Adult neurogenesis: a real hope or a delusion?

Abstract

Adult neurogenesis, the process of creating new neurons, involves the coordinated division, migration, and differentiation of neural stem cells. This process is restricted to neurogenic niches located in two distinct areas of the brain: the subgranular zone of the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle, where new neurons are generated and then migrate to the olfactory bulb. Neurogenesis has been thought to occur only during the embryonic and early postnatal stages and to decline with age due to a continuous depletion of neural stem cells. Interestingly, recent years have seen tremendous progress in our understanding of adult brain neurogenesis, bridging the knowledge gap between embryonic and adult neurogenesis. Here, we discuss the current status of adult brain neurogenesis in light of what we know about neural stem cells. In this notion, we talk about the importance of intracellular signaling molecules in mobilizing endogenous neural stem cell proliferation. Based on the current understanding, we can declare that these molecules play a role in targeting neurogenesis in the mature brain. However, to achieve this goal, we need to avoid the undesired proliferation of neural stem cells by controlling the necessary checkpoints, which can lead to tumorigenesis and prove to be a curse instead of a blessing or hope.

Introduction

The process of generating mature and functional neurons from neural stem cells (NSCs) is known as adult neurogenesis. There are several types of NSCs, such as radial glial cells (RGCs), neuroepithelial cells, intermediate neuronal precursors, basal progenitors, radial astrocytes of the subgranular zone, and astrocytes of the subventricular zone (SVZ). These cells lead to the development of a specific neuronal phenotype and the functional integration of neuronal circuits, including synapse formation and neurotransmitter release. The majority of NSCs in the adult brain are quiescent. Fortunately, NSCs in the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus and the ventricular SVZ (V-SVZ) progressively divide to become transit-amplifying progenitors via a state known as activated NSCs and subsequently produce new neurons. The idea of adult neurogenesis in the mammalian brain dates back to the 1960s, and it has now been established that it largely involves the V-SVZ and SGZ throughout life. Neurogenesis is restricted to specific regions of the adult brain, neurogenic niches, and influences how the brain forms during embryonic development. However, although neurogenesis is thought to occur only during development, recent advances in neuroscience are challenging this old view (Dennis et al., 2016; Cipriani et al., 2018; Moreno-Jiménez et al., 2019; Terstege et al., 2022). In the last decade, different reviews have tried to cover this aspect and find out whether adult neurogenesis is a real hope or a delusion, but until now this question remains unanswered (Zagrean, 2014; Liu and Song, 2016; Kempermann et al., 2018; Shohayeb et al., 2018; Kase et al., 2020).

In accordance with conventional wisdom, neurogenesis only happens during the embryonic and prenatal stages in mammals. This was the “core dogma of neurobiology.” The fundamental idea of “neuron doctrine,” which dates back to 1894, is that the complicated nervous system is made up of clearly defined individual cells called neurons. The widespread consensus for many years was that these specific cells cannot regenerate in the adult brain. Furthermore, Santiago Ramon y Cajal stated in 1913 that “In adult centers, the neural routes are fixed, terminated, and immutable. Nothing can be guaranteed to live forever” (Hamburger, 1980).

This misconception about adult neurogenesis persisted until Altman reported that new neurons could be generated in the DG and SVZ of the adult brain in cat and rat models (Altman, 1962, 1963; Altman and Das, 1965). Subsequently, Fernando Nottebohm found evidence for this in songbirds (Nottebohm, 1989). Adult macaque monkeys also show neurogenesis, but their rate is ten times lower than that of rodents (Gould et al., 1999). On the other hand, whales and dolphins do not show this phenomenon because of their tiny hippocampi. Adult neurogenesis in humans was first documented in the postmortem tissue of cancer patients (Eriksson et al., 1998). Then, in 2013, Jonas Friesen’s lab used carbon dating techniques to determine that the human DG adds up to 700 neurons per day (Spalding et al., 2013). However, experts in the field suspected that the technique might label dying cells instead of dividing ones, creating false signals of neurogenesis, and that the protein markers might unintentionally label a different type of brain cell called glia instead of neurons. As a result, studies using carbon 14 can produce unreliable results and are prone to noise and contamination (Sorrells et al., 2018).

Neural stem/progenitor cells (NSPCs) have the potential to multiply in vitro, when isolated from the embryonic brain tissues, under predetermined cell culture conditions containing fibroblast growth factor-2 or epidermal growth factor. High levels of fibroblast growth factor-2 recruit the multipotent precursor for the generation of both neuronal and glial progenitor populations in the adult brain. This shows that brain regions retain NSPCs as well as the necessary environment, also known as the stem cell niche, for neurogenesis (Palmer et al.,1999; Kuhn et al., 2018). We have found a gap between research approaches that tried to focus on this aspect. We have made an effort to address this issue by focusing on the molecular factors that have the potential to significantly change adult neurogenesis and serve as a promising avenue for future research.

Search Strategy

We employ a variety of search engines, including PubMed, Google Scholar, Scopus, and Web of Science, along with keywords like “adult neurogenesis”, “neural stem cells”, “neurogenic niches”, “Notch”, “Wnt”, “neurotrophic factors”, ‘aging”, and “oxidative stress”. The goal of our work is to identify the variables that are essential for controlling neurogenesis by focusing on NSCs.

