Abstract
Serotonin (5-HT) is a crucial signal in the neurogenic niche microenvironment. Dysregulation of the 5-HT system leads to mood disorders but also to changes in appetite and metabolic rate. Tryptophan hydroxylase 2-deficient (Tph2-/-) mice depleted of brain 5-HT display alterations in these parameters, e.g., increased food consumption, modest impairment of sleep and respiration accompanied by a less anxious phenotype. The newly discovered neural stem cell niche of the adult hypothalamus has potential implications of mediating stress responses and homeostatic functions. Using Tph2-/- mice, we explore stem cell behavior and cell genesis in the adult hypothalamus. Specifically, we examine precursor cell proliferation and survival in Tph2-/- mice at baseline and following Western-type diet (WD). Our results show a decline in BrdU numbers with aging in the absence of 5-HT. Furthermore, wild type mice under dietary challenge decrease cell proliferation and survival in the hypothalamic niche. In contrast, increased high-calorie food intake by Tph2-/- mice does not come along with alterations in cell numbers. However, lack of brain 5-HT results in a shift of cell phenotypes that was abolished under WD. We conclude that precursor cells in the hypothalamus retain fate plasticity and respond to environmental challenges. A novel link between 5-HT signaling and cell genesis in the hypothalamus could be exploited as therapeutic target in metabolic disease.
Highlights
Besides the well-known neurogenic niches, the subventricular zone and the subgranular zone of the dentate gyrus, the hypothalamus has emerged as third region of postnatal neurogenesis and gliogenesis (Kokoeva et al, 2005; Lee et al, 2012; Robins et al, 2013a; Chaker et al, 2016)
When we looked at the distribution of BrdU+ cells within the various hypothalamic areas and nuclei (Figure 1C), the increase at P42 in Tph2−/− mice was reflected by increased cell numbers in the median eminence (Student’s t-test p = 0.0339) and arcuate nucleus (p = 0.0166), a tendency was observed for the ventromedial nucleus (p = 0.0668), while at P1y, Tph2−/− mice revealed significant fewer cells lining the third ventricle relative to CTR (p = 0.0057)
Our data demonstrate an age-dependent decline in cell proliferation in the hypothalamus of Tph2−/− mice, but not in CTR, and a large population of proliferating Sox2/NG2 cells
Summary
Besides the well-known neurogenic niches, the subventricular zone and the subgranular zone of the dentate gyrus, the hypothalamus has emerged as third region of postnatal neurogenesis and gliogenesis (Kokoeva et al, 2005; Lee et al, 2012; Robins et al, 2013a; Chaker et al, 2016). Recent studies indicate the stem cell niche is responsive to mitogens (Haan et al, 2013; Robins et al, 2013a), leptin (Kokoeva et al, 2005) and dietary challenges (Lee et al, 2012, 2014), and thereby regulates appetite and energy expenditure (Pierce and Xu, 2010). The precise role of 5-HT in the regulation of hypothalamic functions remains unknown. We address this using tryptophan hydroxylase 2-deficient (Tph2−/−) mice selectively depleted of brain 5-HT. Our data reveal an age-dependent decline in BrdU numbers and alterations in food intake and cell phenotypes in the lack of brain 5-HT
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