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Pedunculopontine cell loss and protein aggregation direct microglia activation in parkinsonian rats

Abstract

We previously reported a loss of cholinergic neurons within the pedunculopontine tegmental nucleus (PPTg) in rats that had been intra-nigrally lesioned with the proteasomal inhibitor lactacystin, with levels of neuronal loss corresponding to that seen in the post-mortem pedunculopontine nucleus (PPN) of advanced Parkinson’s disease (PD) patients. Here we reveal lower expression values of the acetylcholine synthesising enzyme, choline acetyltransferase, within the remaining PPTg cholinergic neurons of lesioned rats compared to sham controls. We further characterise this animal model entailing dopaminergic- and non-dopaminergic neurodegeneration by reporting on stereological counts of non-cholinergic neurons, to determine whether the toxin is neuro-type specific. Cell counts between lesioned and sham-lesioned rats were analysed in terms of the topological distribution pattern across the rostro-caudal extent of the PPTg. The study also reports somatic hypotrophy in the remaining non-cholinergic neurons, particularly on the side closest to the nigral lesion. The cytotoxicity affecting the PPTg in this rat model of PD involves overexpression and accumulation of alpha-synuclein (αSYN), affecting cholinergic and non-cholinergic neurons as well as microglia on the lesioned hemispheric side. We ascertained that microglia within the PPTg become fully activated due to the extensive neuronal damage and neuronal death resulting from a lactacystin nigral lesion, displaying a distinct rostro-caudal distribution profile which correlates with PPTg neuronal loss, with the added implication that lactacystin-induced αSYN aggregation might trigger neuronophagia for promoting PPTg cell loss. The data provide critical insights into the mechanisms underlying the lactacystin rat model of PD, for studying the PPTg in health and when modelling neurodegenerative disease.

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Abbreviations

ACh:

Acetylcholine

αSYN:

Alpha-synuclein

ChAT:

Choline acetyltransferase

CR3:

Complement receptor type 3 receptor

CD11b:

Cluster of differentiation 11b

CV:

Coefficient of variation

CE:

Coefficient of error

CFV:

Cresyl fast violet

DBS:

Deep-brain stimulation

DAB:

3,3′-Diaminobenzidine

DPX:

Di-n-butyl-phthalate-xylene

DA:

Dopamine

EtOH:

Ethanol

GABA:

Gamma-aminobutyric acid

6-OHDA:

6-Hydroxydopamine

IHC:

Immunohistochemistry

ir:

Immunoreactive

i.p.:

Intraperitoneally

LDTg:

Laterodorsal tegmental nucleus

MFB:

Medial forebrain bundle

NeuN:

Neuronal-specific nuclear

NADPH:

Nicotinamide adenine dinucleotide phosphate

n/s:

Non-significant

NHS:

Normal horse serum

PD:

Parkinson’s disease

PPTg:

Pedunculopontine tegmental

PPN:

Pedunculopontine nucleus

PBS:

Phosphate buffered saline

PET:

Positron emission tomography

ROI:

Region of interest

RT:

Room temperature

SEM:

Standard error of the mean

SNpc:

Substantia nigra pars compacta

SNr:

Substantia nigra pars reticulata

TH:

Tyrosine hydroxylase

UPS:

Ubiquitin proteasomal system

VTA:

Ventral tegmental area

References

  1. Ahlskog JE (2005) Challenging conventional wisdom: the etiologic role of dopamine oxidative stress in Parkinson’s disease. Mov Disord 20:271–282

    PubMed  Article  Google Scholar 

  2. Alessandro S, Ceravolo R, Brusa L, Pierantozzi M, Costa A, Galati S et al (2010) Non-motor functions in parkinsonian patients implanted in the pedunculopontine nucleus: focus on sleep and cognitive domains. J Neurol Sci 289:44–48

    PubMed  Article  Google Scholar 

  3. Banati RB (2002) Visualising microglial activation in vivo. Glia 40:206–217

    PubMed  Article  Google Scholar 

  4. Baquet ZC, Williams D, Brody J, Smeyne RJ (2009) A comparison of model-based (2D) and design-based (3D) stereological methods for estimating cell number in the substantia nigra pars compacta (SNpc) of the C57BL/6J mouse. Neuroscience 161:1082–1090

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Batchelor PE, Liberatore GT, Wong JY, Porritt MJ, Frerichs F, Donnan GA, Howells DW (1999) Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci 19:1708–1716