Embryonic versus Adult Neurogenesis

Only distinct regions of the brain remain active throughout childhood and adulthood in terms of neurogenesis. Neurogenesis appears to occur in the brains of adult mammals, even though it is still controversial. In the embryonic central nervous system, neuronal progenitors are largely found in the SVZ of all ventricles, and under closely regulated circumstances, neurogenesis takes place throughout the nervous system. Adult neurogenesis appears to be restricted to the SVZ and the SGZ of DG in the hippocampus under physiological conditions. In both embryos and adults, neurogenesis is orchestrated by a wide variety of regulatory systems. Paracrine substances, neurotransmitters, and hormones promote or impair the proliferation, differentiation, migration, or maturation of neuronal progenitors. Further, diffusible and membrane-bound substances from the target areas may also draw or repel neuroblasts, affecting how quickly they mature and integrate into the circuitry at their final destination. Moreover, cannabinoid receptors, endocannabinoid synthesis, degradation enzymes, and their presence in NSPCs regulate neurogenesis in both developing and adult brains (Paridaen and Huttner, 2014; de Oliveira et al., 2019).

What makes separate or special regulatory systems necessary for adult neurogenesis? First and foremost, the environment to which NSCs and their progeny are exposed is a key distinction between the developing and the adult brain. Adult NSCs in the subependymal zone, directly neighbor the ependymal cells as well as the vascular network in contrast to the RGCs that are in close touch with migratory neurons in embryos. Many glial cells, including mature oligodendrocytes, NG2 glia, and astrocytes, surround adult NSCs in the DG, which were absent at embryonic stages. The majority of embryonic neurogenesis occurs in a privileged environment where neurogenesis is the default fate and gliogenesis is still prohibited, with RGCs acting as NSCs being the almost only glial cells present (apart from some NG2 glia that arrives at embryonic stages). Adult neurogenesis must overcome this inherently gliogenic milieu because embryos do not experience this problem. Another characteristic that distinguishes adult NSCs from their embryonic counterparts is their control over the cell cycle. In contrast to other brain regions, like the cerebral cortex, where neurogenesis is halted after development, some characteristics of adult NSCs, like self-renewal and relatively slower cell-cycle progression, are already present in the embryonic RGCs in the region generating the adult NSCs at the lateral wall of the lateral ventricle. The mechanisms enabling such region-specific cell-cycle regulation in NSCs in the adult subependymal zone and embryonic lateral ganglionic eminence are an important area for further research (Götz et al., 2016).

It has become clear that embryonic and adult stem cells are not versatile and they are committed to the production of particular neural cells (Taverna et al., 2014). Adult NSCs of the B type can develop into certain kinds of granule cells (GCs) and periglomerular cells in the olfactory bulb in murine V-SVZ. Different transcription factors such as Pax6, Nkx6.2, Gsx2, and Nkx2.1, which were also implicated in the differential domain expression of the embryonic telencephalon, are expressed in different NSCs (López-Juárez et al., 2013; Merkle et al., 2014; Obernier et al., 2014).

Similar to embryonic RGCs, NSCs express Nestin, SRY-box 2 (Sox2), and glial fibrillary acidic protein molecules in adult neurogenic niches. Regarding their quiescence time and location in a stable and sophisticated cellular niche, adult NSCs differ from embryonic NSCs. Moreover, embryonic NSCs are substantially more proliferative than adult NSCs which have specific progeny cells that can spend a long time in the cell cycle’s Go phase to prevent stem cell exhaustion (Orford and Scadden, 2008; Simons and Clevers, 2011).

Notably, gamma-aminobutyric acid (GABA)’s mode of action was comparable throughout both embryonic and adult neurogenesis. It can inhibit adult NSCs activation in the SGZ and reduce the number of proliferating cells in the subependymal zone (Song et al., 2012). GABA activation, however, reduces basal progenitors’ proliferation in embryos while increasing it in the VZ and peripheral neural crest stem cells (Götz et al., 2016).

Different intrinsic regulators are involved in controlling adult neurogenesis and embryonic development. From embryonic to adult neurogenesis, many signaling variables change, although some signaling sources are present and persistently active at both phases. Here, the effects of signaling molecules and transcription factors on neurogenesis in both phases are briefly described. NSCs and granule neurons both release bone morphogenetic proteins (BMPs), which have an impact on NPCs. In both phases of neurogenesis, type 1 BMP receptors are shown to act differently; during embryonic neurogenesis, they promote the proliferation of NPCs, whereas, during adult neurogenesis, they maintain the quiescent state of the stem cells in the SGZ (Mira et al., 2010).

Wnt proteins are also essential for adult and post-natal neurogenesis. Wnts can act in a paracrine or autocrine fashion and are secreted by astrocytes and stem cells. It stimulates the expression of neural differentiation 1 (NeuroD1), neurogenin-2 (Neurog2), and prospero-related homeobox 1 (Prox1) and play role in the maturation and synapse creation of adult-born neurons. It increases NPCs proliferation as well as neuronal differentiation during embryonic development. They are also linked to adult neurogenesis, quiescent stem cell activation, and neuronal differentiation (Kuwabara et al., 2009).

