Hypothalamic Neurons Take Center Stage in the Neural Stem Cell Niche

Abstract

Neural stem cells (NSCs) are a heterogeneous population of cells that generate new neurons in adult animals. Recently in Science, Paul et al. (2017) show that hypothalamic neurons control activation of a subset of NSCs in response to feeding, providing insights into how physiological cues may influence stem cell activation.

Adult endogenous stem cells reside in specialized niches that maintain them in an undifferentiated state. Elucidating the mechanisms that restrict the effects of niche-derived signals to stem cells is critical to understanding how stem cells self-renew while their progeny differentiate. Numerous studies in a variety of tissues have highlighted the importance of the microenvironment in modulating stem cell behavior (Birbrair and Frenette, 2016). Although significant progress has been made in understanding signals that foster stem cell behavior, dissecting the pathways leading to neural stem cell (NSC) activation in the adult brain is challenging due to the complexity of niche composition and its dynamics. Although NSCs are known to be regulated by several neuronal subtypes that project from varied regions of the brain (Lim and Alvarez-Buylla, 2016), how physiological stimuli contribute to NSC activity is not well understood. Deciphering the mechanisms that couple neuronal activity to NSC behavior may lead to understanding how brain plasticity works in normal conditions and in the context of neurological disorders.

In a recent article in Science, Fiona Doetsch and colleagues demonstrated that a subtype of hypothalamic neurons important in the control of hunger and satiety regulate proliferation of a subset of adult NSCs in vivo (Paul et al., 2017). They first performed an in vitro small-molecule screen that identified β-endorphin as an extrinsic cue that activates quiescent NSCs. Since β-endorphin is a posttranslational cleavage product of proopiomelanocortin (POMC), they next investigated the role of POMC-expressing neurons in the NSC niche. Through Cre/LoxP-based labeling of hypothalamic POMC neurons, they found that those neurons selectively innervate only the anterior ventral region of the subventricular zone (AV-SVZ) niche, in which a subpopulation of Nkx2.1 + NSCs resides. Through sophisticated in vivo inducible genetic approaches, the authors acutely increased the activity of POMC-expressing neurons using activating DREADD vectors or selectively eliminated them by genetic activation of cleaved caspase-3. These experiments revealed that POMC-expressing neurons specifically regulate proliferation of the Nkx2.1+ NSC population within the AV-SVZ and, consequently, the production of a specific subtype of olfactory bulb interneuron (Paul et al., 2017). Strikingly, Paul et al. showed that manipulating hypothalamic neural activity via inducing a fast or providing food ad libitum affected NSC proliferation, demonstrating that satiety and hunger states specifically regulate activation of Nkx2.1 + NSCs in the AV-SVZ via POMC-expressing neurons. Thus, this study brings to light a new component of the NSC niche, and it links physiological states to activation of NSCs.

The findings by Paul et al. (2017) reveal that adult neurogenesis is not a disconnected process that is regulated independently of brain activity (Figure 1). Indeed, the generation of new neurons at least in part seems to be an activity-dependent response to experiences that may adapt brain structures for improved reactions to future conditions. The SVZ is innervated by neuronal projections from several brain regions, and defining the cellular and molecular mechanisms through which activity of neuronal networks translates into NSC-mediated structural modifications may prove useful in identifying pharmacologically susceptible targets to adjust NSC activity in homeostasis and in the context of neuro-degenerative processes.

Figure 1. POMC-Expressing Neurons are a Key Component of the SVZ NSC Niche.

The NSC niche is a specialized microenvironment that supports NSCs and provides them with behavioral cues. Paul et al. show that POMC+ neurons projecting from the hypothalamus are a key component of the anterior ventral portion of the SVZ NSC niche. Physiological manipulation of these POMC+ neurons via feeding and fasting leads to activation of a subset of NSCs and a consequent increase in production of a specific subtype of interneuron within the olfactory bulb.

Many of the experiments in this paper utilize POMC-Cre mice. Importantly, however, expression of POMC is not restricted to hypothalamic neurons. Hormone-producing endocrine cells, such as corticotrophs and melanotrophs, also express POMC, and it is possible that they may influence NSC behavior in some of the experiments. Additionally, some neural progenitors express POMC during their specification and differentiation but only a subset adopt a POMC+ terminal fate in adults (Padilla et al., 2010). For example, POMC-expressing neural progenitors can give rise to agouti-related peptide-expressing neurons that mediate energy balance and to Kiss1-expressing neurons that are critical for the regulation of reproductive function (Sanz et al., 2015).

Moreover, neurogenesis in the adult brain is not restricted to the SVZ. The sub-granular zone of the dentate gyrus in the hippocampus is another site of adult neurogenesis (Ming and Song, 2011), and Cre expression is also detected in the hippocampus of POMC-Cre mice (McHugh et al., 2007). Therefore, future studies should focus on investigating the role of POMC-expressing cells in the dentate gyrus niche. Paul and colleagues suggest that β-endorphin activates NSCs (Paul et al., 2017). While β-endorphin can be derived from processing of POMC, the exact source of β-endorphin in the AVSVZ zone remains elusive. β-endorphin is produced in several cell types, including neurons, interneurons, microglia, and others (Fichna et al., 2007), and it is also present in the cerebrospinal fluid. Thus, there are multiple sources of endogenous β-endorphin that may influence NSC activity. Endogenously released β-endorphin specifically activates μ-opioid receptors, and although μ-opioid receptors are widely distributed throughout the nervous system during development (Kim et al., 2006), little is known about their involvement in NSC activation. As NSCs are a heterogeneous population, it remains unclear whether/which quiescent NSCs express β-endorphin receptors. Additionally, as POMC-expressing neurons produce a variety of biologically active peptides, future studies should explore whether other molecules produced by POMC-expressing neurons may be important in NSC regulation.

Paul et al. revealed that hypothalamic POMC-expressing neurons regulate the production of deep granule cell layer interneurons in the olfactory bulb via NSC activation (Paul etal., 2017). Interestingly, it has been suggested that female olfaction is more effective than the male olfactory system (Doty and Cameron, 2009). Although the authors did not examine gender-specific effects in this study (Paul et al., 2017), an important question will be whether NSC microenvironments exhibit gender differences in their physiological maintenance function. Despite these open questions, these findings reveal direct control of a subpopulation of adult NSCs by a select group of hypothalamic neurons that couple physiological and behavioral stimuli to generation of distinct terminal neurons. Together, the work by Paul et al. brings us closer to comprehending neurogenesis in the adult mammalian brain and, eventually, to using this information to develop better therapeutic approaches to neurological disorders.