    CAS  PubMed  Google Scholar 

  6. Beak SK, Hong EY, Lee HS (2010) Collateral projection from the forebrain and mesopontine cholinergic neurons to whisker-related, sensory and motor regions of the rat. Brain Res 1336:30–45

    CAS  PubMed  Article  Google Scholar 

  7. Benarroch EE (1999) Central neurotransmitters and neuromodulators in cardiovascular regulation. In: Mathias CJ, Bannister R (eds) Autonomic failure, 4th edn. Oxford University Press, Oxford, pp 37–44

    Google Scholar 

  8. Bevan MD, Bolam JP (1995) Cholinergic, GABAergic, and glutamate-enriched inputs from the mesopontine tegmentum to the subthalamic nucleus in the rat. J Neurosci 15:7105–7120

    CAS  PubMed  Google Scholar 

  9. Bir A, Sen O, Anand S, Khemka VK, Banerjee P, Cappai R (2014) α-Synuclein-induced mitochondrial dysfunction in isolated preparation and intact cells: implications in the pathogenesis of Parkinson’s disease. J Neurochem 131:868–877

    CAS  PubMed  Article  Google Scholar 

  10. Blackbeard J, O’Dea KP, Wallace VCJ, Segerdahl A, Pheby T, Takata M et al (2007) Quantification of the rat spinal microglial response to peripheral nerve injury as revealed by immunohistochemical image analysis and flow cytometry. J Neurosci Methods 164:207–217

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Bortolanza K, Wietzikoski EC, Boschen SL, Dombrowski PA, Latimer M, McLaren DA et al (2010) Functional disconnection of the substantia nigra pars compacta from the pedunculopontine nucleus impairs learning of a conditioned avoidance task. Neurobiol Learn Mem 94:229–239

    PubMed  PubMed Central  Article  Google Scholar 

  12. Boucetta S, Cisse Y, Mainville L, Morales M, Jones BE (2014) Discharge profiles across the sleep-waking cycle of identified cholinergic, GABAergic, and glutamatergic neurons in the pontomesencephalic tegmentum of the rat. J Neurosci 34:4708–4727

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. Braak H, Del TK, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    PubMed  Article  Google Scholar 

  14. Carman LS, Gage FH, Shults CW (1991) Partial lesion of the substantia nigra: relation between extent of lesion and rotational behaviour. Brain Res 553:275–283

    CAS  PubMed  Article  Google Scholar 

  15. Charara A, Smith Y, Parent A (1996) Glutamatergic inputs from the pedunculopontine nucleus to midbrain dopaminergic neurons in primates: Phaseolus vulgaris-leucoagglutinin anterograde labeling combined with post-embedding glutamate and GABA immunohistochemistry. J Comp Neurol 364:254–266

    CAS  PubMed  Article  Google Scholar 

  16. Clements JR, Grant S (1990) Glutamate-like immunoreactivity in neurons of the laterodorsal tegmental and pedunculopontine nuclei in the rat. Neurosci Lett 120:70

    CAS  PubMed  Article  Google Scholar 

  17. Colburn RW, DeLeo JA, Rickman AJ, Yeager MP, Kwon P, Hickey WF (1997) Dissociation of microglial activation and neuropathic pain behaviours following peripheral nerve injury in the rat. J Neuroimmunol 79:163–175

    CAS  PubMed  Article  Google Scholar 

  18. Datta S, Siwek DF (2002) Single cell activity patterns of pedunculopontine tegmentum neurons across the sleep-wake cycle in the freely moving rats. J Neurosci Res 70:611–621

    CAS  PubMed  Article  Google Scholar 

  19. Dugger BN, Murray ME, Boeve BF, Parisi JE, Benarroch EE, Ferman TJ et al (2012) Neuropathological analysis of brainstem cholinergic and catecholaminergic nuclei in relation to REM sleep behaviour disorder. Neuropathol Appl Neurobiol 38:142–152

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Faure JB, Maques-Carneiro JE, Akimana G, Cosquer B, Ferrandon A, Herbeaux K et al (2014) Attention and executive functions in a rat model of chronic epilepsy. Epilepsia 55:644–653

    PubMed  Article  Google Scholar 

  21. Fogel SM, Smith CT, Beninger RJ (2010) Increased GABAergic activity in the region of the pedunculopontine and deep mesencephalic reticular nuclei reduces REM sleep and impairs learning in rats. Behav Neurosci 124:79–86