It is interesting to note that Notch preserves the pool of NSCs during both embryonic and adult neurogenesis by preventing early differentiation and preventing escape from the quiescent state, respectively. The transcriptional regulator T-box brain protein 2 is essential for the differentiation and proliferation of intermediate progenitor cells (IPCs), Prox1 controls the identity of granule precursor cells, and Neurog2 determines glutamatergic differentiation. Nuclear orphan receptor tailless (Tlx), Cyclin D2 (CcnD2), and achaete-scute homolog 1 (Ascl1) gene expression is necessary for the proliferation of NSCs during adult neurogenesis even though it is not necessary for the development of DG during embryonic neurogenesis (for detail see Urbán and Guillemot, 2014 and Sueda and Kageyama, 2020).

Neurogenic Regions in Adult Brain

In order to maintain the balance and health of a mammalian brain over its lifetime, adult NSCs must continue to divide and differentiate. They continuously give rise to neurons and astrocytes in the neurogenic niches. Upon receiving both intrinsic and external signals, NSCs become active and begin to proliferate. The balance between quiescence and proliferation, self-renewal and differentiation, are intricately regulated by a variety of variables. We will discuss these factors in detail in the next section of this review (Zelentsova et al., 2017).

In the adult brain, there are two specific neurogenic regions where NSCs and originating NPCs generate new neurons under physiological conditions:

1. The SVZ of the lateral ventricles where NPCs give rise to cells that migrate toward the olfactory bulb.

2. The SGZ of the DG in the hippocampus is where new GCs integrate themselves into local neuronal networks (Aimone et al., 2010).

Olfactory bulb

The olfactory bulb is one of the regions in the brain where neurogenesis takes place. First, in adult SVZ, activated radial glia-like (RGL) cells transform into amplifying cells, which eventually give rise to neuroblasts. In the rostral migratory stream, neuroblasts continue to chain together before migrating toward the olfactory bulb through a tube created by astrocytes. These immature neurons grow into intermediate neurons near the center of the olfactory bulb. They primarily develop into GABAergic granule neurons, while some also become GABAergic periglomerular neurons. Although these newly formed adult neurons resemble mature neurons that originated during the embryonic stage, however, at this stage they do not fully possess the characteristics of mature neurons (Ming and Song, 2011).

Hippocampus

The adult hippocampal neurogenic niche is a distinct and dynamic microenvironment that contains both cellular and non-cellular DG components. Bromodeoxyuridine (BrdU) labeling of proliferating cells with cell-type-specific markers, such as neuronal nuclear marker (NeuN) and glial fibrillary acidic protein provided the first proof of adult hippocampal neurogenesis in the human brain. Since then, further evidence has been discovered by employing immunohistochemical, carbon 14 birth dating, and tissue culture techniques (Boldrini et al., 2018; Toda and Gage, 2018). Human hippocampus neurogenesis persists beyond the ninth decade of life and is associated with cognitive function in Alzheimer’s disease (AD) patients (Morello et al., 2018; Tobin et al., 2019). NSCs in the hippocampus give rise to GCs through a regulated process that includes emergence from a quiescence state, posterior divisions, specification to a neuronal fate, neuronal differentiation, and physiological integration in the pre-existing hippocampal circuits (Figure 1). Synapses, intrinsic electrical characteristics, and neuronal morphology all develop concurrently throughout this time toward a fully developed neuronal phenotype (Toni and Schinder, 2015; Toda et al., 2019).

Figure 1.

Neurogenic regions in adult brain.

Neurogenesis occurs at two specific regions of brain including the SVZ of the lateral ventricles and the SGZ of the dentate gyrus of hippocampus. Created with BioRender.com. Aldh1L1: A kind of gene; BLBP: brain lipid binding protein; CD24: singnal transducer; DCX: doublecortin; Dgx: digoxin; DLX2: distal-less homeobox 2; Fox03: forkhead box O-3; GFAP: glial fibrillary acidic protein; GjA1: gap junction alpha 1 protein; GLAST: glutamate transporter; Glul: glutamate-ammonia ligase; Ki67: nuclear antigen; Mash1: transcription factor; MCM2: minichromosome maintaince complex component 2; NeuroD: neuronal differentiation factor; PAX6: paired box protein; Ph3: phosphine; Prox1: prospero homeobox protein 1; PSA-NCAM: polysialylated neuronal cell adhesion molecule; PygB: glycogen phosphorylase B; S100β: calcium binding protein; SGZ: subgranular zone; Sox2: SRY-box 2; Sox6: a kind of gene; SVZ: subventricular zone; TBR2: transcription factor; TLX: orphan nuclear receptor; Tuj1: beta III tublin antibody.

