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Reduction in parvalbumin expression in the zona incerta after 6OHDA lesion in rats

  • Published:
Journal of Neurocytology

Abstract

In an effort to understand better the neurochemical changes that occur in Parkinson disease, we have examined the expression patterns of the calcium-binding protein parvalbumin in the zona incerta in parkinsonian rats. Sprague-Dawley rats had small volumes of either saline (control) or 6 hydroxydopamine (6OHDA) injected into the medial forebrain bundle, the major tract carrying dopaminergic nigrostriatal axons. After various post-lesion survival periods, ranging from 2 hrs to 84 days, rats were perfused with formaldehyde and their brains processed for routine tyrosine hydroxylase (TH) or parvalbumin immunocytochemistry. In the 3 to 84 days post-lesion cases, there was an overall 50% reduction in the number of parvalbumin+ cells in the zona incerta on the 6OHDA-lesioned side when compared to control. In the 2 hrs post-lesion cases, there was no substantial loss of parvalbumin+ cells in the zona incerta after 6OHDA lesion, although in these cases (unlike the longer survival periods), there was limited loss of TH+ cells in the midbrain on the lesion side. The loss of parvalbumin+ cells from the zona incerta was due to a loss of antigen expression rather than a loss of the cells themselves, since the number of Nissl-stained cells in the zona incerta was similar on the control and 6OHDA-lesioned sides. In summary, our results indicate that a loss of the midbrain dopaminergic cells induces a major change in parvalbumin expression within the zona incerta. This change may have key functional and clinical implications.

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Abbreviations

6OHDA:

6 hydroxydopamine

cp:

cerebral peduncle

CPu:

caudate-putamen complex

GP:

globus pallidus

Hb:

habenular complex

IL:

intralaminar nuclei

LG:

lateral geniculate complex

LH:

lateral hypothalamus

mfb:

medial forebrain bundle

ml:

medial lemniscus

PBS:

phosphate buffered saline

Pf:

parafascicular nucleus

Po:

posterior thalamic nucleus

Pv:

parvalbumin

SC:

superior colliculus

SNc:

substantia nigra pars compacta

Sub:

subthalamus

R:

red nucleus

TH:

tyrosine hydroxylase

VP:

ventral posterior nucleus

VTA:

ventral tegmental area

ZI:

zona incerta

References

  • ALUSI, S. H., WORTHINGTON, J., GLICKMAN, S. & BAIN, P. G. (2001) A study of tremor in multiple sclerosis. Brain 124, 720–730.

    Article  PubMed  CAS  Google Scholar 

  • BARKER, D. A. & DREHER, B. (1998) Spatiotemporal patterns of ontogenetic expression of parvalbumin in the superior colliculi of rats and rabbits. Journal of Comparative Neurology 393, 210–230.

    Article  PubMed  CAS  Google Scholar 

  • BLANDINI, F., NAPPI, G., TASSORELLI, C. & MARTIGNONI, E. (2000) Functional changes of the basal ganglia circuitry in Parkinson's disease. Progress in Neurobiology 6, 63–88.

    Article  Google Scholar 

  • BREIT, S., BOUALI-BENAZZOUZ, R., BENABID, A.L. & BENAZZOUZ, A. (2001) Unilateral lesion of the nigrostriatal pathway induces an increase of neuronal activity of the pedunculopontine nucleus, which is reversed by the lesion of the subthalamic nucleus in the rat. European Journal of Neuroscience 14, 1833–1842.

    Article  PubMed  CAS  Google Scholar 

  • BROOKS, B. A., FUCHS, A. F. & FINOCCHIO, D. (1986) Saccadic eye movement deficits in the MPTP monkey model of Parkinson's disease. Brain Research 383, 402–407.

    Article  PubMed  CAS  Google Scholar 

  • BURBAUD, P., GROSS, C., BENAZZOUZ, A., COUSSEMACQ, M. & BIOULAC, B. (1995) Reduction of apomorphine-induced rotational behaviour by subthalamic lesion in 6-OHDA lesioned rats is associated with a normalization of firing rate and discharge pattern of pars reticulata neurons. Experimental Brain Research 105, 48–58.

