Review
Hypothalamic neurogenesis in the adult brain

https://doi.org/10.1016/j.yfrne.2013.05.001Get rights and content

Highlights

  • Hypothalamic neurogenesis is essential in a functioning energy-balance system.

  • Role of hypothalamic neurogenesis in adaptive behavior of animals.

  • The common features of hippocampal, SVZ and hypothalamic neurogenes.

Abstract

Adult-born new neurons are continuously added to the hippocampus and the olfactory bulb to serve aspects of learning and perceptual functions. Recent evidence establishes a third neurogenic niche in the ventral hypothalamic parenchyma surrounding the third ventricle that ensures the plasticity of specific brain circuits to stabilize physiological functions such as the energy-balance regulatory system. Hypothalamic lesion studies have demonstrated that regions associated with reproduction-related functions are also capable of recruiting newborn neurons to restore physiological functions and courtship behavior. Induced by lesion or other stimulation, elevated neurotrophic factors trigger neurogenic cascades that contribute to remodeling of certain neural circuits to meet specific transient functions. This insight raises the possibility that event-specific changes, such as increased GnRH, may be mediated by courtship-sensitive neurotrophic factors. We will discuss the potentially integral and ubiquitous roles of neurogenesis in physiological and biological phenomena, roles that await future experimental exploration.

Introduction

Postnatal neurogenesis is conserved across species, from crustaceans (Harzsch and Dawirs, 1996) to higher vertebrates, including birds (Goldman, 1998, Goldman and Nottebohm, 1983), rodents (Alvarez-Buylla and Lim, 2004, Cameron et al., 1993, Kempermann et al., 1997), primates (Gould et al., 1999b, Kornack and Rakic, 1999), and humans (Arvidsson et al., 2002, Eriksson et al., 1998). In phylogenetically more recent species, however, postnatal neurogenesis appears to be more limited to specific events and specific locations in the brain. For example, it is widely acknowledged that adult neurogenesis in mammals is confined to the hippocampal dentate gyrus and the subependymal layer of the subventricular zone, SVZ (Gage, 2002, Gage et al., 1998). The SVZ neurogenic pool contributes to the olfactory bulb (Lois and Alvarez-Buylla, 1994), the substantial nigra (Zhao et al., 2003), the amygdala and adjoining cortex (Bernier et al., 2002), and striatum (Bedard et al., 2002, Bedard et al., 2006, Dayer et al., 2005, but see Luzzati et al., 2006), and to various telencephalic regions of song bird brain, of which most prominent are some of the song control nuclei (Goldman, 1998, Goldman and Nottebohm, 1983). Findings suggesting that adult neurogenesis occurs in the hypothalamus have been met with skepticism. In 2004, a landmark study (Markakis et al., 2004) isolated neural progenitor cells from the hypothalamus. Subsequently, research identifying neurogenically rich areas of the hypothalamus (Kokoeva et al., 2005, Lee et al., 2012) unveiled a critical role for adult neurogenesis in specific physiological mechanisms, endocrine functions and the behavioral control of hypothalamic functions.

This review will cover (1) evidence for a neurogenic niche in the adult hypothalamus, (2) evidence that adult neurogenesis can be induced by lesions in the hypothalamic regions outside of the neurogenic niche, (3) discussion of the ways in which the unique properties of adult neurogenesis and their link to neurotrophic factors may underlie the adaptive nature of multiple functions of the hypothalamus as well as the hippocampus and SVZ, and (4) critical assessment of many published articles linking adult neurogenesis and behavior, with a call for more stringent criteria for identifying new neurons in studies of the endocrine and behavioral implications of neurogenesis.

Section snippets

The 3rd ventricle

The first evidence that the adult hypothalamus is capable of neurogenesis was demonstrated in culture media (Evans et al., 2002). Blocks from adult hypothalamic tissue were labeled with antibodies to several neuronal and astrocyte markers indicating the presence of mitotic cells at this level. Next, Markakis et al. (2004) identified a range of hypothalamic peptides including corticotrophin-releasing hormone, growth hormone-releasing hormone, gonadotropin-releasing hormone, somatostatin,

3rd ventricle newborn cells and fat-responsive mechanisms

The link of adult-born neurons to the 3rd ventricle became known rather serendipitously during efforts to account for the intriguing finding that the neurocytokine ciliary neurotrophic factor (CNTF) causes anorexia and weight loss (Gloaguen et al., 1997). CNTF and its analogue Axokine were developed as drugs to lower body weight. The drug’s appeal rests on the fact that its weight losseffect continues for weeks, in some cases up to 12 months, after cessation of treatment (Ettinger et al., 2003).

The hypothalamus was originally thought to be a non-neurogenic region

It has been common in scientific and nonscientific literature to single out the hippocampus and the SVZ (Gage, 2002, Gage et al., 1998) as exemplary sites of adult neurogenesis producing neurons that are for example incorporated into the avian song system (Nottebohm, 1985, Nottebohm, 2002). With the finding that lesion-induced neurogenesis occurs in the striatum of adult rats (Margavi et al., 2000), the possibility that neurogenesis occurs elsewhere in the adut brain has been seriously

Survival of new neurons

Adult neurogenesis consists of the following three phases: cell proliferation at the birth site, cell migration to the target site, and differentiation into mature cells that form synaptic contacts and become fully functional. Many factors contribute to the maturation process. Compelling findings suggest that proper external stimulation helps to consolidate synapses and hence survival of the neurons (e.g. Chen et al., 2006, Kempermann et al., 1997). This has been shown in the hippocampus; rats

Characteristics common to neurogenic niches in the hypothalamus, hippocampus and subventricular zone

Two neurogenic niches have been studied extensively and rigorously documented at the time of this writing: they are located in the SVZ (Alvarez-Buylla and Lim, 2004, Lois and Alvarez-Buylla, 1994) and the hippocampus (Gage et al., 1998, Gould, 2007). Recent findings regarding a hypothalamic neurogenic niche in the regions surrounding the 3rd ventricle, in particular the median eminence (Lee et al., 2012, Perez-Martin et al., 2010), indicate that this additional niche shares many features with

Neurotrophic factors and adult neurogenesis

In order to understand the specific roles of the link between neurotrophic factors and neurogenesis in the regulatory functions of physiological and biological systems centered in the hypothalamus, we will first review the established relationships between neurotrophic factors and adult neurogenesis.

The basal proliferative activity in the well-documented neurogenic niches (the SVZ, hippocampus, and hypothalamus) does not seem to rely on endogenous neurotrophic factors (but see Thoenen, 1995),

Transient nature of adult neurogenesis

Animals and human beings alike are equipped with well-regulated functional systems, such as the circulatory and respiratory systems. Both animals and humans also engage in time-sensitive and event-specific activities, such as reproduction. During breeding, the subjects require enhanced or modified neural circuitries and elevated abilities to respond to specific stimuli. By one account, at most 50% of neurons born in the adult brain for a specific event survive for longer than a month (Lledo et

Concluding remarks

In summary, we now have identified three demonstrable physiologically active neurogenic centers in the adult brain of birds and mammals. Newborn neurons observed in other regions besides these three centers have presumably migrated from the SVZ (i.e. Bernier et al., 2002, Cao et al., 2002, Mohapel et al., 2005) or were born following pharmacological manipulations after external infusion of neurotrophic factors (i.e. Pencea et al., 2001, Perez-Martin et al., 2010). In light of the research

Acknowledgments

I would like to thank Dr. Martha Chaiken for expert editing. This work was supported by the Rutgers Research Fund.

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