Abstract
In the present study, we generated a novel parvalbumin (PV)-Cre rat model and conducted detailed morphological and electrophysiological investigations of axons from PV neurons in globus pallidus (GP). The GP is considered as a relay nucleus in the indirect pathway of the basal ganglia (BG). Previous studies have used molecular profiling and projection patterns to demonstrate cellular heterogeneity in the GP; for example, PV-expressing neurons are known to comprise approximately 50% of GP neurons and represent majority of prototypic neurons that project to the subthalamic nucleus and/or output nuclei of BG, entopeduncular nucleus and substantia nigra (SN). The present study aimed to identify the characteristic projection patterns of PV neurons in the GP (PV-GP neurons) and determine whether these neurons target dopaminergic or GABAergic neurons in SN pars compacta (SNc) or reticulata (SNr), respectively. We initially found that (1) 57% of PV neurons co-expressed Lim-homeobox 6, (2) the PV-GP terminals were preferentially distributed in the ventral part of dorsal tier of SNc, (3) PV-GP neurons formed basket-like appositions with the somata of tyrosine hydroxylase, PV, calretinin and cholecystokinin immunoreactive neurons in the SN, and (4) in vitro whole-cell recording during optogenetic photo-stimulation of PV-GP terminals in SNc demonstrated that PV-GP neurons strongly inhibited dopamine neurons via GABAA receptors. These results suggest that dopamine neurons receive direct focal inputs from PV-GP prototypic neurons. The identification of high-contrast inhibitory systems on dopamine neurons might represent a key step toward understanding the BG function.
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Acknowledgements
We thank Dr. N. Tamamaki (Kumamoto University) for providing the PV-Cre transgene construct.
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This study was funded by Grants-in-Aid from The Ministry of Education, Culture, Sports, Science, and Technology (MEXT) for Scientific Research (25282247 and 15K12770 to FF; 26350983 and 16H01622 to FK; 25560435, 16H02840, 16H01623, 16K13115, 16H06543 to ST); MIC SCOPE (152107008) to ST; and for Scientific Researches on Innovative Areas “Adaptive Circuit Shift” (26112001) to FF.
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Y.-M. Oh and F. Karube equally contributed to this work.
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429_2016_1346_MOESM1_ESM.tif
Supplementary Fig. 1 Spatial distribution and co-expression of PV and Lhx6 in the GP neurons. Immunohistochemically identified PV+ (red dot), Lhx6+ (green dots), and PV+/Lhx6+ (blue dots) neurons were plotted in three sagittal planes. The magnified views of the ventral region are shown in the rightmost column. In the rightmost column, PV+/Lhx6– (red dots), PV–/Lhx6+ (green dots), and PV+/Lhx6+ (blue dots) neurons are indicated. Distribution of them was likely to be unbiased in the GP, however, Lhx6+/PV– neurons (green) were outstanding in the ventral region of the GP at LM2.9-3.9 mm (TIFF 2146 kb)
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Supplementary Fig. 2 TdTomato fluorescence, PV (blue) and Lhx6 (green) immunoreactivities in parvalbumin (PV)–Cre rats at 2 weeks after viral injection. High-magnification images displaying the viral injection site in the globus pallidus. Arrowheads indicated the Lhx6+/PV+ neurons. Note that Lhx6+/PV– neurons (arrows) were rarely infected. Photos were taken with a confocal microscope (FV-1200, Olympus, Tokyo, Japan) under the conditions described in the Materials and Methods. Scale bars: 20 µm (TIFF 10991 kb)
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Supplementary Fig. 3 AAV vector used here did not label neurons retrogradely. Fluorescent images of the SN (A), EP (B), and striatum (C) of a rat after AAV injection into the GP. TdTomato labelled axons issuing from PV-GP neurons were observed in all images. Importantly, no retrograde labeling of PV neurons was observed. A neuron-like shape of fluorescence was investigated at some locations in SNr (A2) and EP (B), however, magnified views combined with PV immunoreactivity (green) revealed that these pseudo-cell like fluorescence was not AAV-infected neurons. Actually they were unlabeled neurons which were surrounded by dense PV-GP axons. (C) In striatum, no such image was observed due to relatively weak PV-GP projections. Photos were taken with a confocal microscope (FV-1200, Olympus, Tokyo, Japan) under the conditions described in the Materials and Methods (TIFF 30222 kb)
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Supplementary Fig. 4 Fluorescent images of axons from parvalbumin (PV)–globus pallidus (GP) neurons in the substantia nigra pars compacta (SNc) and reticulata (SNr). (A) Overlay (the most right) of PV-GP axons (red), tyrosine hydroxylase (TH, blue) and PV (green) immunofluorescence in case b. Using TH and PV immunoreactivity SNc and SNr were identified. (B) Fluorescent images of axons from PV-GP neurons in the SN from 5 PV-Cre rats (cases a–e). Fluorescent images in the left column display the virus injection sites in the GP. Five latero-medial planes of SN images are arranged from left (the most lateral plane) to right (the most medial plane), ranged from 1.55 to 2.9 mm. Note that dense boutons of PV-GP axons emerged in the border region between the SNc and SNr. See also Fig. 5 and 6. Photos were taken with an epifluorescent microscope (BX-61, Olympus, Tokyo, Japan) under the conditions described in the Materials and Methods. Scale bars: 500 µm in GP and 200 µm in SN (TIFF 48117 kb)
