Our long-term objective is to reveal the neural mechanisms responsible for sensation. In the near-term, proposed studies will uncover neural circuits that are required for the sense of touch and its """"""""state-dependent"""""""" modulation. The rodent trigeminal (V) system, particularly those portions devoted to the whiskers, has advantages over other systems for addressing mechanisms underlying sensation; namely, a readily visualized and stringent point-to-point topography, stereotypy in single cell structure and function, high innervation density, convenient access to relevant structures, digitized and lever-like receptor organs for quantitative stimulus control, a plethora of thickly myelinated axons that are readily impaled in vivo for recording and staining, and very precise rules governing its development. As such, the """"""""whisker-to-barrel"""""""" neuraxis is a valuable and widely used model system for revealing general principles underlying CNS information processing, pattern formation and plasticity. While a great deal is known about the anatomical, physiological and chemical substrates for information processing in the barrel thalamus and cortex, interpretation of these data is often hampered by a paucity of like data on fundamental features of the brainstem link in this pathway: V nucleus principalis (PrV), the V homolog of the dorsal column nucleus. This gap in our knowledge therefore limits our current understanding of the neural bases for whisker-related tactile sensitivity and discrimination. To fill this gap, proposed experiments address the following questions: (1) How are the terminal clusters of identified V primary afferents distributed relative to each other and to whisker- related """"""""columns"""""""" in PrV? (2) How are dendrites of subclasses of PrV cells, and axon arbors of identified spinal V local circuit neurons, distributed relative to whisker-related """"""""columns"""""""" in PrV? (3) In PrV, is parvalbumin immunoreactivity specific to thalamic-projecting cells with single-whisker receptive fields? (4) In the spinal V nucleus, is calbindin immunoreactivity specific to thalamic-projecting cells with multi-whisker receptive fields? (5) Are synaptic terminals from identified primary afferents, the spinal V nucleus, cerebral cortex and local GABAergic neurons differentially distributed on thalamic-projecting PrV cells, and do these terminals have distinct morphologies? (6) Are the receptive fields of PrV cells affected by inputs from spinal V, cortical and GABAergic neurons, and what are their respective modulatory functions? A multidisciplinary set of experiments is offered to test specific hypothesis derived from the above-listed questions and an evolving model of PrV circuitry. They employ methods such as intracellular multiple labeling of physiologically identified axons and cells, simultaneous staining and confocal rendering of whisker-related """"""""columns"""""""", microintophoresis, and computer-assisted analyses of neuronal response- structure-connectivity relationships. The applicant team has experience with all of these methods and a record of effective collaboration. These studies will uncover general rules governing somatosensation in humans because of recent indications that primates have barrel-like cell and fiber aggregations in subcortical somatosensory nuclei, including PrV.
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