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  • Rick C.S. Lin, PhD

     lin, rick.jpg

    Professor, Neurobiology and Anatomical Sciences, Psychiatry and Human Behavior, Pediatrics|
    Executive Director, Center for Development Disorders Research (CDDR)
    Office: N723
    Phone: (601) 984-1665
    Lab: R722; Phone: (601) 984-1644
    Fax: (601) 984-1655
    E-mail: rlin@umc.edu

    Education

    • BA - Fu Jen Catholic University, Taipei, Taiwan, 1968, Biology
    • MA - Duke University, 1971, Marine Biology
    • PhD - Vanderbilt University, 1973-1976, Neuroanatomy, Advisor: Jon Kaas, PhD
    • Post-doctoral Fellow - University of Virginia, 1976-1979, Neurophysiology. Mentor: Murry Sherman, PhD

    Teaching responsibilities

    • Lecturer for Medical Neurobiology (medical students)
    • Lecturer for Foundation of Neuroscience (graduate students)

    Research interests

    • Sensory information processing
    • Cortical network wiring and re-wiring after insults
    • Developmental plasticity
    • Neurodegeneration and protection

    Research program

    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.

    C. Developmental Plasticity and Network Re-wiring

    Most recently, our laboratory has started attacking key issues related to serotonin dysfunction, development, and autism (ASD) in animal models, especially dealing with neonatal antidepressant exposure such as selective serotonin re-uptake inhibitors (SSRIs), and provided a firm foundation for further study of 5HT dysregulation during development. Finally, my laboratory has published numerous articles related to the cortical network mis-wiring and autistic-like behaviors after perinatal exposure to drugs such SSRIs (Simpson et al., Proc. Natl Acad. Sci. 108:18465-18470, 2011; our findings of this article was press released from NIMH). In particular,  our novel and preliminary findings include abnormal myelin formation of oligodendrocytes in the corpus callosum, as well as inflammatory responses of astrocytes and microglia after early exposures to either neurotoxin or SSRIs. The SSRIs early exposure projects were funded from one of the most prestigious NIH/EUREKA grant. Over the last few years, I edited a top selling book from CRC Press entitled “New concepts in Cerebral Ischemia”, and a special issue from Anatomical Record entitled “New Concepts in Developing Brain Disorders-Autism”. This special issue was highly cited by the Autism research community. Most recently, our novel findings suggested that extensive auditory behavioral training can reverse cortical network mis-wiring induced by early exposure to SSRIs (Zhou et al., Proc. Natl. Acad. Sci. 112:2233-2238, 2015). This very important finding provides us the hope that autistic patients may soon be able to reverse their deficits, if proper and intense therapy is enforced.

     