    Article  CAS  Google Scholar 

  • CELIO, M. R. (1990) Calbindin D-28k and parvalbumin in the rat nervous system. Neuroscience 35, 375–475.

    Article  PubMed  CAS  Google Scholar 

  • CHARD, P. S., JORDAN, J., MARCUCCILLI, C. J., MILLER, R. J., LEIDEN, J. M., ROOS, R. P. & GHADGE, G. D. (1995) Regulation of excitatory transmission at hippocampal synapses by calbindin D28k. Proceedings National Academy of Science USA 92, 5144–5148.

    Article  CAS  Google Scholar 

  • CHRITIN, M., FEUERSTEIN, C. & SAVASTA, M. (1993) Time-course of changes in striatal levels of DA uptake sites, DA D2 receptor and preproenkephalin mRNAs after nigrostriatal dopaminergic denervation in the rat. Brain Research 19, 318–22.

    Article  PubMed  CAS  Google Scholar 

  • CROSSMAN, A. R., MITCHELL, I. J. & SAMBROOK, M. A. (1985) Regional brain uptake of 2-deoxyglucose in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the macaque monkey. Neuropharmacology 24, 587–591.

    Article  PubMed  CAS  Google Scholar 

  • DECKER, D. E., ALTHAUS, J. S., BUXSER, S. E., VONVOIGTLANDER, P. F. & RUPPEL, P. L. (1993) Competitive irreversible inhibition of dopamine uptake by 6-hydroxydopamine. Research Communication Chemical Pathology Pharmacology 79, 195–208.

    CAS  Google Scholar 

  • DEKKERS, J., GREENSMITH, L. & NAVARRETE, R. (2002) Changes in the expression of parvalbumin immunoreactivity in the lumbar spinal cord of the rat following neonatal nerve injury. Developmental Neuroscience 24, 283–293.

    Article  PubMed  CAS  Google Scholar 

  • DELFS, J. M., CIARAMITARO, V. M., PARRY, T. J. & CHESSELET, M. F. (1995) Subthalamic nucleus lesions, widespread effects on changes in gene expression induced by nigrostriatal dopamine depletion in rats. Journal of Neuroscience 15, 6562–6575.

    PubMed  CAS  Google Scholar 

  • DREHER, B., BARKER, D. A., BATH, M. R. & KEAY, K. A. (1996) Spatiotemporal pattern of ontogenetic expression of calbindin-28/kD in the retinorecipient layers of rat superior colliculus. Journal of Comparative Neurology 376, 223–240.

    Article  PubMed  CAS  Google Scholar 

  • EYLES, D. W., MCGRATH, J. J. & REYNOLDS, G. P. (2002) Neuronal calcium-binding proteins and schizophrenia. Schizophrenia Research 57, 27–34.

    Article  PubMed  CAS  Google Scholar 

  • FELDMAN, D., SHERIN, J. E., PRESS, W. A. & BEAR, M. F. (1990) N-methyl-D-aspartate-evoked calcium uptake by kitten visual cortex maintained in vitro. Experimental Brain Research 80, 252–259.

    Article  CAS  Google Scholar 

  • GUNLUK, A. E., BICKFORD, M. E. & SHERMAN, S. M. (1994) Rearing with monocular lid suture induces abnormal NADPH-diaphorase staining in the lateral geniculate nucleus of cats. Journal of Comparative Neurology 350, 215–228.

    Article  PubMed  CAS  Google Scholar 

  • HASSANI, O. K., MOUROUX, M. & FEGER, J. (1996) Increased subthalamic neuronal activity after nigral dopaminergic lesion independent of disinhibition via the globus pallidus. Neuroscience 72, 105–115.

    Article  PubMed  CAS  Google Scholar 

  • HEISE, C. E. & MITROFANIS, J. (2004) Evidence for a glutamatergic projection from the zona incerta to the basal ganglia in rats. Journal of Comparative Neurology 468, 482–495.