Niche of the adult hippocampus

The most crucial area for learning and episodic/spatial memory is the hippocampus. The proliferation, differentiation, maturation, fate determination, and survival of newly formed cells in the DG are regulated by intrinsic and extrinsic stimuli. The majority of the cells in the hippocampal formation are granule and pyramidal cells. Numerous sensory inputs from neocortical regions are received by the hippocampus in a uni-directional manner, which controls hippocampal formation. Type-1 NSCs are located in the condensed region of the SGZ that is between the hilus and the GC layer (Toda and Gage, 2018). The condensed region of SGZ is two to three cell layers thick. Quiescent NSCs that express Nestin, glial fibrillary acidic protein, and Sox2 are also referred to as RGL cells due to their morphology and ontogeny. These cells are the first to go through adult neurogenesis in the hippocampus (Matsubara et al., 2021). Blood vessels are directly connected to these NSCs. In DG, RGL cells produce IPCs that develop into neuroblasts and produce granule neurons. As granule neurons differentiate, integrate into hippocampal circuitry, and sustain hippocampus-dependent memory function, their migration is constrained (Lie et al., 2005; Horgusluoglu et al., 2017). The SGZ offers the NSCs an essential environmental niche, and the local cellular milieu enables them to multiply and preserve the stem cell pool (Patzke et al., 2015). Moreover, NSPC-derived exosomes prevent stem cell senescence and inhibit insulin receptor substrate-1/forkhead box O activation. The modulation of cell fate inside the adult neurogenic niche is also influenced by these extracellular vesicle-mediated signals (Natale et al., 2022). Further, induced NPC-derived extracellular vesicles aid in post-stroke recovery by promoting the proliferation and cell survival of NPCs (Gao et al., 2022).

The microenvironmental factors trigger specific transcriptional programs that further regulate the morphology and physiological traits of GCs at different stages of neuronal development as well as how they respond to external stimuli. These programs drive the maturation of the new cells. Due to cellular variability, some populations of neurons are more susceptible to a variety of disorders and more responsive to the spectrum of variables present in the niche. It is crucial to understand the range of factors that exist in the SGZ niche during neurogenesis because their interaction can promote the development of adult-born neurons under physiopathological conditions (Bonafina et al., 2020).

Hypothalamus: novel adult neurogenic zone

The neuroendocrine system, as well as behavioral and physiological functions, are all homeostatically regulated by the hypothalamus (i.e., thermoregulation, water, food intake, reproduction, circadian rhythms). The anterior region of the hypothalamus known as the supraoptic region contains the preoptic, medial preoptic, anterior, and suprachiasmatic hypothalamic and a paraventricular nucleus. The central part contains a ventromedial, dorsomedial, arcuate, and supraoptic nucleus (Figure 2). In the adult hypothalamus, neurogenesis exists in the ventrolateral region of the ventricle wall due to the presence of NPCs that are known as tanycytes (Maggi et al., 2014; Miana Gabriela et al., 2018). Tanycytes, a specialized RGL cell, line all but the most ventrally located portion of the third ventricular wall in this region (Bolborea and Dale, 2013).

Figure 2.

A sketch of hypothalamic nuclei and their role in major physiological pathways.

Created with BioRender.com. BDNF: Brain derived neurotrophic factor; PGF2α: prostaglandin F2α.

These cells show a high proliferation rate in both stimulated and basal conditions. Notably, the hypothalamic parenchyma also harbors NPCs that are present inferior to the ventricular zone. However, BrdU infusion into the third ventricles revealed that the hypothalamic parenchyma contained significantly more proliferating cells than the ventricular zone because they have a shorter life cycle than ventricular cells and incorporate BrdU more quickly. This raises the postulate that parenchymal NPCs respond swiftly to metabolic signals within the hypothalamus by proliferating and differentiating themselves from new neurons (Sousa-Ferreira et al., 2014).

The ependymal cells show a low but discernible neurogenic potential between post-natal days 56 and 63 in both male and female rats. BrdU was used to identify these cells, and fibroblast growth factor-2 was provided to promote their proliferation (Xu et al., 2005). The median eminence also shows the greatest capacity for neurogenesis. The mouse median eminence’s rate of neurogenesis is five times higher than that of the other hypothalamic regions (Lee et al., 2012a). Alternatively, when we looked at neurogenesis in two mice models of obesity: leptin deficiency and high-fat diet (HFD) induced obesity, in the energy-balancing circuit of the hypothalamic arcuate nucleus, an increase in NSCs in HFD-induced obesity, mice were seen within 48 hours, but many of these cells died off by the 4^th week. Despite an overall rise in the number of hypothalamic NSCs, the proportion of highly proliferative progenitors had decreased. It follows that hypothalamic neurogenesis might be an immediate reaction to metabolic stress. HFD increased the retention of neurons that were proopiomelanocortin and neuropeptide Y tagged, whereas subsequent calorie restriction brought the endogenous neurogenic rate back to normal (McNay et al., 2012).

Signal Transduction in Adult Neurogenesis

The proliferation and differentiation of NSCs as well as the migration and survival of adult-born neurons are regulated by numerous pathways. Here, we will briefly go through the important signaling pathways that play particular roles in adult neurogenesis.

