Hypothalamic neurogenesis persists in the aging brain and is controlled by energy-sensing IGF-I pathway

Abstract

International audienceHypothalamic tanycytes are specialized glial cells lining the third ventricle. They are recently identified as adult stem and/or progenitor cells, able to self-renew and give rise to new neurons postnatally. However, the long-term neurogenic potential of tanycytes and the pathways regulating lifelong cell replacement in the adult hypothalamus are largely unexplored. Using inducible nestin-CreERT2 for conditional mutagenesis, we performed lineage tracing of adult hypothalamic stem and/or progenitor cells (HySC) and demonstrated that new neurons continue to be born throughout adult life. This neurogenesis was targeted to numerous hypothalamic nuclei and produced different types of neurons in the dorsal periventricular regions. Some adult-born neurons integrated the median eminence and arcuate nucleus during aging and produced growth hormone releasing hormone. We showed that adult hypothalamic neurogenesis was tightly controlled by insulin-like growth factors (IGF). Knockout of IGF-1 receptor from hypothalamic stem and/or progenitor cells increased neuronal production and enhanced α-tanycyte self-renewal, preserving this stem cell–like population from age-related attrition. Our data indicate that adult hypothalamus retains the capacity of cell renewal, and thus, a substantial degree of structural plasticity throughout lifespan

Tanycytes As Regulators of Seasonal Cycles in Neuroendocrine Function

“…Contrasting studies have suggested that subpopulations of tanycytes constitute the source (63–66). This in itself, however, is controversial as both α- and β-tanycytes have been identified as the possible neurogenic niche, as well as a possible role for insulin-like growth factor (63, 65, 67). Interestingly, in one study, exposure of mice to a high fat diet depleted numbers of putative hypothalamic stem cells, which was associated with impaired glucose tolerance and subsequent obesity (68).…”

Neural Stem Cells and Nutrients: Poised Between Quiescence and Exhaustion

“…Studies in transgenic mice harboring mutations along the insulin/IGF-I cascade have revealed a major role for this pathway in NSC exit from quiescence ( Figure 2B) and in premature exhaustion [8,[50][51][52]. Accordingly, mice deficient in FOXO (which is inhibited by insulin signaling), or lacking its transcriptional target and cell cycle inhibitor p21, both display NSC hyperproliferation in vitro and premature exhaustion in vivo [8,50].…”

“…Accordingly, mice deficient in FOXO (which is inhibited by insulin signaling), or lacking its transcriptional target and cell cycle inhibitor p21, both display NSC hyperproliferation in vitro and premature exhaustion in vivo [8,50]. Conversely, ablation of IGF-I signals in NSCs has been shown to delay age-related decline of adult neurogenesis in olfactory bulb [51] and to enhance [ 1 8 _ T D $ D I F F ] /-tanycyte self-renewal in the hypothalamus of aged mice, preserving this stem cell-like population from age-related attrition [52]. These beneficial effects are reminiscent of neurogenesis rejuvenation by periodic fasting [53] and likely reflect the long-term preservation of the quiescent NSC pool.…”

“…Indiscriminate activation of the amino acid-and energy-sensitive pathway triggered by mTOR promotes stem cell commitment to proliferative expansion and to differentiation at the expense of self-renewal, eventually leading to premature exhaustion of the stem cell pool [3,4,51,52]. Mechanistic details of this rather general phenomenon are still elusive; however, recent elegant studies on differentiation of T lymphocytes following antigenic challenge suggest that asymmetric inheritance of the mTOR signaling machinery (including amino acid transporters that are necessary for mTORC1 activation) between daughter cells is key to determine a proliferative versus a nonproliferative fate.…”

Hypothalamic Neurogenesis as an Adaptive Metabolic Mechanism

“…They also express the molecular machinery that permits glucose sensing (García et al, 2003; Cortés-Campos et al, 2011; Orellana et al, 2012) and transmit signals to AN neurons (Elizondo-Vega et al, 2016). Due to their privileged position in the hypothalamus, tanycytes can also detect mitogenic and neurodifferentiating signals present in the peripheral blood or in the CSF (Robins et al, 2013; Chaker et al, 2016). …”