    Article  PubMed  CAS  Google Scholar 

  • HENDERSON, J. M., PELL, M., O'SULLIVAN, D. J., MCCUSKEY, E. A., FUNG, V. S., PHEDGES, B. & HALLIDAY, G. M. (2002) Postmortem analysis of bilateral subthalamic electrode implants in Parkinson disease. Movement Disorders 17, 133–137.

    Article  PubMed  Google Scholar 

  • JEON, M. F., HA, Y., CHO, Y. H., LEE, B. H., PARK, Y. G. & CHANG, J. W. (2003) Effect of ipsilateral subthalamic nucleus lesioning in a rat parkinsonian model: Study of behaviour correlated with neuronal activity in the pedunculopontine nucleus. Journal of Neurosurgery 99, 762–767.

    PubMed  Google Scholar 

  • KATO, M., MIYASHITA, N., HIKOSAKA, O., MATSUMURA, M., USUI, S. & KORI, A. (1995) Eye movements in monkeys with local dopamine depletion in the caudate nucleus I Deficits in spontaneous saccades. Journal of Neuroscience 15, 12–27.

    Google Scholar 

  • KAWANA, E. & WATANABE, K. (1981) A cytoarchitectonic study of zona incerta in the rat. Journal of Hirnforsch 22, 535–541.

    CAS  Google Scholar 

  • KINCAID, A. E., ALBIN, R. L., NEWMAN, S. W., PENNEY, J. B. & YOUNG, A. B. (1992) 6-Hydroxydopamine lesions of the nigrostriatal pathway alter the expression of glutamate decarboxylase messenger RNA in the rat globus pallidus. Neuroscience 51, 705–718.

    Article  PubMed  CAS  Google Scholar 

  • KOHR, G., LAMBERT, C. E. & MODY, I. (1991) Calbindin-D28K (CaBP) levels and calcium currents in acutely dissociated epileptic neurons. Experimental Brain Research 85, 543–545.

    CAS  Google Scholar 

  • KOLMAC, C. I. & MITROFANIS, J. (1999) Distribution of various neurochemicals within zona incerta: An immunocytochemical and histochemical study. Anatomy and Embryology 199, 265–280.

    Article  PubMed  CAS  Google Scholar 

  • KOLMAC, C. I., POWER, B. D. & MITROFANIS, J. (1998) Patterns of connections between the zona incerta and brainstem in rats. Journal of Comparative Neurology 396, 544–555.

    Article  PubMed  CAS  Google Scholar 

  • KORI, A., MIYASHITA, N.,KATO, M., HIKOSAKA, O. & USUI, S. (1995) Matsumura M Eye movements in monkeys with local dopamine depletion in the caudate nucleus II Deficits in voluntary saccades. Journal of Neuroscience 15, 928–941.

    PubMed  CAS  Google Scholar 

  • MA, T. P. (1996) Saccade-related omnivectoral pause neurones in the primate the zona incerta. Neuroreport 7, 2713–2716.

    PubMed  CAS  Google Scholar 

  • MARTORANA, A., FUSCO, F. R., D'ANGELO, V., SANCESARIO, G. & BERNARDI, G. (2003) Enkephalin, neurotensin, and substance P immunoreactive neurones of the rat GP following 6-hydroxydopamine lesion of the substantia nigra. Experimental Neurology 183, 311–319.

    Article  PubMed  CAS  Google Scholar 

  • MATTSON, M. P., RYCHLIK, B., YOU, J. S. & SISKEN, J. E. (1991) Sensitivity of cultured human embryonic cerebral cortical neurons to excitatory amino acid-induced calcium influx and neurotoxicity. Brain Research 542, 97–106.

    Article  PubMed  CAS  Google Scholar 

  • MAY, P. J., SUN, W. & HALLS, W. C. (1997) Reciprocal connections between the zona incerta and the pretectum and superior colliculus of the cat. Neuroscience 77, 1091–1114.

    Article  PubMed  CAS  Google Scholar 

  • MITROFANIS, J. & MIKULETIC, L. (1999) Organisation of the cortical projection to the zona incerta of the thalamus. Journal of Comparative Neurology 412, 173–185.

