Ascending cerebellar output on its way to the cortex is processed in the thalamus, mainly in the ventral lateral nucleus (VL). In the primate, the role of the thalamus appears to be essentially more than a simple relay. A number of subcortical and cortical afferents converge in VL and a complex interneuronal circuitry is intimately involved in the processing of this information. Traditionally, VL has been implicated in manifestations of movement disorders such as Parkinsonian tremor and rigidity, but the mechanisms of this involvement remain unclear. Moreover, recent data point to the role of the cerebellum and its output to the cortex in cognition. Yet, in these modern concepts the thalamus is ignored mostly because of the lack of understanding of the role of thalamic circuitry in the processing of cerebellar information. The application proposes in-depth analysis of the anatomical organization of VL in the nonhuman primate. The studies focus on VL connections with different regions of neocortex (primary motor, premotor, prefrontal, posterier parietal and anterior cingulate), cerebellar nuclei (dentate, fastigial and posterior interpositus), and the spinal cord. The goals are to: (i) evaluate the topographic relationships of different inputs; (ii) evaluate the branching pattern of individual afferent fibers from each source and the size and density of their terminal fields: and (iii) determine the mode of termination of each system at the ultrastructural level. The major hypotheses to be tested are: (i) in the nonhuman primate VL, functionally different subregions exist that can be characterized by specific combinations of cortical and subcortical inputs; (ii) the mode of termination of afferents from individual cerebellar nuclei differ reflecting a specific role of each in movement control and cognition; and (iii) VL afferents from association cortices are involved in complex synaptic arrangements and this input is mediated by GABAergic local circuit neurons unlike the input from the primary motor cortex. Studies will be performed with neuroanatomical tracers, BDA and WGA-HRP, postembedding immunocytochemistry with GABA antibody, computer assisted charting of projection zones and tracing of individual fibers and their terminal fields, analysis of ultrathin serial sections and 3D computer reconstructions of synaptic boutons with associated postsynaptic elements. The study will yield unique information for understanding the mechanisms of interaction between corticothalamic, cerebellothalamic and spinothalamic afferents in VL, and thereby be an essential background against which abnormalities expressed as movement disorders can be assessed. Moreover, the same data will provide insights for the manner in which thalamic nuclei may contribute to """"""""cognition"""""""" and/or """"""""mental"""""""" activities within the context of complex behavior, both normal and abnormal.
