title: Distinct Effects of Chronic Dopaminergic Stimulation on Hippocampal Neurogenesis and Striatal Doublecortin Expression in Adult Mice.
abstract: While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ), recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g., the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA) receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX), and Ropinirole (ROP), on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2'-deoxyuridine (BrdU) a proliferation paradigm was performed in which two BrdU injections (100 mg/kg) were applied intraperitoneally within 12 h after a 14-days-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS)-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and Neuronal Nuclei (NeuN) 32 days after the last of five BrdU injections (50 mg/kg) applied at the beginning of 14-days DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX) in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX(+) neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active and quiescent neurogenic niches, might be related to the proportional higher D3 receptor affinity of PPX, non-dopaminergic effects of PPX, or altered motor behavior.
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg Erlangen, Germany.
authors.forename: Rachele
authors.initials: R
authors.lastname: Salvi
authors.affiliation: Department of Neurology, Friedrich-Alexander University Erlangen-NürnbergErlangen, Germany; Department of Palliative Medicine, Friedrich-Alexander University Erlangen-NürnbergErlangen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Steigleder
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-NürnbergErlangen, Germany; Department of Cellular and Molecular Medicine, University of CaliforniaSan Diego, CA, USA.
authors.forename: Johannes C M
authors.initials: JC
authors.lastname: Schlachetzki
authors.affiliation: Department of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander University Erlangen-Nürnberg Erlangen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Waldmann
authors.affiliation: Department of Neurology, Friedrich-Alexander University Erlangen-Nürnberg Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwab
authors.affiliation: IZKF Junior Research Group III and BMBF Research Group Neuroscience, Friedrich-Alexander University Erlangen-Nürnberg Erlangen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Winner
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg Erlangen, Germany.
authors.forename: Zacharias
authors.initials: Z
authors.lastname: Kohl
keywords: Parkinson's disease; adult neurogenesis; dentate gyrus; dopamine agonist; dopamine receptor; doublecortin; neuroblast; striatum