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Positive modulators of ahNG are environmental enrichment, physical exercise, and learning (van Praag et al. Several studies indicate that chronic administration of classical monoaminergic antidepressant drug results in enhanced hippocampal neurogenesis in the adult human and rodent DG (Santarelli et al.

More generally speaking, these studies suggest that ahNG can be modulated pharmacologically, and this may have therapeutic relevance in several CNS disorders. In the last decade, our laboratory has contributed to the identification of novel molecular regulators of ahNG with potential therapeutic relevance (Denis-Donini et al. Through these activities, we have been able to demonstrate that several drugs utilized in the clinical setting are endowed with the ability to promote ahNG in vitro and, more importantly, in vivo (Valente et al.

These accomplishments have allowed us to propose novel therapeutic indications for these drugs. Since the established observations that the hippocampus receives dense noradrenergic innervations from the locus coeruleus (LC) (Sara et al.

Guido Iaccarino, Federico II University, Naples, Italy. Mice were housed in a light- and temperature-controlled room in high-efficiency particulate air (HEPA)-filtered Thoren units (Thoren Caging Systems) at the University of Piemonte Orientale animal facility. In vitro drug concentrations were chosen based on Ki values at their target receptors. Isolation and culture of adult hippocampal neural progenitor cells (ahNPCs). Neural progenitor cell proliferation, differentiation, and survival.

NPC were treated in the presence of the indicated drug concentrations or vehicle for 96 h. In differentiation assays, NPCs were plated onto laminin-coated (2. NPCs were differentiated for 24 h in presence of indicated concentration of drugs or vehicle. The percentage of apoptotic NPCs was evaluated after counterstaining with 0. Apoptotic nuclei were counted in drug- or vehicle-treated cells using a fluorescence microscope DMIRB (Leica, Wetzlar, Germany) with a 60X objective (Meneghini et al.

All in vitro experiments were run in triplicates using different cell preparations and repeated at least three times. Primary antibodies were as follows: anti-nestin (chicken monoclonal, 1:1,500, Neuromics, Edina, MN), anti-microtubule-associated protein-2 (MAP-2, rabbit polyclonal, 1: 600, Millipore, Milan, Italy), anti-glial fibrillary acidic protein (GFAP, mouse polyclonal, 1:600, Millipore), and anti-chondroitin sulfate proteoglycan (NG-2, rabbit polyclonal, 1:500, Millipore).

Nuclei were counterstained with 0. Immunopositive cells for each marker were counted, and their percentage over total viable cells was calculated. During the first 5 days of the treatment, mice were also intraperitoneally (i. For doublecortin (DCX) staining, procedure was as previously described (Dellarole and Grilli, 2008). Briefly, sections were incubated with goat anti-DCX primary antibody (1:1,000, Santa Cruz Biotechnology, Santa Cruz, CA) followed by biotinylated horse anti-goat secondary antibody (1:200, Vector Laboratories, Burlingame, CA).

For triple immunostaining, the following antibodies were used: rat monoclonal anti-BrdU (1:200, Novus Biologicals Inc. Quantification and phenotypical characterization of newborn cells. A modified unbiased, stereological protocol was used for quantification and phenotypic characterization of cells, as previously described (Denis-Donini et al.

The SGZ was identified as corresponding to two cell bodies wide, along the border of the GCL. For DCX analysis, positive cells were quantified using a 60X objective along the rostrocaudal extension of DG.

For the dorsal and ventral DG analysis, the anatomical coordinates were selected according to The Mouse Brain Atlas (Paxinos and Franklin, 2004). Analysis of Dendritic Morphology. Statistical significance level was set for p values Bates et al. Upon removal of growth factors followed by exposure to a serum-free defined medium, ahNPCs stop dividing and differentiating onto laminin-coated dishes.

Under these experimental conditions, norepinephrine (0. In absence of growth factors, ahNPCs differentiate not only toward neuronal but also glial lineages. Both populations were not affected by NE treatment as shown in Figure 1B, C (ANOVA). Altogether, these data confirm that, in vitro, NE promotes neuronal differentiation of ahNPCs in absence of changes in glial differentiation and survival rate. Figure 1 Norepinephrine (NE) promotes neuronal differentiation and proliferation of ahNPCs via distinct receptor subtypes.

Adult hippocampal NPCs were differentiated in presence of NE (0. As shown in Figure 2A, NE significantly promoted ahNPC proliferation compared to vehicle-treated cells (p Figure 2B, p vs.