked movements will be determined. The whisker movements will be recorded using a high speed videotape system. Olivocerebellar activity will be monitored with multiple electrode recordings of complex spike (CS) activity from Purkinje cells, the main target of the olivocerebellar system. Multiple electrode recordings allow determination of the spatial patterns of synchronous CS activity. The first goal will be to investigate how CS responses to motor cortical activity are shaped by the oscillatory properties of the inferior olivary neurons. The second goal will be to test the hypothesis that the periodic synchronous discharges of the olivocerebellar system gate the efficacy cortical activity are shaped by the oscillatory properties of the inferior olivary neurons. The second goal will be to test the hypothesis that the periodic synchronous discharges of the olivocerebellar system gate the efficacy of motor cortex activity to generate movements. That is, to test the idea that the rhythmic nature of olivocerebellar activity allows it to function as a internal clock for organizing motor outputs in time. The third goal will be to determine the major brain sites where the interactions between these systems occur. Finally the question of whether changes in the patterns of synchronous discharge of the olivocerebellar system result in changes in the pattern of coupling of different muscles will be addressed. In sum, these experiments should help define the role of the olivocerebellar system in motor control as well as the reasons why cerebellar damage results in motor coordination deficits. They represent a step toward the more general goal of understanding cerebro-cerebellar interactions in motor control.

DESCRIPTION (provided by applicant): The experiments of this proposal will test the hypothesis that abnormally high levels of complex spike (CS) synchrony and rhythmicity in the olivocerebellar system underlie the tremor observed during alcohol withdrawal. This hypothesis is motivated by a series of findings. CS activity when normally synchronized is associated with coordinated movement, but when hypersynchronized causes tremors. These tremors show similarities to withdrawal tremor and can be antagonized by ethanol. Moreover, ethanol affects olivocerebellar firing rates, acutely and chronically, and our preliminary data suggests that acutely ethanol acts to suppress CS synchrony. These findings are in line with the general idea that ethanol acutely acts to depress brain activity in large part via a reduction of NMDA-mediated activity and/or an increase in GABA-A-mediated activity, and that with prolonged ethanol exposure, compensatory down and up regulation of GABA-A and NMDA functioning, respectively, occurs. Loss of GABA-A activity, in particular, in the inferior olive (IO), leads to hypersynchronized CS activity and tremor. Thus, we are led to the hypothesis that during withdrawal, abnormal neurotransmitter functioning in the IO leads to hypersynchronized CS activity that in turn causes tremor. There are two specific aims in this proposal related to testing this hypothesis. The first aim centers on using multiple electrode recording of CS activity during the withdrawal process to determine the patterns of CS synchrony and rhythmicity during withdrawal, and to correlate these patterns with the tremor characteristics. The second aim centers on establishing a causal link between olivocerebellar activity and the tremor's characteristics. To this end the characteristics of olivocerebellar activity will be pharmacologically manipulated using direct microinjections into the IO while EMG recordings are being made of the tremor in order to assess the resulting changes in muscle activity patterns. It is hoped that by using tremor as a tool for demonstrating that the olivocerebellar system is a site at which alcohol acts to cause movement abnormalities, the results of these initial studies will form a basis for future investigations into whether alcohol's action on olivocerebellar activity underlies, at least in part, alcohol's disruptive effects on motor coordination. The proposed experiments will provide information on the specific changes in brain activity that underlie alcohol withdrawal tremor, which may aid in designing new and more successful treatments not only for withdrawal symptoms, but for the motor coordination problems associated with acute and chronic alcohol use and abuse. In particular, demonstration of the olivocerebellar system as a target of alcohol's actions should increase our understanding of how alcohol affects motor coordination. With an estimated 17.6 million adults being either alcoholics or alcohol abusers with an increased risk of becoming alcoholics, alcoholism is clearly a major health problem in the United States. Moreover, with impaired motor coordination a major reason for alcohol being a factor in traffic accidents and deaths, understanding alcohol's actions on motor systems is of obvious medical significance.

? DESCRIPTION (provided by applicant): The traditional view of the cerebellum as being essential only for the control of movement is being increasingly challenged by findings that implicate it in cognitive and affective functions, and as a result, motor deficits that occur with cerebellar lesions are now being thought of in more generalized and extended forms as the basis of various cognitive and psychiatric disorders. Recent work indicates cognitive functions, and in particular, time perception, likely depend on interactions between the cerebellum and the prefrontal cortex; however, these interactions, and their derangement in disease states, are not understood. Recent anatomical studies have shown the lateral cerebellum, in particular, is strongly interconnected with other brain regions involved in processing temporal information (e.g., prefrontal cortex), and these pathways provide a substrate for the cerebellum's participation in a network involved in temporal information processing; however, little is known about the information conveyed from the cerebellum to other parts of this network. Thus, the goal of the proposed experiments is to investigate the function of the cerebellar-prefrontal cortical circuits in timing behavior to provide a basis for understanding how cerebellar damage leads to cognitive deficits. The cerebellum is thought to be critical for temporal processing, particularly for short durations (<1 second); however, decisions based on this temporal information require prefrontal cortex involvement. Thus, there must be a dedicated system involving the transfer of this information from cerebellum to the prefrontal cortex. We will investigate how the cerebellum encodes temporal information about a stimulus and how it transfers this information to the prefrontal cortex for storage in working memory and ultimately for making decisions. In addition, we will investigate whether continued cerebellar input is necessary for the proper functioning of the prefrontal circuits involved in working memory and decision-making. To address these issues we will use rodents trained to discriminate stimuli based on temporal (duration) and nontemporal (e.g., pitch of a tone) characteristics. In the first aim, optogenetic techniques will be used to manipulate in a precisely timed manner the actual signals (i.e., the activity of the dentate nucleus cells) that leave the cerebellum in order to investigate the effects on the timing judgments of the animal. The resulting alterations in behavior should provide information about how the cerebellum computes temporal information, when it transfers that information to the prefrontal cortex, and whether cerebellar activity affect memory processes in the prefrontal cortex. In the second aim we will obtain extracellular recordings of the activity of the dentate nuclear neurons during performance of the task to investigate the specific encoding of temporal information by the cerebellum. Such information would significantly improve our understanding of how the cerebellum and cerebrum interact, and of how dysfunction of the cerebellum and prefrontal cortex leads to a variety of neurological and psychiatric disorders and diseases.