    CAS  PubMed  Article  Google Scholar 

  22. Ford B, Holmes CJ, Mainville L, Jones BE (1995) GABAergic neurons in the rat pontomesencephalic tegmentum: co-distribution with cholinergic and other tegmental neurons projecting to the posterior lateral hypothalamus. J Comp Neurol 363:177–196

    CAS  PubMed  Article  Google Scholar 

  23. Fort P, Luppi PH, Jouver M (1993) Glycine immunoreactive neurons in the cat brain stem reticular formation. Neuroreport 4:1123–1126

    CAS  PubMed  Google Scholar 

  24. Gianetti P, Politis M, Su P, Turkheimer FE, Malik O, Keihaninejad S et al (2015) Increased PK11195-PET binding in normal-appearing white matter in clinically isolated syndrome. Brain 138:110–119

    Article  Google Scholar 

  25. Glezer I, Lapointe A, Rivest S (2006) Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries. FASEB J 20:750–752

    CAS  PubMed  Google Scholar 

  26. Gomez-Tortosa E, Newell K, Irizarry MC, Albert M, Growdon JH, Hyman BT (1999) Clinical and quantitative pathologic correlates of dementia with Lewy bodies. Neurology 53:1284–1291

    CAS  PubMed  Article  Google Scholar 

  27. Graeber MB, Banati RB, Streit WJ, Kreutzberg GW (1989) Immunophenotypic characterisation of rat brain macrophages in culture. Neurosci Lett 103:241–246

    CAS  PubMed  Article  Google Scholar 

  28. Gundersen HJG, Jensen EB (1987) The efficiency of systematic sampling in stereology and its prediction. J Microsc 147:229–263

    CAS  PubMed  Article  Google Scholar 

  29. Healy-Stoffel M, Ahmad SO, Stanford JA, Levant B (2012) A novel use of combined tyrosine hydroxylase and solver nucleolar staining to determine the effects of a unilateral intrastriatal 6-hydroxydopamine lesion in the substantia nigra: a stereological study. J Neurosci Methods 210:187–194

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 8:382–397

    CAS  PubMed  Article  Google Scholar 

  31. Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F (1987) Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci USA 84:5976–5980

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Hobson JA, Pace-Schott EF (2002) The cognitive neuroscience of sleep: neuronal systems, consciousness and learning. Nat Rev Neurosci 3:679–693

    CAS  PubMed  Article  Google Scholar 

  33. Hudson JL, van Horne CG, Strömberg I, Brock S, Clayton J, Masserano J et al (1993) Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats. Brain Res 626:167–174

    CAS  PubMed  Article  Google Scholar 

  34. Ichinohe N, Teng B, Kitai ST (2000) Morphological study of the tegmental pedunculopontine nucleus, substantia nigra and subthalamic nucleus, and their interconnections in rat organotypic culture. Anat Embryol (Berl) 201:435–453

    CAS  Article  Google Scholar 

  35. Jenkinson N, Nandi D, Aziz TZ, Stein JF (2005) Pedunculopontine nucleus: a new target for deep brain stimulation for akinesia. Neuroreport 16:1875–1876

    PubMed  Article  Google Scholar 

  36. Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53:S26–S36

    CAS  PubMed  Article  Google Scholar 

  37. Jia HG, Yamuy J, Sampogna S, Morales FR, Chase MH (2003) Colocalization of gamma aminobutyric acid and acetylcholine in neurons in the laterodorsal and pedunculopontine tegmental nuclei in the cat: a light and electron microscopic study. Brain Res 992:205–219

    CAS  PubMed  Article  Google Scholar 

  38. Karperien A, Ahammer H, Jelinek HF (2013) Quantitating the subtleties of microglial morphology with fractal analysis. Front Cell Neurosci 7:3

    PubMed  PubMed Central  Article  Google Scholar 

  39. Kaur C, Ling EA (1992) Activation and re-expression of surface antigen in microglia following an epidural application of kainic acid in the rat brain. J Anat 180:333–342

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kettenmann H, Hanisch U, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553

    CAS  PubMed  Article  Google Scholar 

  41. Kramer ML, Schulz-Schaeffer WJ (2007) Presynaptic αsynuclein aggregates, not lewy bodies, cause neurodegeneration in dementia with lewy bodies. J Neurosci 27:1405–1410