Notch signaling

Notch signaling acts as a major regulator of the maintenance of NSPCs and the control of their fate in mammals (Chen et al., 2021). The hairy and enhancer of split (Hes) family genes, which include Hes3, Hes5, and Hey1-null genes, appear to contribute to normal nervous system development, but further deletion of Hes1 upregulates Ascl1 and Neurog2 expression and speeds up neurogenesis while prematurely depleting NSCs in the telencephalon (Sueda et al., 2019). Curcumin administration stimulates the Notch signaling by upregulating Notch1 and Hes1 expression, suggesting that this pathway is necessary for the activation of NSCs proliferation (Li et al., 2019).

microRNA (miR)-153 enhances neurogenesis, prevents NSCs gliogenesis, and alleviates cognitive impairment in mice by suppressing the Notch signaling. These findings imply that miR-153 holds significant promise for improving learning, memory, and cognitive function in AD patients (Qiao et al., 2020). Moreover, the Notch intracellular domain interacts with hypoxia-induced factor 1α to activate Notch signaling in epilepsy and promote neurogenesis (Li et al., 2018).

Following a stab injury, the downregulation of Notch signaling is seen by a decrease in the expression of Her4 and Her6, which leads to an increase in proliferative radial glia (RG), but prevents the development of newborn neurons from RG. These findings imply that high levels of Notch signaling keep RG dormant and that the proper levels of Notch signaling are necessary for the development of newborn neurons from RG (Ueda et al., 2018). Hence, the level of Notch1 must be tightly regulated since the overactivation of this pathway in the adult hippocampus leads to an increase in NSCs proliferation. Moreover, Pros1 deletion drastically decreases active Notch1 signaling in NSCs by downregulating the expression of Notch1, Jagged, and Hes5 (Zelentsova et al., 2017).

Sonic hedgehog signaling

Sonic hedgehog (Shh) signaling plays a critical role in mediating developmental neurogenesis and also influences adult SVZ neurogenesis (Wang et al., 2022). Studies concentrating on Shh signaling gain/loss of functions have shown that it is essential for controlling adult neurogenesis in the SVZ utilizing transgenic mouse models (Antonelli et al., 2018). Shh signaling is involved in both neurogenesis and neuro repair, as evidenced by the fact that smoothened agonist therapy enhances behavioral recovery in mice after stroke and promotes neurogenesis (Jin et al., 2017).

NSCs proliferation increased when Shh was removed from the adult DG, indicating that Shh prevents NSCs activation in the adult DG (Gonzalez-Reyes et al., 2019). This signaling appears to encourage NSCs activation and proliferation to increase the NSC pool in the early post-natal stage, in contrast to reports that Shh signaling suppression hinders the expansion of long-lived NSCs as a result of the NSCs transition into a quiescent state during DG development (Noguchi et al., 2019). For details please see Gupta et al. (2022).

The conditional knockout of Smo gene, the Shh signaling receptor, in NSCs results in a decrease in neurogenesis at both the SVZ and SGZ in young-adult mice and an accelerated loss of neurogenic cells as they age. Additionally, Smo conditional knockout mice have a delayed return of motor function and elevated anxiety levels. It indicates that this signaling is crucial for maintaining neurogenesis during aging (Wang et al., 2022). In both larval and adult zebrafish, hedgehog/Gli signaling favorably modulates hypothalamus neurogenesis and is both required and sufficient for appropriate hypothalamic proliferation rates (Male et al., 2020).

Phosphoinositide-3-kinase-Akt-mammalian target of rapamycin 1 signaling

Adult neurogenesis in the DG has been linked to protein kinase B (Akt) signaling. When mammalian target of rapamycin (mTOR) activity is downregulated, cognitive impairment is seen in Akt3 knockout mice. Akt3 protein was expressed by neuroblasts, progenitor cells, and mature newborn neurons in the hippocampal DG (Zhang et al., 2021a). The phosphoinositide-3-kinase (PI3K)-Akt-mTOR1 pathway controls the maintenance and activation of quiescence in adult NSCs. When Mfge8 binds to Itgb and activates phosphatase and tensin homolog (PTEN), a crucial inhibitor of PI3K activation, the activation of Akt is blocked. Mfge8 blocks Akt-mediated activation of mTOR to stop the proliferation of NSCs induced by PI3K-Akt activation. Additionally, PTEN ablation causes NSCs in DG to become active, showing that PTEN keeps NSCs in a dormant condition. In fibroblasts, Akt causes glycogen synthase kinase 3β phosphorylation, which enables β-catenin and cyclin D1 activation to enhance transcription and cell cycle progression. It is also known that Akt phosphorylates and inactivates forkhead box O3 for the maintenance of quiescent NSCs in the adult DG. By inhibiting Ascl1-mediated activation, forkhead box O3 keeps NSCs from becoming activated (Matsubara et al., 2021).

In the rat model of Parkinson’s disease, glycogen synthase kinase 3β inhibition increases the proliferation of NSCs, RG cells, and self-renewal in the SGZ and the SVZ. Glycogen synthase kinase 3β inhibition boosts granular neurons’ survival and dendritic arborization and NSCs differentiation toward the neuronal phenotype in the Parkinson’s disease model (Singh et al., 2018). Interestingly, miR-212-3p reduces early neurogenesis by disrupting the activation of the Akt/mTOR pathway via targeting Methyl-CpG binding protein 2 (Zhai et al., 2020).