    Article  PubMed  CAS  Google Scholar 

  • MITROFANIS, J. (2004) Some certainty for the “zone of uncertainty”? Exploring the function of the zona incerta. Neuroscience 30, 1–15.

    Google Scholar 

  • MOK, D. & MOGENSON, G. J. (1986) Contribution of zona incerta to osmotically induced drinking in rats. American Journal of Physiology 251, 823–832.

    Google Scholar 

  • MOSCHOVAKIS, A. K. (1996) The superior colliculus and eye movement control. Current Opinion in Neurobiology 6, 811–816.

    Article  PubMed  CAS  Google Scholar 

  • MUNDINGER, F. (1965) Stereotaxic interventions on the zona incerta area for treatment of extrapyramidal motor disturbances and their results. Confin Neurology 26, 222–230.

    CAS  Google Scholar 

  • MURER, M. G., RIQUELME, L. A., TSENG, K. Y. & PAZO, J. H. (1997) Substantia nigra pars reticulata single unit activity in normal and 60HDA-lesioned rats: Effects of intrastriatal apomorphine and subthalamic lesions. Synapse 27, 278–293.

    Article  PubMed  CAS  Google Scholar 

  • NANDI, D., CHIR, M., LIU, X., BAIN, P., PARKIN, S., JOINT, C., WINTER, J., STEIN, J.F., SCOTT, R., GREGORY, R. & AZIZ, T. (2002a) Electrophysiological confirmation of the zona incerta as a target for surgical treatment of disabling involuntary arm movements in multiple sclerosis: Use of local field potentials. Journal of Clinical Neuroscience 9, 64–68.

    Article  CAS  Google Scholar 

  • NANDI, D., AZIZ, T. Z., LIU X. & STEIN, J. F. (2002b) Brainstem motor loops in the control of movement. Movement Disorders 17, S22–S27.

    Article  Google Scholar 

  • NI, Z., BOUALI-BENAZZOUZ, R., GAO, D., BENABID, A. L. & BENAZZOUZ, A. (2000) Changes in the firing pattern of globus pallidus neurons after the degeneration of nigrostriatal pathway are mediated by the subthalamic nucleus in the rat. European Journal of Neuroscience 12, 4338–4344.

    Article  PubMed  CAS  Google Scholar 

  • NICOLELIS, M. A., CHAPIN, J. K. & LIN, R. C. (1992) Somatotopic maps within the zona incerta relay parallel GABAergic somatosensory pathways to the neocortex, superior colliculus and brainstem. Brain Research 577, 134–141.

    Article  PubMed  CAS  Google Scholar 

  • NICOLELIS, M. A., CHAPIN, J. K. & LIN, R. C. (1995) Development of direct GABAergic projections from the zona incerta to the somatosensory cortex of the rat. Neuroscience 65, 609–631.

    Article  PubMed  CAS  Google Scholar 

  • ORIEUX, G., FRANCOIS, C., FEGER, J., YELNIK, J., VILA, M., RUBERG, M., AGID, Y. & HIRSCH, E.C. (2000) Metabolic activity of excitatory parafascicular and pedunculopontine inputs to the subthalamic nucleus in a rat model of Parkinson's disease. Neuroscience 97, 79–88.

    Article  PubMed  CAS  Google Scholar 

  • ORIEUX, G., FRANCOIS, C., FEGER, J. & HIRSCH, E. C. (2002) Consequences of dopaminergic denervation on the metabolic activity of the cortical neurons projecting to the subthalamic nucleus in the rat. Journal of Neuroscience 22, 8762–8770.

    PubMed  CAS  Google Scholar 

  • PAHAPILL, A. P. & LOZANO, A. M. (2000) The pedunculopontine nucleus and Parkinson disease. Brain 123, 1767–1783.

    Article  PubMed  Google Scholar 

  • PAN, H. S. & WALTERS, J. R. (1988) Unilateral lesion of the nigrostriatal pathway decreases the firing rate and alters the firing pattern of globus pallidus neurons in the rat. Synapse 2, 650–656.