    CAS  PubMed  Article  Google Scholar 

  42. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318

    CAS  PubMed  Article  Google Scholar 

  43. Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, Czlonkowski A, Czlonkowska A (1999) MHC class II positive microglia and lymphocytic infiltration are present in the substantia nigra and striatum in mouse model of Parkinson’s disease. Acta Neurobiol Exp (Wars) 59:1–8

    CAS  Google Scholar 

  44. Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D (1999) Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol 46:598–605

    CAS  PubMed  Article  Google Scholar 

  45. Lavoie B, Parent A (1994) Pedunculopontine nucleus in the squirrel monkey: projections to the basal ganglia as revealed by anterograde tract-tracing methods. J Comp Neurol 344:210–231

    CAS  PubMed  Article  Google Scholar 

  46. Li Y, Gao H, Wang Y, Dai C (2014) Investigation the mechanism of the apoptosis induced by lactacystin in gastric cancer cells. Tumour Biol. doi:10.1007/s13277-014-2982-x)

    Google Scholar 

  47. Lorenc-Koci E, Lenda T, Antkiewicz-Michaluk L, Wardas J, Domin H, Smiałowska M et al (2011) Different effects of intranigral and intrastriatal administration of the proteasome inhibitor lactacystin on typical neurochemical and histological markers of Parkinson’s disease in rats. Neurochem Int 58:839–849

    CAS  PubMed  Article  Google Scholar 

  48. Luk KC, Song C, O’Brien P, Stieber A, Branch JR, Brunden KR et al (2009) Exogenous α-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. PNAS 106:20051–20056

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. MacInnes N, Iravani MM, Perry E, Piggott M, Perry R, Jenner P et al (2008) Proteasomal abnormalities in cortical Lewy body disease and the impact of proteasomal inhibition within cortical and cholinergic systems. J Neural Transm 115:869–878

    CAS  PubMed  Article  Google Scholar 

  50. MacKey S, Jing Y, Flores J, Dinelle K, Doudet DJ (2013) Direct intranigral administration of an ubiquitin proteasome system inhibitor in rat: behaviour, positron emission tomography, immunohistochemistry. Exp Neurol 247:19–24

    CAS  PubMed  Article  Google Scholar 

  51. Maia S, Arlicot N, Vierron E, Bodard S, Vergote J, Guilloteau D et al (2012) Longitudinal and parallel monitoring of neuroinflammation and neurodegeneration in a 6-hydroxydopamine rat model of Parkinson’s disease. Synapse 66:573–583

    CAS  PubMed  Article  Google Scholar 

  52. Manaye KF, Zweig R, Wu D, Hersh LB, De Lacalle S, Saper CB et al (1999) Quantification of cholinergic and select non-cholinergic mesopontine neuronal populations in the human brain. Neuroscience 89:759

    CAS  PubMed  Article  Google Scholar 

  53. Marella M, Chabry J (2004) Neurons and astrocytes respond to prion infection by inducing microglia recruitment. J Neurosci 24:620–627

    CAS  PubMed  Article  Google Scholar 

  54. Marinova-Mutafchieva L, Sadeghian M, Broom L, David JB, Medhurst AD, Dexter DT (2009) Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6-hydroxydopamine model of Parkinson’s disease. J Neurochem 110:966–975

    CAS  PubMed  Article  Google Scholar 

  55. Martinez-Gonzalez C, Bolam JP, Mena-Segovia J (2011) Topographical organization of the pedunculopontine nucleus. Front Neuroanat 5:22

    PubMed  PubMed Central  Article  Google Scholar 

  56. Martinez-Gonzalez C, Wang HL, Micklem BR, Bolam JP, Mena-Segovia J (2012) Subpopulations of cholinergic, GABAergic and glutamatergic neurons in the pedunculopontine nucleus contain calcium-binding proteins and are heterogeneously distributed. Eur J Neurosci 35:723–734

    PubMed  Article  Google Scholar 

  57. Maskos U (2008) The cholinergic mesopontine tegmentum is a relatively neglected nicotinic master modulator of the dopaminergic system: relevance to drugs of abuse and pathology. Br J Pharmacol 153:S438–S445

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Mazzone P, Lozano A, Stanzione P, Galati S, Scarnati E, Peppe A et al (2005) Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson’s disease. Neuroreport 16:1877–1881

    PubMed  Article  Google Scholar 

  59. McGeer P, Itagaki L, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLADR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291

