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A new dopaminergic nigro-olfactory projection

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Abstract

Parkinson disease (PD) is a neurodegenerative disorder characterized by massive loss of midbrain dopaminergic neurons. Whereas onset of motor impairments reflects a rather advanced stage of the disorder, hyposmia often marks the beginning of the disease. Little is known about the role of the nigro-striatal system in olfaction under physiological conditions and the anatomical basis of hyposmia in PD. Yet, the early occurrence of olfactory dysfunction implies that pathogens such as environmental toxins could incite the disease via the olfactory system. In the present study, we demonstrate a dopaminergic innervation from neurons in the substantia nigra to the olfactory bulb by axonal tracing studies. Injection of two dopaminergic neurotoxins—1-methyl-4-phenylpyridinium and 6-hydroxydopamine—into the olfactory bulb induced a decrease in the number of dopaminergic neurons in the substantia nigra. In turn, ablation of the nigral projection led to impaired olfactory perception. Hyposmia following dopaminergic deafferentation was reversed by treatment with the D1/D2/D3 dopamine receptor agonist rotigotine. Hence, we demonstrate for the first time the existence of a direct dopaminergic projection into the olfactory bulb and identify its origin in the substantia nigra in rats. These observations may provide a neuroanatomical basis for invasion of environmental toxins into the basal ganglia and for hyposmia as frequent symptom in PD.

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Acknowledgments

This work was supported by the German Federal Ministry of Education and Research Network “Stem Cells in PD” (Grant 01GN0513), the Deutsche Forschungsgemeinschaft (DFG; HO2402/6-2 to GUH), the German Academic Exchange Service (DAAD to OAC), intramural funds of the University of Lübeck (to DAF), UCB Pharma S.A., the Förderverein Neurologie Marburg and the Charitable Hertie Foundation, Frankfurt/Main, Germany (to WHO).

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The authors have declared that no conflict of interest exists.

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    Authors and Affiliations

    1. Department of Neurology, Technical University Munich, 81377, Munich, Germany

      Günter U. Höglinger & Oscar Arias-Carrión

    2. Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), 81677, Munich, Germany

      Günter U. Höglinger & Oscar Arias-Carrión

    3. Department of Neurology, Philipps University, 35033, Marburg, Germany

      Günter U. Höglinger, Oscar Arias-Carrión, Miriam Djufri, Andrea Windolph, Ursula Keber, Andreas Borta, Vincent Ries & Wolfgang H. Oertel

    4. Trastornos del Movimiento y Sueño (TMS), Hospital General Dr. Manuel Gea González/IFC-UNAM, Mexico City, Mexico

      Oscar Arias-Carrión

    5. Institute of Neurogenetics, University of Luebeck, 23562, Luebeck, Germany

      Daniel Alvarez-Fischer

    6. Department of Psychiatry and Psychotherapy, University of Luebeck, 23562, Luebeck, Germany

      Daniel Alvarez-Fischer

    7. Experimental and Biological Psychology, Philipps-University, 35032, Marburg, Germany

      Andreas Borta & Rainer K. W. Schwarting

    8. UCB Pharma S.A., CNS Research, 1420, Braine-l’Alleud, Belgium

      Dieter Scheller

    9. German Center for Neurodegenerative Diseases e.V. (DZNE), Chair for Translational Neurodegeneration, Technical University Munich (TUM), Feodor-Lynen Str. 17, 81377, Munich, Germany

      Günter U. Höglinger

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    1. Günter U. Höglinger
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    Correspondence to Günter U. Höglinger.

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    G. U. Höglinger, D. Alvarez-Fischer and O. Arias-Carrión contributed equally to the work.

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    401_2015_1451_MOESM1_ESM.pptx

    Supplementary Figure S1 | Axonal projection of the substantia nigra pars compacta into the olfactory bulb (Anterograde tracing). (a) Sagittal section of a rat brain immunostained for tyrosine hydroxylase (TH, brown) shows the location of the dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) in the midbrain, as well as their axonal projections via the medial forebrain bundle (MFB) to the striatum (Str), nucleus accumbens (NA) and olfactory tubercle (OT). The periphery of the olfactory bulb (OB) also contains dopaminergic neurons. The lines indicate the level of the photographs shown at higher magnifications in coronal sections in the panels (b-e). (b) Confocal microscopic image showing as overview and at higher magnification of the boxed area that the tracer substance DiI (red) was injected precisely into SNc (TH+ neurons in green) and that there was no local diffusion to surrounding tissues. (c) Confocal microscopic image with 3D-reconstruction showing the SVZ, delineated by the dashed lines, located between the Str and the lateral ventricle (LV), which contains numerous newborn BrdU+ neuroblasts (blue) and TH+ fibers (green, green arrows), some of which were DiI+ (red, red arrows) after injection of the tracer into the SNc. The crossed lines depict a TH+ DiI+ fiber in the lower left quadrant; colocalization of both markers is verified in the x–z and y–z axis. (d) Confocal microscopic image of the OB, using NeuN immunostaining (red) to delineate the anatomical regions, shown as overview and at higher magnification of the boxed area, demonstrating TH+ (green) neurons in the glomerular layer (GL) and TH+ fibers in the external plexiform layer (EPL), mitral cell layer (MCL) and granular cell layer (GCL). Internal plexiform layer (IPL) (e) Confocal microscopic image from the OB at high magnification, showing TH+ (green) fibers containing DiI (red) in the EPL, the GCL, and mainly in the MCL, but not in the GL, after injection of the DiI tracer into the SNc. Scale bars: 400 µm (a); 100 µm (b-e); 50 µm (insert in d). (PPTX 9998 kb)

    401_2015_1451_MOESM2_ESM.pptx

    Supplementary Figure S2 | Rotigotine stimulates precursor cell proliferation in the subventricular zone. (a) The efficacy of the 6-OHDA lesion was demonstrated by a marked reduction in TH+ fibers in the striatum ipsilateral to the 6-OHDA injection. Staining of adjacent sections for BrdU demonstrated reduced numbers of newborn BrdU+ neuroblasts in the SVZ of the 6-OHDA-lesioned side compared to the unlesioned control side. (b) Amphetamine-induced net rotational scores ipsiversive to the side of the 6-OHDA lesion demonstrate functionally effective lesions of the nigro-striatal dopaminergic pathway in all groups; there were no significant differences in the degree of rotations between the experimental groups; the rotigotine doses given in the x-axis represent future group assignment, i.e. no rotigotine treatment was given prior to or during this examination. (c) Optical density measures of the TH-immunostained striatum showed a reduction in dopaminergic fibers on the lesioned side compared to the contralateral control side by about 70 % in all experimental groups (*p < 0.05 lesioned vs. control side, two-sided t-test), without significant differences in the degree of lesion between groups. (d) Effect of rotigotine administered in different concentrations for 14 days on the BrdU+ cell number in the SVZ. Black: unlesioned control side. White: 6-OHDA-lesioned side. * P < 0.05 vs. unlesioned side, 0 mg rotigotine; # P < 0.01 vs. lesioned side, 0 mg rotigotine; ANOVA, post hoc LSD test. (e) Reduction in the number of BrdU+ cells in the SVZ on the lesioned side, expressed as  % of the control side. * p < 0.05 vs. lesioned vs. unlesioned side, same rotigotine-dose; ANOVA, post hoc-LSD test. (PPTX 1239 kb)

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    Höglinger, G.U., Alvarez-Fischer, D., Arias-Carrión, O. et al. A new dopaminergic nigro-olfactory projection. Acta Neuropathol 130, 333–348 (2015). https://doi.org/10.1007/s00401-015-1451-y

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