Wnt signaling

Wnt signaling modulates adult hippocampal neurogenesis on molecular, cellular, and behavioral levels (Horgusluoglu et al., 2017). Wnt signaling regulates the proliferation and cell fate of NSCs during hippocampal neurogenesis (Gonçalves et al., 2016). Wnt-3 is expressed by the astrocytes and the hilar cells of the DG and promotes stem cell proliferation and differentiation into hippocampal granule neurons through activation of NeuroD1 (Kuwabara et al., 2009). During traumatic brain injury in the adult brain, the Wnt pathway component survivin promotes neurogenesis in the hippocampus (Zhang et al., 2013).

NSCs in both the V-SVZ and SGZ are shown to self-renew and proliferate NPCs by responding to canonical (β-catenin-mediated) Wnt signaling. The Wnt inhibitors, like secreted frizzled related protein 3 (SFRP3) and Dickkopf Wnt signaling pathway inhibitor 1 (DKK1), are produced by the DG’s NPCs and granule neurons. The level of Wnt signaling regulates the rate of NSCs activity because NSCs are activated at extraordinarily high rates in both SFRP3 and DKK1 mutant animals. Non-canonical Wnt signaling promotes NSCs anchoring to the niche through the small GTPase, cell division control protein 42, keeping V-SVZ NSCs inactive. The potential that activation of NSCs in this niche requires a switch from non-canonical to canonical Wnt signaling is raised by this data. Further explanation of the switch’s underlying mechanism, such as a change in the availability of Wnt ligands, is required to be explored in the future (Urbán et al., 2019).

Mitogen-activated protein kinase signaling

The mitogen-activated protein kinase (MAPK) signaling pathway consists of three different types of kinases, each of which has several members: p38 kinase, Jun amino-terminal kinases/stress-activated kinases, and extracellular regulated kinases (Albert-Gascó et al., 2020).

p38 MAPK signaling is seen to be involved in the proliferation, differentiation, migration, and apoptosis of NSPCs (Faigle et al., 2004; Wang et al., 2017). Age-related decline in adult neurogenesis is caused by reduced p38 MAPK activation, which is necessary for the continued proliferation of NPCs in the adult neurogenic niche through modulation of Wnt signaling. In addition, forcing p38a expression in aged mice’s NSPCs in the SVZ halted the reduction in adult neurogenesis and slowed age-related SVZ atrophy without exhausting NSCs. In NSPCs, deletion of p38a selectively decreases NPCs proliferation but does not affect stem cells. On the other hand, age-dependent SVZ atrophy is avoided by induced expression of p38a in NSPCs in the elderly mouse SVZ by restoring NPCs proliferation and neurogenesis. Additionally, p38 is required for inhibiting the expression of the Wnt antagonists DKK1 and SFRP3, which stop the proliferation of NPCs (Kase et al., 2019). It shows how p38 and Wnt signaling are interdependent in regulating neurogenesis. Inhibiting NF-κB and Jun amino-terminal kinase-MAPK signaling in mice are thought to be how the water-soluble arginyl-diosgenin analog suppresses the production of pro-inflammatory cytokines and the activation of microglia to regulate neurogenesis (Cai et al., 2019).

BMP signaling

The regulation of NSCs proliferation in the adult V-SVZ is greatly influenced by extracellular signals called BMPs. The apical surface of the embryonic neuroepithelium expresses low-density lipoprotein-related protein 2 (LRP2), which controls BMPs in the developing neural tube. LRP2 is still expressed by the cells of the V-ependymal SVZ, and its absence reduces this niche’s capacity to promote cell proliferation. BMP2/4 protein expression and the BMP signaling components phospho-Smad1/5/8 and Id3 are both increased in the adult LRP2-deficient mouse. These findings imply that LRP2 functions in ependymal cells as a negative modulator of BMP signaling to enhance adult V-SVZ neurogenesis (Figure 3). Additionally, it leads to restoring Smad5, which is inhibited by Noggin, and the proliferation of NSPCs co-cultured with endothelial cells (Quaresima et al., 2022).

Figure 3.

Signal transduction in different neurogenic zones of adult undergoing neurogenesis leading to initiate the signaling pathways.

Created with BioRender.com. Akt: Protein kinase B; BMP: bone morphogenetic proteins; CBP/300: a kind of protein; FZD: Frizzled receptor; GLI/βcatenin/Wnt/Smad: a kind of protein; Hes: hairy and enhancer of split; ID: inhibitor of differentiation; Jag1: Jagged1; Mfge8: milk fat globule-epidermal growth factor 8 protein; mTOR: mammalian target of rapamycin; NeuroD1: neuronal differentiation 1; NSC: neural stem cell; Patch1: a kind of gene; PI3K: phosphatidylinositol 3-kinase; PTEN: phosphatase and tensin homolog; Shh: sonic hedgehog; Smo: smoothened protein.