    CAS  PubMed  Article  Google Scholar 

  60. McNaught KS, Jenner P (2001) Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci Lett 297:191–194

    CAS  PubMed  Article  Google Scholar 

  61. McNaught KS, Shashidharan P, Perl DP, Jenner P, Olanow CW (2002) Aggresome-related biogenesis of Lewy bodies. Eur J Neurosci 16:2136–2148

    PubMed  Article  Google Scholar 

  62. Mena-Segovia J, Micklem BR, Nair-Roberts RG, Ungless MA, Bolam JP (2009) GABAergic neuron distribution in the pedunculopontine nucleus defines functional subterritories. J Comp Neurol 515:397–408

    CAS  PubMed  Article  Google Scholar 

  63. Mesulam MM, Mufson EJ, Wainer BH, Levey AI (1983) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1–Ch6). Neuroscience 10:1185–1201

    CAS  PubMed  Article  Google Scholar 

  64. Mineff EM, Popratiloff A, Romansky R, Kazakos V, Kaimaktschieff V, Usunoff KG et al (1998) Evidence for a possible glycinergic inhibitory neurotransmission in the midbrain and rostral pons of the rat studied by gephyrin. Arch Physiol Biochem 106:210–220

    CAS  PubMed  Article  Google Scholar 

  65. Morioka T, Kalehua AN, Streot WJ (1992) Progressive expression of immunomolecules on microglial cells in rat dorsal hippocampus following transient forebrain ischemia. Acta Neuropathol 83:149–157

    CAS  PubMed  Article  Google Scholar 

  66. Moro E, Hamani C, Poon Y-Y, Al-Khairallah T, Dostrovsky JO, Hutchison WD et al (2010) Unilateral pedunculopontine stimulation improves falls in Parkinson’s disease. Brain 133:215–224

    PubMed  Article  Google Scholar 

  67. Morrison HW, Filosa JA (2013) A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion. J Neuroinflammation 10:4

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Moses D, Drago J, Teper Y, Gantois I, Finkelstein DI, Horne MK (2008) Fetal striatum- and ventral mesencephalon-derived expanded neurospheres rescue dopaminergic neurons in vitro and the nigro-striatal system in vivo. Neuroscience 154:606–620

    CAS  PubMed  Article  Google Scholar 

  69. Nagatsu T, Sawada M (2005) Inflammatory process in Parkinson’s disease: role for cytokines. Curr Pharm Des 11:999–1016

    CAS  PubMed  Article  Google Scholar 

  70. Nakajima K, Yamamoto S, Kohsaka S, Kurihara T (2008) Neuronal stimulation leading to upregulation of glutamate transporter-1 (GLT-1) in rat microglia in vitro. Neurosci Lett 436:331–334

    CAS  PubMed  Article  Google Scholar 

  71. Neumann J, Gunzer M, Gutzeit HO, Ullrich O, Reymann KG, Dinkel K (2006) Microglia provide neuroprotection after ischemia. FASEB J 20:714–716

    CAS  PubMed  Google Scholar 

  72. Nikolaus S, Antke C, Muller HW (2009) In vivo imaging of synaptic function in the central nervous system: I. Movement disorders and dementia. Behav Brain Res 204:1–31

    PubMed  Article  Google Scholar 

  73. Niu C, Mei J, Pan Q, Fu X (2009) Nigral degeneration with inclusion body formation and behavioral changes in rats after proteasomal inhibition. Stereotact Funct Neurosurg 87:69–81

    PubMed  PubMed Central  Article  Google Scholar 

  74. O’Keefe GM, Nguyen VT, Benveniste EN (2002) Regulation and function of class II major histocompatibility complex, CD40, and B7 expression in macrophages and microglia: implications in neurological diseases. J Neurovirol 8:496–512

    PubMed  Article  CAS  Google Scholar 

  75. Olszewski J, Baxter D (1982) Cytoarchitecture of the human brain stem. S. Karger, Basel

    Google Scholar 

  76. Oorschot DE (1996) Total number of neurons in the neostriatal, pallidal, subthalamic, and substantia nigral nuclei of the rat basal ganglia: a stereological study using the cavalieri and optical dissector methods. J Comp Neurol 366:580–599

    CAS  PubMed  Article  Google Scholar 

  77. Orlowski RZ (1999) The role of the ubiquitin-proteasome pathway in apoptosis. Cell Death Differ 6:303–313

    CAS  PubMed  Article  Google Scholar 

  78. Patt S, Gerhard LA (1993) Golgi study of human locus coeruleus in normal brains and in Parkinson’s disease. Neuropathol Appl Neurobiol 19:519–523