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Supplementary Fig. 5 Procedure for subdivision of the SN area. (A) The area of SNc was defined by TH immunoreactivity. (B) The leftmost and rightmost positions of the polygon were identified, respectively (green dots). (C) The bottom polygonal line (red) was defined as the border between SNc and SNr. (D) A line connecting coordinates of the horizontal axis of the positions was equally divided into 100 positions (top dots). (E) At each divided position, points that bisect a perpendicular line intersecting the polygon were identified (ex. blue dot). A polygonal line that connects all the bisection points was defined as a border between area I and area II (green polygonal line). (F) Points that are arranged symmetrically against the bisection point in the vertical direction with the border between SNc and SNr as the axis of symmetry at each divided location were identified, and then a polygonal line that connects the points was defined as a border between area III and area IV (blue polygonal line). (G) Points that are arranged symmetrically against the point on the border between SNc and SNr in the vertical direction with the border between area III and area IV as the axis of symmetry at each divided location were identified, and then a polygonal line that connects the points was defined as a bottom edge of all the area (blue dotted polygonal line). (H) The identified four areas (I – IV) of SN (TIFF 1795 kb)
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Supplementary Fig. 6 Fluorescent images of CB, CCK, CR or NOS-positive cell body and axons from PV-GP neurons in the SN. Overlay of PV-GP axons (red), CB, CCK, CR or NOS (green) immunofluorescence in SN (A), SNc (B) and SNr (C). Note that PV-GP axons formed basket-like appositions with CCK (b) and CR (c) but CB (a) immunoreactive somata in the SNc and with NOS (C) immunoreactive soma in the SNr. PV-GP axons in the border region between the SNc and SNr formed basket-like appositions with CCK and CR somata. Photos were taken with a confocal microscope (FV-1200, Olympus, Tokyo, Japan) under the conditions described in the Materials and Methods. Scale bar: low magnification, 200 µm; high magnification, 20 µm (TIFF 33669 kb)
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Supplementary Fig. 7 Estimated distances between the centers of the TH-positive cell bodies and PV-GP boutons. Sample IDs are indicated in the topmost section, which are the same as those in Fig. 6. (A) Average frequency of the number of boutons per TH-positive cell as a function of the normalized distance between the cell center and edge. Red bars indicate standard errors of the mean. (B) Bar graph shows the sum total of boutons for each cell within the near-center and near-edge regions, respectively. The borderline between the cell center and edge is set at the midpoint. Red bars indicate standard deviations. Wilcoxon rank-sum test, *: p<0.05, ***: p<0.001 (TIFF 2453 kb)
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Supplementary Fig. 8 Estimated distances between the centers of the PV-positive cell bodies and PV-GP boutons. Sample IDs are indicated in the topmost section, which are the same as those in Fig. 6. (A) Average frequency of the number of boutons per PV-positive cell as a function of the normalized distance between the cell center and edge. Red bars indicate standard errors of the mean. (B) Bar graph shows the sum total of boutons for each cell within the near-center and near-edge regions, respectively. The borderline between the cell center and edge is set at the midpoint. Red bars indicate standard deviations. Wilcoxon rank-sum test, *: p<0.05, **: p<0.01, ***: p<0.001 (TIFF 1523 kb)
429_2016_1346_MOESM9_ESM.tif
Supplementary Fig. 9 Estimated distances between the centers of the CB, CCK, CR or NOS-positive cell bodies and PV-GP boutons. Sample IDs are indicated in the topmost section, which are the same as those in Fig. 6. (A) Average frequency of the number of boutons per CB (f), CCK (g), CR (h) or NOS (i) -positive cell as a function of the normalized distance between the cell center and edge. Red bars indicate standard errors of the mean. (B) Bar graph shows the sum total of boutons for each cell within the near-center and near-edge regions, respectively. The borderline between the cell center and edge is set at the midpoint. Red bars indicate standard deviations. Wilcoxon rank-sum test, ***: p<0.001. Since for CB and NOS - positive cells, few boutons were located around the cell body, statistical test could not be performed (TIFF 1433 kb)
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Oh, YM., Karube, F., Takahashi, S. et al. Using a novel PV-Cre rat model to characterize pallidonigral cells and their terminations. Brain Struct Funct 222, 2359–2378 (2017). https://doi.org/10.1007/s00429-016-1346-2
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DOI: https://doi.org/10.1007/s00429-016-1346-2