Ephrin signaling

Ephrin (Eph) signaling has been identified as a critical regulator of stem cell function. EphB2 presented by astrocytes interacts with the EphB4 receptors on NSCs to encourage neuronal differentiation (Bonafina et al., 2019). The intercellular communication between adult GCs and NSCs controls how quiescent NSCs become newborn neurons. Ephrin-B3 on mature GCs functions as a negative regulator for activating nearby NSCs that express the EphB2 receptor when membrane-bound ligand is present during running (Dong et al., 2019).

Modulation of the Neurogenesis

It is well-recognized that a variety of intracellular and extracellular variables can negatively and favorably affect adult neurogenesis.

Intracellular factors influencing neurogenesis

Neurogenic niches

The neurogenic niche is a specialized microenvironment that tightly controls NSCs growth. The maintenance of NSCs in adult mammalian brains depends on numerous factors, including vasculature (Licht and Keshet, 2015). NSCs lined the ventricles and established contact with endothelial cells to preserve stemness and Notch signaling activation (Ottone et al., 2014). The differentiation and proliferation of NSCs are promoted by astrocytes in the SVZ and SGZ, which are essential components of the adult neurogenic niche. They also facilitate the integration of new neurons into existing brain networks (Lee et al., 2012b).

Role of neurotransmitters

Neurotransmitters including GABA, glutamate, serotonin, dopamine and acetylcholine regulate not only neuronal communication but are also involved in embryonic and adult neurogenesis (Song et al., 2017b). Glutamate is a key excitatory neurotransmitter, and its receptors are expressed in SVZ cells (Ota et al., 2023). In SVZ, NSCs express glutamate receptors such as N-methyl-D-aspartate, metabotropic glutamate receptors, and kianate. This receptor-ligand interaction in NSCs initiates a signaling cascade and mediates cell proliferation (Young et al., 2011). Metabotropic glutamate receptor4 inhibits NSPCs proliferation, improves neuronal differentiation, and controls PTEN expression to regulate NSPC behaviors (Zhang et al., 2021b). In transgenic mice expressing the light-gated channelrhodopsin-2 in glutamatergic neurons, optogenetic stimulation causes glutamate release into the SVZ region and induces membrane currents. It leads to the influx of calcium and increases the proliferation of SVZ neuroblasts which is mediated by AMPA receptor activation. They also enhance neuronal differentiation and improve long-term functional recovery (Song et al., 2017a).

The striatum’s GABAergic neurons transmit axonal processes into the SVZ, release GABA, and control SVZ cellular activity by activating the GABAA receptor (Young et al., 2014). α7 nicotinic acetylcholine receptors influence spatial discrimination function in male, but not female mice, and also regulate adult neurogenesis through a process involving nestin⁺ NSCs and their successors (Otto and Yakel, 2019). The mammalian brain’s neurogenic niches are controlled by serotonergic inputs, which regulate cell proliferation, migration, and survival in adult neurogenesis. Serotonergic inputs also give adult-born cells certain functional qualities that enable them to perform a particular role in integrating environmental cues in a brain state-specific manner, even after they have fully integrated into the surrounding neuronal circuitry and grown there (Fomin-Thunemann and Garaschuk, 2022). Cholinergic injuries cause deficits in memory and learning as well as a decrease in new neuron creation and survival in DG, suggesting that acetylcholine has a positive impact on adult neurogenesis (Van Kampen and Eckman, 2010).

Epigenetic modulators

The expression of Pax6, Neurog2, and NeuroD1 in mouse hippocampus NSCs was shown to be downregulated by kappa opioid receptor (OPRK1) agonists. Pax6 interacts with the promoters of Neurog2 and Neurod1 to regulate their transcription. OPRK1 inhibits the expression of these genes through the miR-7a/Pax6 pathway, which prevents NSCs from differentiating into neurons and further retards adult hippocampus neurogenesis (Xu et al., 2021). Moreover, sirtuins, particularly Sirtuin 1, regulate adult hippocampus neurogenesis and neural progenitor cells (Saharan et al., 2013; Ma et al., 2014). Sirtuin 7 has a marginally protective effect on neurogenesis and the adaptive immune system (Burg et al., 2018).

NPCs experience cell death when Sox21 expression is drastically lowered; at low levels of Sox21 expression, NPCs develop into neurons; greater levels of Sox21 expression restrict neurogenesis while increasing SoxB1 expression and progenitor maintenance (Whittington et al., 2015). During the development of the nervous system and adult neurogenesis, SOX transcription factors are significant regulators of neuronal and glial differentiation (reviewed in Stevanovic et al., 2021). miRs have been found to regulate the activity of NSCs. Conditional knockout of the miR-17-92 cluster significantly reduces inhibitor of differentiation 1 and increases enigma homolog 1, PTEN. This cluster regulates behavioral and cognitive function in NSCs and mediates neurogenesis via targeting enigma homolog 1/inhibitor of differentiation 1 signaling (Pan et al., 2019).