    CAS  PubMed  Article  Google Scholar 

  79. Patt S, Gertz HJ, Gerhard L, Cervos-Navarro J (1991) Pathological changes in dendrites of substantia nigra neurons in Parkinson’ disease: a Golgi study. Histol Histopathol 6:373–380

    CAS  PubMed  Google Scholar 

  80. Paxinos G, Watson C (2009) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, San Diego

    Google Scholar 

  81. Pienaar IS, Van de Berg W (2013) A non-cholinergic neuronal loss in the pedunculopontine nucleus of toxin-evoked parkinsonian rats. Exp Neurol 248:213–223

    CAS  PubMed  Article  Google Scholar 

  82. Pienaar IS, Elson JL, Racca C, Nelson G, Turnbull DM, Morris CM (2013) Mitochondrial abnormality associates with type-specific neuronal loss and cell morphology changes in the pedunculopontine nucleus in Parkinson disease. Am J Pathol 183:1826–1840

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Pienaar IS, Harrison IF, Elson JL, Bury A, Woll P, Simon AK et al (2015a) An animal model mimicking pedunculopontine nucleus cholinergic degeneration in Parkinson’s disease. Brain Struct Funct 220:479–500

    CAS  PubMed  Article  Google Scholar 

  84. Pienaar IS, Lee CH, Elson JL, McGuinness L, Gentleman SM, Kalaria RN et al (2015b) Deep-brain stimulation associates with improved microvascular integrity in the subthalamic nucleus in Parkinson’s disease. Neurobiol Dis 74:392–405

    PubMed  Article  Google Scholar 

  85. Plaha P, Gill SS (2005) Bilateral deep brain stimulation of the pedunculopontine nucleus for Parkinson’s disease. Neuroreport 16:1883–1887

    PubMed  Article  Google Scholar 

  86. Rinne JO, Ma SY, Lee MS, Collan Y, Röyttä M (2008) Loss of cholinergic neurons in the pedunculopontine nucleus in Parkinson’s disease is related to disability of the patients. Parkinsonism Relat Disord 14:553–557

    PubMed  Article  Google Scholar 

  87. Rodriguez-Pallares J, Parga JA, Munoz A, Rey P, Guerra MJ, Labandeira-Garcia JL (2007) Mechanism of 6-hydroxydopamine neurotoxicity: role of NADPH oxidase and microglial activation in 6-hydroxydopamine induced degeneration of dopaminergic neurons. J Neurochem 103:145–156

    CAS  PubMed  Google Scholar 

  88. Ros H, Magill PJ, Moss J, Bolam JP, Mena-Segovia J (2010) Distinct types of non-cholinergic pedunculopontine neurons are differentially modulated during global brain states. Neuroscience 170:78–91

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Rye DB, Saper CB, Lee HJ, Wainer BH (1987) Pedunculopontine tegmental nucleus of the rat: cytoarchitecture, cytochemistry, and some extrapyramidal connections of the mesopontine tegmentum. J Comp Neurol 259:483–528

    CAS  PubMed  Article  Google Scholar 

  90. Sakurai A, Okamoto K, Yaguchi M, Fujita Y, Mizuno Y, Nakazato Y et al (2002) Pathology of the inferior olivary nucleus in patients with multiple system atrophy. Acta Neuropathol 103:550–554

    CAS  PubMed  Article  Google Scholar 

  91. Saryyeya A, Nakamura M, Krauss JK, Schwabe K (2011) c-Fos expression after deep brain stimulation of the pedunculopontine tegmental nucleus in the rat 6-hydroxydopamine Parkinson model. J Chem Neuroanat 42:210–217

    Article  CAS  Google Scholar 

  92. Schiefer J, Kampe K, Dodt HU, Zieglgansberger W, Kreutzberg GW (1999) Microglial motility in the rat facial nucleus following peripheral axotomy. J Neurocytol 28:439–453

    CAS  PubMed  Article  Google Scholar 

  93. Schmitz C, Hof PR (2005) Design-based stereology in neuroscience. Neuroscience 130:813–831

    CAS  PubMed  Article  Google Scholar 

  94. Schulz-Schaeffer WJ (2010) The synaptic pathology of a-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia. Acta Neuropathol 120:131–143

