Chronic fluoxetine increases extra-hippocampal neurogenesis in adult mice - PubMed (original) (raw)

Chronic fluoxetine increases extra-hippocampal neurogenesis in adult mice

Benjamin D Sachs et al. Int J Neuropsychopharmacol. 2014.

Abstract

Background: Chronic treatment with antidepressants has been shown to enhance neurogenesis in the adult mammalian brain. Although this effect was initially reported to be restricted to the hippocampus, recent work has suggested that fluoxetine, a selective serotonin reuptake inhibitor, also promotes neurogenesis in the cortex. However, whether antidepressants target neural progenitor cells in other brain regions has not been examined.

Methods: Here, we used BrdU labeling and immunohistochemistry with a transgenic mouse line in which nestin+ neural progenitor cells can be inducibly labeled with the fluorescent protein, Tomato, following tamoxifen administration. We investigated the effects of chronic fluoxetine on cell proliferation and nestin+ progenitor cells in periventricular areas in the medial hypothalamus and medial habenula, two brain areas involved in stress and anxiety responses.

Results: Our data provide the first in vivo evidence that fluoxetine promotes cell proliferation and neurogenesis and increases the mRNA levels of BDNF in the hypothalamus and habenula.

Conclusions: By identifying novel cellular targets of fluoxetine, our results may provide new insight into the mechanisms underlying antidepressant responses.

Keywords: antidepressant; habenula; hypothalamus; neurogenesis.

© The Author 2015. Published by Oxford University Press on behalf of CINP.

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Figures

Figure 1.

Figure 1.

Fluoxetine leads to increased cell proliferation in the brain. (A) Quantification of BrdU incorporation data in the hippocampus of control and FLX-treated animals. Representative images from the hippocampus of control (B) and FLX-treated (C) mice are also shown. (D) Quantification of BrdU incorporation data in the hypothalamus of control and FLX-treated animals. Representative images from the hypothalamus of control (E) and FLX-treated (F) mice are also shown. (G) Quantification of BrdU incorporation data in the habenula of control and FLX-treated animals. Representative images from the hippocampus of control (H) and FLX-treated (I) mice are also shown. (J) A whole brain image with the hippocampus, habenula, and hypothalamus marked is shown for reference. BrdU is shown in red, nuclei are shown in blue. n = 10 control and 11 FLX for A–C; n = 15 per group for D–F; n = 10 per group for G–I. *p < 0.05 by _t_-test.

Figure 2.

Figure 2.

Fluoxetine does not affect the percentage of BrdU+ cells that become neurons. A representative image from the hippocampus (A), hypothalamus (C), and habenula (E) of a FLX-treated mouse is shown, and quantification is shown for the hippocampus (B), hypothalamus (D), and habenula (F). For all images, BrdU is shown in red, NeuN is shown in green, and nuclei are shown in blue. Arrowheads indicate double-positive cells. n = 9–11 per group.

Figure 3.

Figure 3.

Fluoxetine does not affect the percentage of BrdU+ cells that become astrocytes. Representative images from the hippocampus (A), hypothalamus (C), and habenula (E) of a FLX-treated mouse are shown. Quantification of these results is presented for the hippocampus (B), hypothalamus (D), and habenula (F). For all images, BrdU is shown in red, GFAP is shown in green, and nuclei are shown in blue. n = 8–10 per group.

Figure 4.

Figure 4.

Fluoxetine leads to increased numbers of nestin+ cells in the brain. (A) Quantification of the number of Tomato+ cells in the hippocampus with representative images from control (B) and FLX-treated (C) animals. (D) Quantification of the number of Tomato+ cells in the hypothalamus, with representative images from control (E) and FLX-treated (F) animals. (G) Quantification of the number of Tomato+ cells in the habenula with representative images from control (H) and FLX-treated (I) animals. Tomato expression is shown in red, nuclei are shown in blue. n = 8 per group. *p < 0.05 by _t_-test.

Figure 5.

Figure 5.

Neurogenesis from nestin+ precursors. Representative images of nestin-Tomato+/NeuN+ neurons in the hippocampus (A), hypothalamus (B), and (C) habenula. Tomato expression is shown in red, NeuN expression is shown in green, and nuclei are shown in blue. Arrows indicate double-positive cells.

Figure 6.

Figure 6.

Doublecortin immunoreactivity in adult mouse brain. Representative images from the hippocampus (A), hypothalamus (B), habenula (C), and subventricular (D) zone of the lateral ventricle. Nuclei are shown in blue, and doublecortin (DCX) is shown in green.

Figure 7.

Figure 7.

Gliogenesis from nestin+ precursors. Representative images of nestin-Tomato+ /GFAP+ glia in the hippocampus (A), hypothalamus (B), and habenula (C, D) in NCERT mice. Tomato expression is shown in red, NeuN expression is shown in green, and nuclei are shown in blue. C demonstrates the medial habenula itself, whereas D shows the region immediately dorsal to the medial habenula, the stria medullaris of the thalamus. Tomato expression is shown in red, GFAP expression is shown in green, and nuclei are shown in blue. Arrows indicate double-positive cells.

Figure 8.

Figure 8.

Vimentin expression in nestin-Tomato+ cells in NCERT mice. Representative images of nestin-Tomato+ cells (red) in the hippocampus (A), hypothalamus (B), and habenula (C) that stain positive with vimentin (green). Nuclei are shown in blue.

Figure 9.

Figure 9.

BDNF and CREB mRNA expression in the hypothalamus and habenula following chronic FLX. Quantification of real-time PCR data reveals that chronic FLX leads to an increase in the expression of BDNF in the hypothalamus (A) and habenula (B), but not to an increase in CREB in these brain regions (C and D). *p < 0.05 by _t_-test. n = 7 per group.

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