Neural stem cells residing in specialized niches of the postnatal mammalian brain represent a cell population that can aid in the regeneration of injured areas. While new neurons continue to be born postnatally in the constitutively active germinal zones of the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus, other more quiescent germinal zones may exist. Although controversial, emerging evidence is beginning to suggest that postnatal neurogenesis occurs in the mammalian hypothalamus, traditionally considered a non-neurogenic region. Despite this evidence for hypothalamic neurogenesis, the question of the relevance of this process, as well as the cell of origin of these new neurons is entirely unclear. It is highly contentious whether new hypothalamic neurons are derived from the hypothalamic ventricular zone (HVZ) or from a parenchymal source. We hypothesize that the HVZ harbors a reservoir for quiescent neural stem cells. We also hypothesize that these neural stem cells can contribute to regenerative neurogenesis following hypothalamic injury. We propose here to 1) characterize the existence of low levels of hypothalamic neurogenesis in the postnatal mammalian brain. We will use an inducible cell fate mapping strategy in a mouse model to prospectively label cells within the HVZ. Using this strategy, we will be able to determine if HVZ contains neural stem cells that may be able to give rise to a variety of newly born cells. 2) We will characterize if neural stem cells within the HVZ aid in the regeneration of neurons following hypothalamic injury. We will employ a chemical lesion that eliminates neurons of the arcuate nucleus, a substructure within the ventral hypothalamus. We will use bromodeoxyuridine administration, to prospectively determine if proliferating cells within the postnatal HVZ may give rise to new neurons that reappear later at the injury site. The proposed experiments will focus on identifying if the HVZ contains neural stem or precursor cells, and to determine the role that these cells may play in cell regeneration of the brain. Relevance to Public Health: The identification of whether novel neural stem cell populations exist in the postnatal hypothalamus presents exciting avenues for understanding the role of neurogenesis in health and disease, as well as developing possible treatments or preventative therapies to mitigate the effects of a wide variety of neurodegenerative diseases or injuries.
|Salvatierra, Juan; Lee, Daniel A; Zibetti, Cristina et al. (2014) The LIM homeodomain factor Lhx2 is required for hypothalamic tanycyte specification and differentiation. J Neurosci 34:16809-20|
|Lee, Daniel A; Blackshaw, Seth (2014) Feed your head: neurodevelopmental control of feeding and metabolism. Annu Rev Physiol 76:197-223|
|Lee, Daniel A; Yoo, Sooyeon; Pak, Thomas et al. (2014) Dietary and sex-specific factors regulate hypothalamic neurogenesis in young adult mice. Front Neurosci 8:157|
|Lee, Daniel A; Salvatierra, Juan; Velarde, Esteban et al. (2013) Functional interrogation of adult hypothalamic neurogenesis with focal radiological inhibition. J Vis Exp :e50716|
|Lee, Daniel A; Blackshaw, Seth (2012) Functional implications of hypothalamic neurogenesis in the adult mammalian brain. Int J Dev Neurosci 30:615-21|
|Lee, Daniel A; Bedont, Joseph L; Pak, Thomas et al. (2012) Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche. Nat Neurosci 15:700-2|