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. Sharma P, Pienaar IS (2014) Pharmacogenetic and optical dissection for mechanistic understanding of Parkinson’s disease: potential utilities revealed through behavioural assessment. Neurosci Biobehav Rev 47:87–100

    PubMed  Article  Google Scholar 

  96. Slomianka L, West MJ (2005) Estimators of the precision of stereological estimates: an example based on the CA1 pyramidal cell layer of rats. Neuroscience 136:757–767

    CAS  PubMed  Article  Google Scholar 

  97. Spann BM, Grofova I (1992) Cholinergic and non-cholinergic neurons in the rat pedunculopontine tegmental nucleus. Anat Embryol (Berl) 186:215–227

    CAS  Article  Google Scholar 

  98. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 95:6469–6473

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Stefani A, Peppe A, Galati S, Bassi MS, D’Angelo V, Pierantozzi M (2013) The serendipity case of the pedunculopontine nucleus low-frequency brain stimulation: chasing a gait response, finding sleep, and cognition improvement. Front Neurol 4:68

    PubMed  PubMed Central  Article  Google Scholar 

  100. Steininger TL, Wainer BH, Rye DB (1997) Ultrastructural study of cholinergic and noncholinergic neurons in the pars compacta of the rat pedunculopontine tegmental nucleus. J Comp Neurol 382:285–301

    CAS  PubMed  Article  Google Scholar 

  101. Taylor CL, Kozak R, Latimer MP, Winn P (2004) Effects of changing reward on performance of the delayed spatial win-shift radial maze task in pedunculopontine tegmental nucleus lesioned rats. Behav Brain Res 153:431–438

    PubMed  Article  Google Scholar 

  102. Topchiy I, Waxman J, Radulovacki M, Carley DW (2010) Functional topography of respiratory, cardiovascular and pontine-wave responses to glutamate microstimulation of the pedunculopontine tegmentum of the rat. Resp Physiol Neurobiol 173:64–70

    CAS  Article  Google Scholar 

  103. Van Dort CJ, Zachs DP, Kenny JD, Zheng S, Goldblum RR, Gelwan NA et al (2015) Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep. Proc Natl Acad Sci USA 112:584–589

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. Vernon AC, Johansson SM, Modo MM (2010) Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson’s disease. BMC Neurosci 11:1471–2202

    Article  CAS  Google Scholar 

  105. Wang HL, Morales M (2009) Pedunculopontine and laterodorsal tegmental nuclei contain distinct populations of cholinergic, glutamatergic and GABAergic neurons in the rat. Eur J Neurosci 29:340–358

    PubMed  Article  Google Scholar 

  106. West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482–497

    CAS  PubMed  Article  Google Scholar 

  107. Wu Y, Luo H, Kanaan N, Wu J (2000) The proteasome controls the expression of a proliferation-associated nuclear antigen Ki-67. J Cell Biochem 76:596–604

    CAS  PubMed  Article  Google Scholar 

  108. Yamada T, McGeer PL, McGeer EG (1992) Lewy bodies in Parkinson’s disease are recognised by antibodies to complement proteins. Acta Nauropathol 84:100–104

    CAS  Article  Google Scholar 

  109. Ye M, Havar A, Strotman B, Garcia-Rill E (2010) Cholinergic modulation of fast inhibitory and excitatory transmission to pedunculopontine thalamic projecting neurons. J Neurophysiol 103:2417–2432

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML et al (2005) Aggregated α-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19:533–542

    CAS  PubMed  Article  Google Scholar 

  111. Zweig RM, Whitehouse PJ, Casanova MF, Walker WC, Jankel WR, Price DL (1987) Loss of pedunculopontine neurons in progressive supranuclear palsy. Ann Neurol 22:18e25

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Acknowledgments

This study received grant support from the British Pharmacological Society and the Rosetrees Trust, with both grants awarded to ISP.

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Correspondence to Ilse S. Pienaar.

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Elson, J.L., Yates, A. & Pienaar, I.S. Pedunculopontine cell loss and protein aggregation direct microglia activation in parkinsonian rats. Brain Struct Funct 221, 2319–2341 (2016). https://doi.org/10.1007/s00429-015-1045-4

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Keywords

  • Lactacystin
  • Microglia
  • Neuronophagia
  • Parkinson’s disease
  • Pedunculopontine tegmental nucleus
  • α-Synuclein