    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.
    • de Villers-Sidani, E., et al., Recovery of functional and structural age-related changes in the rat primary auditory cortex with operant training. Proc Natl. Acad. Sci., 107:13900-13905, 2010
    • Bortolato M., et al., Monoamine oxidase A and A/B knockout mice display autistic-like features. Int J Neuropsychopharmacology 16:869-888, 2013. doi: 10.1017/S1461145712000715
    • Alzghoul L., et al., Altered cerebellar organization and function in monoamine oxidase A hypomorphic mice. Neuropharmacology 63:1208-1217, 2012. doi:10.1159/000346156
    • Simpson, K.L. et al., Perinatal antidepressant exposure alters cortical network function in rodents. Proc. Natl. Acad. Sci., 108:18465-18470, 2011. doi: 10.1073/pnas.1109353108
    • Darling, R.D. et al., Perinatal citalopram exposure selectively increases locus ceruleus circuit function in male rats. J. of Neuroscience 31(46):16709-16715, 2011. doi: 10.1523/JNEUROSCI.3736-11.2011
    • Fan, L-W., et al., Dopaminergic neuronal injury in the adult rat brain following neonatal exposure to lipopolysaccharide and the silent neurotoxicity. Brain, Behavior, and Immunity 25:286-297, 2011. doi: 10.1016/j.bbi.2010.09.020
    • Fan, L-W. et al., Neonatal exposure to lipopolysaccharide enhances vulnerability of nigrostraital dopaminergic neurons to rotenone neurotoxicity in later life. Neurobiology of Disease 44:304-316, 2011. doi: 1.1016/j.nbd.2011.07.011
    • Zhang et al., Altered expression of tyrosine hydroxylase in the locus coeruleus noradrenergic system in citalopram neonatally exposed rats and monoamine oxidase A knock our mice. Anatomical Record 294: 1685-1697, 2011. doi: 10.1002/ar.21350
    • Weaver et al., Neonatal exposure to citalopram selectively alters the expression of the serotonin transporter in the hippocampus:dose-response effects. Anatomical Record 293:1920-1932, 2010. doi: 10.1002/ar.21245
    • Zhang Junlin, Dennis, K.A. Darling, R.D., Alzghoul, A, Paul, I.A., Simpson, K.L. Rick C.S. Lin (2013). Neonatal citalopram exposure decreases serotoninergic fiber density in the olfactory bulb of male but not female adult rats. Frontier in Cellular Neuroscience 7:article 67. doi: 10.3389/fncel.2013.00067
    • Zhengwei Cai, Lir-wan Fan, A. Kaizaki, Lu-Tai Tien, Tangeng Ma, Yi Pang, Shuying Lin, Rick C.S. Lin, K.L. Simpson (2013) Neonatal systematic exposure to lipopolysaccharide enhances susceptibility of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Developmental Neuroscience 35:155-171. doi:10.1159/000346156
    • Yi Pang, Lir-Wan Fan, Lu-Tai Tien, XueMei Dai, Baoying Zheng, Zhengwei Cai, Rick C.S. Lin, Abhay Bhatt (2013) Differential roles of astrocyte and microglia in supporting oligodendrocyte development and myelination in vitro. Brain and Behavior doi.10.1002/brb3.152.
    • Nidhi Khatri, K.L. Simpson, Rick Lin, I.A. Paul (2014) Lasting neurobehavioral abnormalities in rats after neonatal activation of serotonin 1A and 1B receptors: possible mechanisms for serotonin dysfunction in autistic spectrum disorders. Psychopharmacology 231:1191-1200 .
    • Zhou, Xiaoming, Jordan Y.F. Lu, Ryan D. Darling, Kimberly L. Simpson, Xiaoqing Zhu, Fang Wang, Liping Yu, Xinde Sun, Michael M. Merzenich and Rick C.S. Lin (2015) Behavioral training reverses global cortical network dysfunction induced by perinatal antidepressant exposure. Proc. Natl Acad. Sci. USA112: 2233-2238, 2015. doi:10.1073/pnas.1730682100
    • Fan, Lir-Wan, Abhay Bhatt, Lu-Tai, Tien, B. Zheng, Kimberly L. Simpson, Rick C.S. Lin, ZW Cai, Praveen Kumar, and Yi Pang. Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro. J. Neurochemistry, 133:532-543, 2015. doi: 10.1111/jnc.12988

    Current funding

    Currently active: 

    • R01 NIH NS080844 L-W, Fan (PI) - 7/1/2013-6/30/2018
      Title: Early life inflammation and vulnerability to neurodegeneration in late life
      Goal: To understand the biological mechanism of dopaminergic neurons responding to early and later insults
      Role: Co-I
    • R21 AG050049-01A1 F, Fan (PI)  - 10/01/2015-09/30/2017 (2% percentile)
      Title: Animal model of impaired autoregulation for study of age related vascular cognitive impairment
      Goal: To understand the biological mechanism of vascular regulation with neurodegeneration and memory impairment.
      Role: Co-I 

    Previous appointment

    • 1979-81 - Assistant Professor, Department of Cell Biology, University of Texas Health Science Center
    • 1981-87 -  Assistant Professor, Department of Anatomy, Duke University Medical Center
    • 1987-88 - Assistant Professor, Department of Neurobiology, Duke University Medical Center
    • 1988-92 - Associate Professor, Department of Physiology and Biophysics, Hahnemann University
    • 1992-94 - Professor, Department of Physiology and Biophysics, Hahnemann University
    • 1994-96 - Professor, Department of Neurobiology and Anatomy, Hahnemann University
    • 1996-98 - Professor, Department of Neurobiology and Anatomy, Allegheny University

    Accomplishments and honors

    • NIH and NSF grant reviewer since 1981
    • 2014 - M2 Professor of the Year
    • 2008-12 - NIH/EUREKA program project grant