    Article  PubMed  CAS  Google Scholar 

  • PARENT, A. (1996) Carpenters Human Neuroanatomy. 9th edn, Williams and Wilkins PA USA.

    Google Scholar 

  • PEDNEAULT, S. & SOGHOMONIAN, J. J. (1994) Glutamate decarboxylase (GAD65) mRNA levels in the striatum and pallidum of MPTP-treated monkeys. Molecular Brain Research 25, 351–354.

    Article  PubMed  CAS  Google Scholar 

  • PELLED, G., BERGMAN, H. & GOELMAN, G. (2002) Bilateral overactivation of the sensorimotor cortex in the unilateral rodent model of Parkinson's disease—a functional magnetic resonance imaging study. European Journal of Neuroscience 15, 389–394.

    Article  PubMed  Google Scholar 

  • PÈRIER, C., MIQUELL, V., JEAN, F., YVES, A. & ETIENNE, C. H. (2000) Functional activity of zona incerta neurons is altered after nigrostriatal denervation in hemiparkinsonian rats. Experimental Neurology 162, 215–224

    Article  PubMed  Google Scholar 

  • POWER, B. D. & MITROFANIS, J. (2001) Zona incerta: Substrate for contralateral interconnectivity in the thalamus of rats. Journal of Comparative Neurology 436, 52–63.

    Article  PubMed  CAS  Google Scholar 

  • RICARDO, J. A. (1981) Efferent connections of subthalamic region in rat II The zona incerta. Brain Research 214, 43–60

    Article  PubMed  CAS  Google Scholar 

  • ROBLEDO, P. & FEGER, J. (1991) Acute monoaminergic depletion in the rat potentiates the excitatory effect of the subthalamic nucleus in the substantia nigra pars reticulata but not in the pallidal complex. J Neural Trans 86, 115–126.

    Article  CAS  Google Scholar 

  • ROGER, M. & CADUSSEAU, J. (1985) Afferents to the zona incerta in the rat: a combined retrograde and anterograde study. Journal of Comparative Neurology 241, 480–492.

    Article  PubMed  CAS  Google Scholar 

  • ROMANOWSKI, C. A., J, MITCHELL. I. J. & CROSSMAN, A. R. (1985) The organisation of the efferent projections of the zona incerta. Journal of Anatomy 143, 75–95.

    PubMed  CAS  Google Scholar 

  • SCHALL, J. D. (1995) Neural basis of saccade target selection. Review in Neuroscience 6, 63–85.

    CAS  Google Scholar 

  • SCHOBER, A. (2004) Classic toxin-induced animal models of Parkinson's disease: 6-OHDA and MPTP. Cell and Tissue Research 318, 215–224.

    Article  PubMed  Google Scholar 

  • SCHROEDER, J. A. & SCHNEIDER, J. S. (2001) Alterations in expression of messenger RNAs encoding two isoforms of glutamic acid decarboxylase in the globus pallidus and entopeduncular nucleus in animals symptomatic for and recovered from experimental parkinsonism. Brain Research 888, 180–183.

    Article  PubMed  CAS  Google Scholar 

  • SCHULLER, J. J. & MARSHALL, J. F. (2000) Acute immediate-early gene response to 6-hydroxydopamine infusions into the medial forebrain bundle. Neuroscience 96, 51–58.

    Article  PubMed  CAS  Google Scholar 

  • SCHULLER, J. J., BILLINGS, L. M. & MARSHALL, J. F. (1999) Dopaminergic modulation of pallidal preproenkephalin mRNA. Brain Research 69, 149–153.

    Article  PubMed  CAS  Google Scholar 

  • SCHULTZ, W., ROMO, R., SCARNATI, E., SUNDSTROM, E., JONSSON, G. & STUDER, A. (1989) Saccadic reaction times, eye-arm coordination and spontaneous eye movements in normal and MPTP-treated monkeys. Experimental Brain Research 78, 253–267.

