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Frontiers in Biology

Front. Biol.    2016, Vol. 11 Issue (3) : 246-255     https://doi.org/10.1007/s11515-016-1404-4
RESEARCH ARTICLE
Combined immunohistochemical and retrograde tracing reveals little evidence of innervation of the rat dentate gyrus by midbrain dopamine neurons
Charlotte M. Ermine1,*(),Jordan L. Wright1,2,Clare L. Parish1,Davor Stanic1,Lachlan H. Thompson1
1. The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
2. Current address Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK
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Abstract

Although the functional neuroanatomy of the midbrain dopamine (mDA) system has been well characterized, the literature regarding its capacity to innervate the hippocampal formation has been inconsistent. The lack of expression of definitive markers for dopaminergic fibers, such as the dopamine transporter, in the hippocampus has complicated studies in this area. Here we have used immunohistochemical techniques to characterize the tyrosine hydroxylase expressing fiber network in the rat hippocampus, combined with retrograde tracing from the dentate gyrus to assess the capacity for afferent innervation by mDA neurons. The results indicate that virtually all tyrosine hydroxylase fibers throughout the hippocampus are of a noradrenergic phenotype, while the overlying cortex contains both dopaminergic and noradrenergic fiber networks. Furthermore, retrograde tracing from the dentate gyrus robustly labels tyrosine hydroxylase-immunoreactive noradrenergic neurons in the locus coeruleus but not mDA neurons.

Keywords noradrenaline      hippocampus      connectivity      DAT      neurogenesis     
Corresponding Author(s): Charlotte M. Ermine   
Just Accepted Date: 25 May 2016   Online First Date: 23 June 2016    Issue Date: 05 July 2016
 Cite this article:   
Charlotte M. Ermine,Jordan L. Wright,Clare L. Parish, et al. Combined immunohistochemical and retrograde tracing reveals little evidence of innervation of the rat dentate gyrus by midbrain dopamine neurons[J]. Front. Biol., 2016, 11(3): 246-255.
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http://journal.hep.com.cn/fib/EN/10.1007/s11515-016-1404-4
http://journal.hep.com.cn/fib/EN/Y2016/V11/I3/246
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Charlotte M. Ermine
Jordan L. Wright
Clare L. Parish
Davor Stanic
Lachlan H. Thompson
Fig.1  Immunohistochemical detection of dopamine and noradrenaline fibers in the rat dentate gyrus. The dentate gyrus contains a fiber network that can be labeled with antibodies against tyrosine hydroxylase (A) or dopamine-b-hydroxylase (F) but not the dopamine transporter (K). Enlargements of the boxed areas in A and F show that TH (B–E) and DBH (G–J)fiber innervation is particularly dense in and around the sub-granular and granular layers, identified by doublecortin and Prox1 respectively, while there is a complete absence of DAT expression (L–O). Triple-labeling for TH, DBH, and DAT (P-S) shows that all TH+ fibers express DBH, while none co-label with DAT. Scale bars:A, F, and K, 200 µm and B-E, G–J, L–O, and P–S, 50 µm. Abbreviations: DAT, Dopamine transporter; DBH, Dopamine-beta-hydroxylase; DCX, Doublecortin; Prox1, Prospero homeobox1; TH, Tyrosine hydroxylase.
Fig.2  Overview of dopamine and noradrenergic fibers in the septal hippocampus and overlying cortex. A) Photomontage of immunohistochemical detection of TH, DBH, and DAT in the rat hippocampus and cortex. Boxed areas are shown as enlarged views of hippocampal areas with prominent TH fiberlabeling, including the sub-granular zone and molecular layer of the dentate gyrus (B) and CA3 (C) and also the overlying cortex (D) where TH+/DA+ fibers (arrows) were intermingled with TH/DBH fibers. Scale bars: A, 200 µm and B–D, 50 µm. Abbreviations: CA1, Cornus Ammonis 1; CA3, Cornus Ammonis 3; DGmol, Dentate gyrus molecular layer.
Fig.3  Retrograde labeling of midbrain neurons 5–7 days following injection of fluorogold into the dentate gyrus. Immunolabeling of fluorogold in a representative animal at the injection site (A) showing distribution in the dentate gyrus and some labeling in the overlying molecular layer and CA1, and in the midbrain(B), showing retrogradely labeled neurons with TH labeling (green) shown for anatomical reference. (C–E) Merged image and individual color channels showing fluorogold-labeled cells (arrows) interspersed among, but not overlapping with TH+ DA neurons in the VTA. (F) Representative fluorogold labeling at the injection site in one of two animals where fluorogold labeling was found along the injection tract in the cortex. (G–I) In these animals a total of three fluorogold-labeled TH+ DA neurons were identified in the midbrain. Scale bars:A, B, F, 200 µm; C–E and G–I, 50 µm. Abbreviations: FG, Fluorogold; TH, Tyrosine hydroxylase.
Fig.4  Cumulative spatial representation of fluorogold labeling in the midbrain of 10 animals 5–7 days after injection of fluorogold into the dentate gyrus. (A) Schematic overview of three representative coronal levels spanning the A9-A10 cell groups illustrating the location of all 605 fluorogold-labeled cells, indicated as red circles for FG+/TH- cells and yellow circles for FG+/TH+ cells. The black arrow represents the ipsilateral side injected with fluorogold. (B–D) Co-labeling for GABA showed that some of the FG+ neurons innervating the hippocampus were GABAergic projection neurons. Scale bars: B–D, 50 µm. Abbreviations: FG, Fluorogold; fr, fasciculus retroflexus; GABA, g aminobutyric acid; IPC, Interpeduncular nucleus central; MT, Medial terminal nucleus accessory optic tract; SNr, Substantia nigra reticular; VTA, Ventral tegmental area.
Fig.5  Retrograde labeling of noradrenergic neurons in the locus coeruleus 5–7 days after injection of fluorogold into the dentate gyrus. (A–C) Immunolabeling of fluorogold and TH showed extensive overlap in the locus coeruleus (arrowheads) as well as a minor population of FG+/TH- cells (arrows). (D) Schematic overview of three representative coronal levels spanning the locus coeruleus where the location of fluorogold labeled cells are indicated as red circles for FG+/TH- cells and yellow circles for FG+/TH+ cells. The black arrow represents the ipsilateral side injected with fluorogold. Scale bars: A–C, 200 µm. Abbreviations: FG, fluorogold; TH, tyrosine hydroxylase; PCG, pontine central gray; PDTg, posterodorsal tegmental nucleus.
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