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Rick C. S. Lin, Ph.D.Professor
of Anatomy
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Rick C. S. Lin, Ph.D.Professor
of Anatomy
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Ph.D., Vanderbilt University, 1976 |
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A. Network Processing of Information The functional role of the GABAergic pathway from the zona incerta to the neocortex and superior colliculus. Recently, we made a surprising discovery that GABAergic neurons in the zona incerta (ZI) of the ventral thalamus project widely throughout the neocortex. In addition, we found that this GABAergic incerto-cortical pathway develops very early and may even be present pre-natally. Based on evidence from several different approaches, we hypothesize that: 1) GABA released from ZI axons may serve both a trophic and a neuromodulatory role in incertal target regions during early development; and 2) ZI may provide a tonic GABAergic inhibition to a wide spectrum of targets. This tonic inhibition is likely to gate neuronal recruitment or synchronization in the cortex, and may be involved in shifting attention/orientation through its connection with the visual midbrain. The role of ZI is being studied with extracellular and intracellular recordings using in vivo and in vitro preparations. Simultaneous, multi-neuron recording techniques are also being utilized to study the ensemble discharge properties of cells in the ZI, neocortex and tectal/pretectal nuclei. The anatomical and neurochemical organization of brainstem modulatory systems with respect to the ascending trigeminal somatosensory pathway.Recent studies have shown that the noradrenergic locus coeruleus (LC) and the serotonergic raphe nuclei may play important roles in modulating the neuronal responses of sensory neurons. Since these systems may regulate signal transmission along modality specific pathways via anatomically or neurochemically distinct efferent projections, we have characterized the spatial distribution and transmitter identity of perikarya and axons from these neuronal populations which innervate multiple functionally related structures along the rat ascending trigeminal somatosensory pathway. Fluorescent retrograde tracing strategies were utilized in conjunction with a variety of immunohistochemical techniques. Namely, we stained for NADPH-d, galanin (GAL), and GAD/GABA, because these substances are known to co-localize with either serotonin in the raphe complex or tyrosine hydroxylase/dopamine-B-hydroxylase (DBH) in the LC. These studies have shown that: 1) the raphe nuclear complex is topographically organized with respect to the rat trigeminal somatosensory and ventricular systems; 2) the major output from the LC to the somatosensory system follows the crossed trajectory of this modality specific system; 3) there is a propensity for individual LC neurons to send axon collaterals to neuronal ensembles engaged in similar sensory functions; 4) fine-caliber GAL (+) terminals are randomly distributed through out each trigeminal relay, while large-varicose GAL (+) fibers are only present along the medial border of the reticular thalamic nucleus, the dorsal aspect of the ZI, and laminae I/II of the spinal trigeminal nucleus caudalis; and 5) every GAL- immunoreactive fiber, which demonstrates a thin morpholological profile, co-stains for the noradrenergic marker enzyme, DBH. These findings suggest that upon activation the patterned outputs of these modulatory systems could coordinate the selective release of transmitter agents within functionally-related neuronal circuits. Our future goals will be to further examine the synaptic characteristics of coeruleo- and raphe- somatosensory axonal profiles; and 2) use physiological/pharmacological tools to better understand the interactions which occur in the terminal fields of these processes. B. Mechanisms of NeurodegenerationDendritic breakdown as an indicator of early pathogenesis after injury. We have recently reported that dendritic breakdown of microtubule associated protein 2 (MAP-2) is one of the earliest and most sensitive indicators of pathogenesis in the ischemic forebrain. The cellular mechanism of MAP-2 degeneration in selectively vulnerable neurons appears to be mediated by the calcium- activated neutral protease, calpain, and this process precedes neuronal death. We have also found that the beaded appearance of MAP-2 immunostained apical dendrites of CA1 hippocampal pyramidal cells precedes general dendritic morphological changes. This interesting finding was achieved by combining intracellular recording and dye injection with MAP-2 immunofluorescent staining in individual cells. Our future goals are to determine: 1) whether MAP-2 mRNA is down-regulated in the dendritic segments of the CA1 pyramidal cells after injury; 2) whether secondary excessive accumulation of calcium is the key element leading to dendritic breakdown and 3) whether treatment with calpain inhibitors can prevent excessive calcium accumulation and subsequent dendritic degradation of structural proteins. In situ hybridization and real time calcium confocal laser image techniques will be used to elucidate the cellular mechanism(s) of pathogenesis. Neuronal protection after ischemic insult.At present, clinical efforts to prevent stroke-induced injury and neurological disease remain unsuccessful. Our goal is to identify agents that have a protective capability, but minimal negative side effects. To this end, we have investigated the potential usefulness of agonists and antagonists to adenosine receptors. We have found, that the A3 receptor agonist, IB-MECA, potentiates ischemic injury, whereas the A3 receptor antagonist, MRS-1191, confers protection against ischemia-induced neuronal damage. Future experiments will be directed toward understanding the cellular mechanisms underlying the protective capacity of such compounds. |
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