Review articleRegulation and function of neurogenesis in the adult mammalian hypothalamus
Introduction
For much of the 20th century, it was regarded as an iron-clad fact that mammalian neurogenesis occurs during embryonic and early postnatal development (Colucci-D’Amato et al., 2006). Dubbed by some the ‘central dogma of neurobiology’, this is still widely believed by lay audiences, and remains one of the most broadly held public misconceptions about the brain (Horstman, 2010). Over the past few decades, with the development of progressively better tools for labeling and tracking newborn neurons, studies in multiple species has made it clear that substantial levels of neurogenesis occur in several brain regions in adult mammals.
The two main regions of active neurogenesis in adult rodent brain occur in the subventricular zone (SVZ) of lateral ventricles and the subgranular zone (SGZ) of dentate gyrus in hippocampus. The SVZ produces immature neurons that can migrate along the rostral migratory stream (RMS) connecting to the olfactory bulb, where they then differentiate into mature neurons that process olfactory input (Lim and Alvarez-Buylla, 2016). The SGZ gives rise to granule cells of the dentate gyrus, which process information relevant to learning and memory (Song et al., 2012). The behavioral phenotypes that are observed following inhibition of adult neurogenesis in these regions, along with the fact that adult neurogenesis is observed in many different mammalian species, implies that this process is functionally important and evolutionarily conserved (Christian et al., 2014, Valley et al., 2009, Yun et al., 2016, Sakamoto et al., 2011). These studies have in turn raised the question of whether neurogenesis may occur in other brain regions, either at lower levels or in response to specific physiological states. Over the past decade, evidence has accumulated that low levels of post-developmental neurogenesis occur in multiple mammalian brain regions, including the neocortex, striatum and spinal cord (Qin et al., 2015). For several reasons, the brain region that has received the most attention as a possible site of low-level adult neurogenesis is the hypothalamus.
First among these reasons is the presence of a plausible candidate neurogenic niche in the form of the ventricular zone of the basal hypothalamus. Analysis of neurogenic zones in the SVZ and SGZ, as well as the more broadly distributed ventricular neurogenic zones of cold-blooded vertebrates, have identified several common components of a neurogenic niche (Bjornsson et al., 2015). These include firstly, a stem/progenitor cell population; secondly, the presence of perivascular basal lamina and other extracellular matrixes harboring soluble factors and cellular molecules that are derived from nearby cells and blood vessels; and finally, persistent expression of developmental morphogens and signaling molecules that contribute to the maintenance or regulation of multipotency and proliferative competence. In the hypothalamus, tanycytes and associated cells of the ventricular zone are strong candidate stem/progenitor cells, while the highly vascularized basal hypothalamic parenchyma and persistent expression of multiple morphogens, cytokines and growth factors all constitute a potentially favorable extracellular environment for neurogenesis.
A second reason is that very low levels of hypothalamic neurogenesis can potentially have outsized effects on physiology and behavior. The hypothalamus is a central homeostatic regulator of many different physiological processes, including sleep, circadian rhythms, core body temperature, blood pressure, thirst, and appetite (Swaab, 2004). It serves as the cockpit of the neuroendocrine system, secreting hormones to the blood that regulate release of pituitary hormones. Located partially outside the blood-brain barrier, the hypothalamus also serves as the main site where changes in levels of circulating metabolites and hormones are sensed, and are used to modulate behavior. The hypothalamus is thus exquisitely positioned to undergo plastic changes in response to long-term changes in environmental conditions. Adding small numbers of specific subtypes of neurons to neural circuits that control these processes could be an effective and parsimonious means of accomplishing this. For this reason, we would expect any levels of hypothalamic neurogenesis to both be low and be highly dependent on changes in diet or hormonal state. These facts add the challenge of detecting and studying hypothalamic neurogenesis.
Third, over the past decade, evidence has accumulated from multiple groups for the existence of postnatal hypothalamic neurogenesis in mammals, although there remains considerable disagreement about its extent, regulation and the source and function of newborn neurons. This review aims to critically review these findings, and build a clearer picture of the precise characteristics of the hypothalamic neural niche, the role of extrinsic factors in controlling hypothalamic neurogenesis, and the function of new neurons generated in juvenile and adult hypothalamus.
Section snippets
The neurogenic niche in postnatal hypothalamus
The existence of neural stem cells in the adult hypothalamus was first proposed following studies that reported that cells of the hypothalamic ventricular zone were capable of forming multipotent neurospheres in vitro, which gave rise to neurons, astrocytes and oligodendrocytes (Weiss and Multipotent et al., 1996). Though the neurogenic potential of hypothalamic ventricular cells was small compared to that of lateral ventricles, cells of the hypothalamic parenchyma showed negligible neurogenic
Control of energy homeostasis
For several reasons, most studies of the functional role of postnatal hypothalamic neurogenesis have focused on its role in regulating metabolism and body weight (Sousa-Ferreira et al., 2014). First among these reasons is the fact that the mediobasal hypothalamus, where the great majority of studies on this topic focused, is a central regulator of food intake and activity. Neurons of the ArcN and ME, in particular, are directly responsive to cues that regulate feeding and satiety. Other nuclei
Conclusion
The past two decades have seen a steady accumulation of evidence suggesting that neurogenesis can occur in the adult mammalian hypothalamus (Table 1, Table 2, Table 3). The first studies to hint at this possibility arose from in vitro analysis of neurosphere formation (Weiss and Multipotent et al., 1996), or used slow i.c.v. infusion of BrdU to label neurons in the hypothalamic parenchyma (Pencea et al., 2001). Later studies used viral or genetic cell lineage analysis to identify both tanycytes
Acknowledgements
We thank W. Yap for comments on the manuscript. This work was supported by a grant from NIH (R01DK108230) to S.B.
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