    Article  CAS  Google Scholar 

  • SHAMMAH-LAGNADO, S. J., NEGRAO, N. & RICARDO, J. A. (1985) Afferent connections of the zona incerta: A horseradish peroxidase study in the rat. Neuroscience 15, 109–134.

    Article  PubMed  CAS  Google Scholar 

  • SHIBASAKI, H., TSUJI, S. & KUROIWA, Y. (1979) Oculomotor abnormalities in Parkinson's disease. Archive in Neurology 36, 360–364.

    CAS  Google Scholar 

  • SKINNER, R. D., KINJO, N., HENDERSON, V. & GARCIA-RILL, E. (1990) Locomotor projections from the pedunculopontine nucleus to the spinal cord. Neuroreport 1, 183–186.

    Article  PubMed  CAS  Google Scholar 

  • SOGHOMONIAN, J. J. & CHESSELET, M. F. (1992) Effects of nigrostriatal lesions on the levels of messenger RNAs encoding two isoforms of glutamate decarboxylase in the globus pallidus and entopeduncular nucleus of the rat. Synapse 11, 124–133.

    Article  PubMed  CAS  Google Scholar 

  • SOGHOMONIAN, J. J., PEDNEAULT, S., AUDET, G. & PARENT, A. (1994) Increased glutamate decarboxylase mRNA levels in the striatum and pallidum of MPTP-treated primates. Journal of Neuroscience 14, 6256–6265.

    PubMed  CAS  Google Scholar 

  • SOGHOMONIAN, J. J. & LAPRADE, N. (1997) Glutamate decarboxylase (GAD67 and GAD65) gene expression is increased in a subpopulation of neurons in the putamen of Parkinsonian monkeys. Synapse 27, 122–132.

    Article  PubMed  CAS  Google Scholar 

  • STEINER, H. & KITAI, S. T. (2001) Unilateral striatal dopamine depletion: Time-dependent effects on cortical function and behavioural correlates. European Journal of Neuroscience 14, 1390–1440.

    Article  PubMed  CAS  Google Scholar 

  • TERESHCHENKO, L. V., YUDIN, A. G., KUZNETSOV, Y., LATANOV, A. V. & SHUL'GOVSKII, V. V. (2002) Disturbances of saccadic eye movements in monkeys during development of MPTP-induced syndrome. Bulletin Experimental Biological Medicine 133, 182–184.

    Article  CAS  Google Scholar 

  • VOGES, J., VOLKMANN, J., ALLERT, N., LEHRKE, R., KOULOUSAKIS, A., FREUND, H. J. & STURM, V. (2002) Bilateral high-frequency stimulation in the subthalamic nucleus for the treatment of Parkinson Disease: Correlation of therapeutic effect with anatomical electrode position. Journal of Neurosurgery 96, 269–279.

    Article  PubMed  Google Scholar 

  • WAGNER, C. K., EATON, M. J., MOORE, K. E. & LOOKINGLAND, K. J. (1995) Efferent projections from the region of the medial zona incerta containing A13 dopaminer gic neurones: A PHA-L anterograde tract-tracing study in the rat. Brain Research 677, 229–237.

    Article  PubMed  CAS  Google Scholar 

  • WATANABE, K. & KAWANA, E. (1982) The cells of origin of incertofugal projections to the tectum, thalamus, tegmentum, and spinal cord in rat: A study using autoradiographic and horseradish peroxidase methods. Neuroscience 10, 2389–2406.

    Article  Google Scholar 

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  1. Department of Anatomy & Histology, University of Sydney, Australia

    Claire E. Heise & John Mitrofanis

  2. Medical School, Australian National University, Australia

    John Mitrofanis

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  1. Claire E. Heise
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  2. John Mitrofanis
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Correspondence to John Mitrofanis.

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Grant Sponsors: Tenix Corp and Salteri Family.

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Heise, C.E., Mitrofanis, J. Reduction in parvalbumin expression in the zona incerta after 6OHDA lesion in rats. J Neurocytol 34, 421–434 (2005). https://doi.org/10.1007/s11068-006-8728-y

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