Elsevier

Progress in Neurobiology

Volume 170, November 2018, Pages 53-66
Progress in Neurobiology

Review article
Regulation and function of neurogenesis in the adult mammalian hypothalamus

https://doi.org/10.1016/j.pneurobio.2018.04.001Get rights and content

Highlights

  • Over the past two decades, evidence has accumulated neurogenesis can occur in the adult mammalian hypothalamus.

  • Levels of adult hypothalamic neurogenesis are very low, age-dependent, and regulated by a range of physiological conditions.

  • The source of newborn neurons is controversial. Tanycytes are the most likely candidate, although cells may contribute.

  • Standardizing experimental protocols and model systems is likely to substantially accelerate future progress in the field.

  • Studies of radial glial cell types such as retinal Müller glia may help identify genes regulating hypothalamic neurogenesis.

Abstract

Over the past two decades, evidence has accumulated that neurogenesis can occur in both the juvenile and adult mammalian hypothalamus. Levels of hypothalamic neurogenesis can be regulated by dietary, environmental and hormonal signals. Since the hypothalamus has a central role in controlling a broad range of homeostatic physiological processes, these findings may have far ranging behavioral and medical implications. However, many questions in the field remain unresolved, including the cells of origin of newborn hypothalamic neurons and the extent to which these cells actually regulate hypothalamic-controlled behaviors. In this manuscript, we conduct a critical review of the literature on postnatal hypothalamic neurogenesis in mammals, lay out the main outstanding controversies in the field, and discuss how best to advance our knowledge of this fascinating but still poorly understood process.

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.

References (145)

  • J.K. Elmquist

    Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin

    Physiol. Behav.

    (2001)
  • N.G. Forger

    Cell death and sexual differentiation of the nervous system

    Neuroscience

    (2006)
  • T. Furukawa

    rax: Hes1, and notch1 promote the formation of Muller glia by postnatal retinal progenitor cells

    Neuron

    (2000)
  • D. Gallina et al.

    A comparative analysis of Muller glia-mediated regeneration in the vertebrate retina

    Exp. Eye Res.

    (2014)
  • R.A. Gorsuch

    Sox2 regulates Muller glia reprogramming and proliferation in the regenerating zebrafish retina via Lin28 and Ascl1a

    Exp. Eye Res.

    (2017)
  • M. Horowitz

    From molecular and cellular to integrative heat defense during exposure to chronic heat

    Comp. Biochem. Physiol. A Mol. Integr. Physiol.

    (2002)
  • I. Iandiev

    Atypical gliosis in Muller cells of the slowly degenerating rds mutant mouse retina

    Exp. Eye Res.

    (2006)
  • S.H. Kang

    NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration

    Neuron

    (2010)
  • S.G. Kernie et al.

    Forebrain neurogenesis after focal Ischemic and traumatic brain injury

    Neurobiol. Dis.

    (2010)
  • O. Lazarov

    When neurogenesis encounters aging and disease

    Trends Neurosci.

    (2010)
  • J.R. Lenkowski et al.

    Muller glia: stem cells for generation and regeneration of retinal neurons in teleost fish

    Prog. Retin. Eye Res.

    (2014)
  • M.S. Ma

    Multipotent stem cell factor UGS148 is a marker for tanycytes in the adult hypothalamus

    Mol. Cell. Neurosci.

    (2015)
  • M. Migaud

    Seasonal regulation of structural plasticity and neurogenesis in the adult mammalian brain: focus on the sheep hypothalamus

    Front. Neuroendocrinol.

    (2015)
  • S. Murakami et al.

    Neuronal death in the developing sexually dimorphic periventricular nucleus of the preoptic area in the female rat: effect of neonatal androgen treatment

    Neurosci. Lett.

    (1989)
  • H. Nakatomi

    Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors

    Cell

    (2002)
  • E.I. Ahmed

    Pubertal hormones modulate the addition of new cells to sexually dimorphic brain regions

    Nat. Neurosci.

