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  • Rick C.S. Lin, PhD

     lin, rick.jpg

    Professor
    Office: N723
    Phone: (601) 984-1665
    Lab: R722; Phone: (601) 984-1644
    Fax: (601) 984-1655
    E-mail: rlin@umc.edu

    Education

    • PhD - Vanderbilt University, 1976

    Major research interests

    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 prenatally. 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 morphological 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 neurodegeneration

    • Dendritic 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.

    Selected publications

    • Lin, C.-S., Nicolelis, M.A.L., Schneider, J.S., and Chapin, J.K. (1990) A major direct GABAergic pathway from zona incerta to neocortex. Science 248:1553-1556.
    • Nicolelis, M.A.L., Chapin, J.K., and Lin, R.C.S. (1992) Somatotopic maps within the zona incerta relay parallel GABAergic somatosensory pathways to the neocortex, superior colliculus, and brainstem. Brain Res. 577:134-141.
    • Nicolelis, M.A.L., Lin, R.C.S., Woodward, D.J., Chapin, J.K. (1993) Dynamic and distributed properties of many-neuron ensembles in the ventral posterior medial (VPM) thalamus of awake rats. Proc. Natl. Acad. Sci. 90:2212-2216.
    • Nicolelis, M.A.L., Lin, R.C.S., Woodward, D.J., and Chapin J.K. (1993) Peripheral block of ascending cutaneous information induces immediate spatio-temporal changes in thalamic networks. Nature 361:533-536.
    • Nicolelis, M.A.L., Baccala, L.A., Lin, R.C.S., and Chapin, J.K. (1995) Sensorimotor encoding by synchronous neural ensemble activity at multiple levels of the somatosensory system. Science 268:1353-1358.
    • Von Lubitz, D.K.J.E., Beenhakker, M., Lin, R.C.S., Carter, M.F., Paul, I.A., Bischofberger, N., and Jacobson, K.A. (1996) Reduction of postischemic brain damage and memory deficits following treatment with the selective adenosine A1 receptor agonist. Eur. J. Pharmacol. 302:43-48.
    • Simpson, K.L., Altman, D.W., Wang, L., Kirifides, M., Lin, R.C.S., and Waterhouse, B.D. (1997) Lateralization and functional organization of the locus coeruleus projection to the trigeminal somatosensory pathway in rat. J. Comp. Neurol. 385:135-147.
    • Lin, R.C.S., Matesic, D.F., and Connor, J.A. (1997) The role of dendritic dysfunction in neurodegeneration. Ann. N.Y. Acad. Sci. 825:134-145.
    • Simpson, K.L., Fisher, T.M., Lin, R.C.S., and Waterhouse, B.D. (1998) Projection patterns from the raphe nuclear complex to the ependymal wall of the ventricular system in the rat. J. Comp. Neurol. 399:61-72.
    • Connor, J.A., Razani-Boroujerdi, S., Greenwood, A.C., Cormier, R.J., Petrozzino, J.J., and Lin, R.C.S. (1999) Reduced voltage-dependent calcium signaling in CA1 neurons after brief ischemia in gerbils. J. Neurophysiol. 81:299-306.
    • Von Lubitz, D.K.J.E., Lin, R.C.S., Boyd, M., Bischofberger, N., Jacobson, K.A. (1999) Chronic administration of adenosine A3 receptor agonist and cerebral ischemia:neuronal and glial effects. Eur. J. Pharmacol. 367:157-163.
    • Simpson, K.L., Waterhouse, B.D., and Lin, R.C.S. (1999) Origin, distribution, and morphology of galaninergic fibers in the rodent trigeminal system. J. Comp. Neurol. 411:524-534.
    • Maciag, D., Simpson, K.L., Coppinger, D., Lu, Y.F., Wanf, Y., Lin, R.C.S. and Paul, I.A. (2006) Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry. Neuropsychopharmacology, 31:47-57.
    • Simpson, K.L. and Lin, R.C.S. (2006) Characterization of neurochemically specific projections from the locus coeruleus with respect to somatosensory-related barrels. The Anatomical Record, 288:166-173.
    • Perkins, E., Warren, S., Lin, R.C.S. and P.J. May. (2006) Projections of somatosensory cortex and frontal eye fields upon incertotectal neurons in the cat. The Anatomical Record 288A: 1310-1329.
    • Simpson, K.L. and Lin, R.C.S. (2007) Neuroanatomical and chemical organization of the locus coeruleus. In M. Schwartz., A. Frazer., and G. Ordway (eds.) Norepinephrine: Neurobiology and Therapeutics for the 21st Century (Cambridge University Press).
    • Simpson, K.L., Wang Yue and Lin, R.C.S. (2008) Patterns of convergence in rat zona incerta from the trigeminal nuclear complex: a light and electron microscopic study. J. Comp. Neurol., 507:1521-1541.
    • de Villers-Sidani, E., Simpson, K.L., Lu, Y-F., Lin, R.C.S., Merzenich, M.M. (online July 6th, 2008) Manipulating critical period closure across different sectors of the primary auditory cortex. Nature Neuroscience.
    • Fan, L-W., Chen, R-F., Mitchell, H.J., Lin, R.C.S., Simpson, K.L., Rhodes, P.G. and Cai, Z-W. (2008) alpha-phyenyl-n-tert-nitrone attenuates lipopolysaccharide-induced brain injury and improves neurological reflexes and early sensorimotor behavioral performance in juvenile rats. J. Neurosci. Res. 86:3536-3547.
    • Liao et al. (2010) Distribution of large terminal inputs from the primary and secondary somatosensory cortices to the dorsal thalamus in the rodent. J. Comp. Neurol 518: 2592-2611.