Faculty Bibliography

The olivo-cerebellar network plays a key role in the organization of vertebrate motor control. The oscillatory properties of inferior olive (IO) neurons have been shown to provide timing signals for motor coordination in which spatio-temporal coherent oscillatory neuronal clusters control movement dynamics. Based on the neuronal connectivity and electrophysiology of the olivo-cerebellar network we have developed a general-purpose control approach, which we refer to as a universal control system (UCS), capable of dealing with a large number of actuator parameters in real time. In this UCS, the imposed goal and the resultant feedback from the actuators specify system properties. The goal is realized through implementing an architecture that can regulate a large number of parameters simultaneously by providing stimuli-modulated spatio-temporal cluster dynamics

Clearly, more clinical experience must be amassed to define in detail the possibilities of this surgical approach in disabling neuropsychiatric disorders. We propose, however, that the evidence for benign and efficient surgical intervention against the neuropsychiatric TCD syndrome is already compelling. The potential appearance of strong postoperative reactive manifestations requires a close association between surgery and psychotherapy, with the latter providing support for the integration of the new situation as well as the resolution of old unresolved issues

Oxidative stress is widely considered to be involved in the pathogenesis of various neurological disorders to include Alzheimer's disease. This stress is thought to include, in addition to cell death, neuronal dysfunctions such as neurotransmission deficits. Here, we examined H2O2-induced alterations of electrophysiological properties of Purkinje cell in acute cerebellar slices, and assessed the effects of several neuroprotective agents.Electrophysiological and fura-2 fluorescence imaging techniques were used to determine intercellular calcium concentration ((Ca2+)i). H2O2 (100 muM) reversibly reduced both holding current and EPSC amplitude in voltage clamped neurons, and produced, in addition, (Ca2+)i elevation. Both the antioxidant 2-mercaptoethanol and the neuroprotective/neurotrophic agent T-817 (1-\{3-(2-(1-benzothiophen-5-yl)ethoxy)propyl\}-3-azethidinol maleate), partially inhibit these physiological changes. We are presently investigating the mechanism for reactive oxygen spices alteration of neuronal properties, mitocondrial function, (Ca2+)i mobilization, and cell viability, in the presence of the T-817

Coordinated limb movements require the proper interaction between neuronal, muscular, and skeletal systems. The link between such systems may be addressed using mathematical models that simulate muscle contraction and that resulting joint rotations. A computer model for limb movement is presented that mimics muscle contraction and joint rotations as a function of motor neuron firing frequencies. The model generates angular changes in each joint with activation of a flexor-extensor muscle pair. The issue is that there are a large number of possible solutions to the generation of angular changes in a joint with muscle activation. This known as the over completeness problem We address it by proposing that in each joint only one of the muscles (the flexor or the extensor) is activated at a certain moment. The model considers the intersegmental joint angles, the lengths and masses of limb segments, the sites of muscle attachments, the force-length and force-frequency relationships of the muscles. The motor command for each muscle in each time interval is the firing rate of the muscle's motoneuron pool. This command generates angular motions in the joint. We apply the model to ankle muscle activities in two groups of swimming rats. One group spend 16 days in microgravity (flight) while the second group remained in the terrestrial environment. For both groups swimming was recorded on land. We computed firing rates of motoneuron pools to mimic joint angle changes that were recorded experimentally. The model predicts an increased firing rate for the muscles of the flight group. We propose that this is the result of the differences in motor control developed under different environmental conditions. The predicted higher firing rate is compatible with the observed higher flexions in the joints of the rats of the flight group

Calcium mobilization in cerebellar Purkinje cell (PC) of CD38 knockout mouse was imaged using two photon microscopy. CD38 is a homolog of ADP-ribosyl cyclase which activates Cyclic ADP-ribose, an endogenous Calcium Induced Calcium Release (CICR)regulator (Lee, 2001 ). In the CD38 knockout mouse (CD38(-/-)), which showed no phenotypic motor abnormalities, whole cerebellar cyclic ADP-ribose (cADPR) was reduced to a quarter of that in a wild control (CD38(+/+)). In addition caffeine treated CD38(-/-) PC dendrite showed a markedly reduced calcium response to a test depolarizing pulse most probably related to the reduced CICR. Cerebellar long-term depression (LTD) induced by the parallel fiber (PF) -climbing fiber (CF) conjunctional stimulation was absent in CD38(-/-) PC. However, during very prolonged direct depolarization of Purkinje cell somata, or when the test (PF) stimulation was quite close to the cell body during direct somatic depolarization, LTD could be induced in CD38(-/-) PC by the PF/depolarizing pulse conjunction. Overall, the CD38/cADPR system seems to be sensing/regulating intradendritic calcium levels. This seems to be an important modulator of the integrative properties of Purkinje cell activity. It seems clear that if (Ca)i becomes high enough to be deleterious to neuronal viability such system must be down regulated via LTD as a neuroprotective response to reduce further calcium increase. Immuno-staining study with a polyclonal CD38 antibody is presently in progress which is expected to find different levels of CD38 on the Purkinje cell soma, dendrites and spines of wild type mouse (CD38(+/+)) vs CD38 knockout cerebella