The experiments proposed here will determine and compare the organization of divergent axonal projections which arise from the midbrain raphe nuclei, locus coeruleus, and trigeminal nuclei. Recently developed, sensitive double retrograde axonal tracing techniques will be employed using the tracers wheat germ agglutinin (WGA), N-[acetyl-3H] and WGA conjugated to horseradish peroxidase (HRP) as well as fluorescent tracers in paired injection strategies within projection targets of these brainstem neuronal groups to reveal the order of their collateralized and unbranched axonal projections. Light and fluorescence microscopic analysis of tissue sections from these studies will determine differences or similarities that exist in the organization of divergent axonal projections arising from brainstem monoaminergic neurons versus those which arise from sensory relay neurons of the midbrain and medullary trigeminal nuclei. Preliminary experiments have revealed that each CNS structure receiving midbrain raphe projections has its own unique representation within a topographically distinct portion of the raphe. It also appears that raphe-innervated structures possessing interconnections with each other are interrelated by a topographically distinct group of collaterilized raphe projection neurons. Correlative anterograde axonal tracing experiments using small injections of lectins within portions of the raphe, locus coeruleus, and trigeminal nuclei will reveal different patterns of topographical organization and geometric orderliness within target structures of these divergently projecting brainstem neurons. Locus coeruleus, raphe, and trigeminal neurons all project to the forebrain (e.g., thalamus and cerebral cortex), midbrain (e.g., tectum and mesencephalic reticular formation), hindbrain (e.g., cerebellum) and spinal sites. Studies proposed here which attempt to resolve the different plans for organizing brainstem neurons and their axonal projections to various central nervous system structures will reveal the ways in which brainstem neurons interrelate neuronal circuitries in such structures as the cerebral and cerebellar cortices. When these circuits are altered, usually a consequence of neuronal loss, central nervous system disease states such as Parkinson's Disease or Cerebral Palsy can follow. Understanding the development, maintenance, and interrelative schemes of brainstem-target circuitries will shed light on the cause and possible treatments for such diseases.
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