    (2008)
  • A. Arvidsson

    Neuronal replacement from endogenous precursors in the adult brain after stroke

    Nat. Med.

    (2002)
  • D.F. Aschauer

    Analysis of transduction efficiency, tropism and axonal transport of AAV serotypes 1, 2, 5, 6, 8 and 9 in the mouse brain

    PLoS One

    (2013)
  • M. Batailler

    DCX-expressing cells in the vicinity of the hypothalamic neurogenic niche: a comparative study between mouse, sheep, and human tissues

    J. Comp. Neurol.

    (2014)
  • M. Batailler

    Sensitivity to the photoperiod and potential migratory features of neuroblasts in the adult sheep hypothalamus

    Brain Struct. Funct.

    (2016)
  • R.L. Bernardos

    Late-stage neuronal progenitors in the retina are radial Muller glia that function as retinal stem cells

    J. Neurosci.

    (2007)
  • E.P. Bless

    Oestradiol and diet modulate energy homeostasis and hypothalamic neurogenesis in the adult female mouse

    J. Neuroendocrinol.

    (2014)
  • E.P. Bless

    Adult neurogenesis in the female mouse hypothalamus: estradiol and high-fat diet alter the generation of newborn neurons expressing estrogen receptor alpha

    eNeuro

    (2016)
  • J.R. Brawer et al.

    Response of tanycytes to aging in the median eminence of the rat

    Am. J. Anat.

    (1982)
  • L. Butruille

    Seasonal reorganization of hypothalamic neurogenic niche in adult sheep

    Brain Struct. Funct.

    (2018)
  • J.N. Campbell

    A molecular census of arcuate hypothalamus and median eminence cell types

    Nat. Neurosci.

    (2017)
  • Z. Chaker

    Suppression of IGF-I signals in neural stem cells enhances neurogenesis and olfactory function during aging

    Aging Cell

    (2015)
  • M.L. Chang

    Reactive changes of retinal astrocytes and Muller glial cells in kainate-induced neuroexcitotoxicity

    J. Anat.

    (2007)
  • K.M. Christian et al.

    Functions and dysfunctions of adult hippocampal neurogenesis

    Annu. Rev. Neurosci.

    (2014)
  • J.L. Close

    Retinal neurons regulate proliferation of postnatal progenitors and Muller glia in the rat retina via TGF beta signaling

    Development

    (2005)
  • L. Colucci-D’Amato

    The end of the central dogma of neurobiology: stem cells and neurogenesis in adult CNS

    Neurol. Sci.

    (2006)
  • C. Conner

    Repressing notch signaling and expressing TNFalpha are sufficient to mimic retinal regeneration by inducing Muller glial proliferation to generate committed progenitor cells

    J. Neurosci.

    (2014)
  • J. de Melo

    Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2

    Proc. Natl. Acad. Sci. U. S. A.

    (2012)
  • S. Darmanis

    A survey of human brain transcriptome diversity at the single cell level

    Proc. Natl. Acad. Sci. U. S. A.

    (2015)
  • L. Dimou

    Progeny of Olig2-expressing progenitors in the gray and white matter of the adult mouse cerebral cortex

    J. Neurosci.

    (2008)
  • A.J. Fischer et al.

    Turning Muller glia into neural progenitors in the retina

    Mol. Neurobiol.

    (2010)
  • A.J. Fischer et al.

    Muller glia are a potential source of neural regeneration in the postnatal chicken retina

    Nat. Neurosci.

    (2001)
  • A.J. Fischer

    Insulin and fibroblast growth factor 2 activate a neurogenic program in Muller glia of the chicken retina

    J. Neurosci.

    (2002)
  • A.J. Fischer

    Different aspects of gliosis in retinal Muller glia can be induced by CNTF, insulin, and FGF2 in the absence of damage

    Mol. Vis.

    (2004)
  • L.G. Fritsche

    Seven new loci associated with age-related macular degeneration

    Nat. Genet.

    (2013)
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