In vivo study demonstrates that a higher level of miR-153 in the hippocampus upregulates neurogenesis and significantly improves the cognitive function of the aged mice. Additionally, it influences neurogenesis by controlling the Notch signaling and contributes to age-related cognitive deficits and neurodegenerative illnesses (Qiao et al., 2020). In the ischemic mouse brain, miR 126-3p and 126-5p encourage angiogenesis and neurogenesis. They also enhance neurobehavioral outcomes by triggering the AKT and extracellular regulated kinase signaling pathways and directly inhibiting their target, tyrosine-protein phosphatase non-receptor type 9 (Qu et al., 2019). Above mentioned epigenetic modulators emphasize the need of looking beyond the genome for a better understanding of the molecular fundamentals of neurogenesis.

Neurotrophic growth factors

Some of the substances secreted by the NSCs include vascular endothelial growth factor, neurotrophin-3, pleiotrophin, and brain derived neurotrophic factor (BDNF). It is widely known how neurotrophins contribute to adult neurogenesis in the hippocampal region. Conditional ablation of neurotrophin-3 in the brain throughout development results in normal proliferation in the SGZ, a decrease in the number of newly formed granule neurons, and an increase in the proportion of cells that do not express differentiation markers (Bonafina et al., 2020).

BDNF has a crucial role in the migration of SVZ-derived cells, although it does not significantly alter cell proliferation and survival. Additionally, BDNF demonstrates a crucial role in controlling the dendritic complexity and synaptic development, maturation, and plasticity of developing neurons through TrkB (a BDNF receptor) signaling (Ferreira et al., 2018). It is found to control neurogenesis following a neurological trauma like subarachnoid hemorrhage or ischemia. Additionally, on days 5 and 7 following subarachnoid hemorrhage induction in a rat model, elevated BDNF was seen in cerebrospinal fluid (Lee et al., 2016).

Glial-derived neurotrophic factor (GDNF), a novel regulator of the integration of new GCs, was first identified for its powerful impact on the survival of dopaminergic nigrostriatal neurons. Both immature and mature adult-born GCs express the GDNF receptor known as the GPI-linked protein glial cell line derived neurotrophic factor receptor α1 (GFRα1). The GDNF/GFRα1 complex is necessary for the proper growth and integration of adult-born GCs into preexisting hippocampus circuits. GFRα1 conditional knockout mice show behavioral pattern separation abnormalities that lead to adult neurogenesis deficiency. The ablation of GFRα1 in the newborn GCs reverses the increase in dendritic complexity brought on by running, indicating that the effect of running on dendrite growth is dependent in part on GDNF expression (Bonafina et al., 2019). However, Zhang et al. (2020) demonstrated that conditional GDNF deletion decreased adult neurogenesis in the hippocampus.

Influence of hormones

Hormones are intrinsic signaling molecules of the neuro-endocrine system and act as modulators of neuronal plasticity and adult neurogenesis (Triviño-Paredes et al., 2016). Androgens, progesterone, and estrogen are predominant sex hormones released by the ovaries or testes. The sex hormones influence the newly proliferated cells under stress conditions in middle age (Tzeng et al., 2016). Sex hormone expression is highest in adolescence and declines with age, both of which are correlated with lower rates of proliferation and survival for newly generated neurons. After 6–7 days of ovariectomy, ablation of the ovaries caused a reduction in hippocampal growth (Mahmoud et al., 2016).

Within the DG, testosterone stimulates adult neurogenesis via an androgen-dependent mechanism [For details please see Spritzer and Roy (2020)]. Triiodothyronine is one of the thyroid hormones that is used to not only treat traumatic brain damage by preventing neuronal death through mitophagy but also stimulate neurogenesis through neuron NSCs crosstalk (Lin et al., 2020).

Impact of immune system

The immune system regulates the flow of information between the neurogenic niche and the environment hence influencing neural plasticity and behavioral processes. Adult hippocampal neurogenesis and cognition are influenced by the release of activated microglia and inflammatory cytokines (Figure 4). Astrocytes and microglia and the cells around the choroid plexus such as T cells and B cells play important roles in immune-derived remodeling by controlling interactions with the environment, such as the exchange of nutrients and other compounds, between the brain and the rest of the body, and modulate neural progenitor proliferation and differentiation in the adult hippocampus (Musaelyan et al., 2014).

Figure 4.

Role of intracellular factors in mediating neurogenesis.

Created with BioRender.com. Ascl1: Proneural gene; BDNF: brain derived neurotrophic factor; GDNF: glial cell derived neurotrophic factor; IGF-1: insulin-like growth factor 1; NeuroD1: neuronal differentiation 1; NGF: nerve growth factor; Pax6: paired box protein; SOX 2: SRY-box 2 transcription factor; Tbr2: eomesodermin gene; TLX: nuclear orphan receptor tailless.

Microglia cell populations are distributed in the dentate hilus and GC layer and regulate the apoptosis of newborn cells via phagocytosis during hippocampal neurogenesis (Sierra et al., 2010). They sense the microenvironment and interact with neurons and astrocytes for the maintenance of NSCs homeostasis and immune surveillance (Hussain et al., 2018). Additionally, interleukin 10 stimulates microglial-induced proliferation of NSCs and neuronal differentiation in culture (Kiyota et al., 2012).

Neurogenesis and diseases

Higher glucocorticoid levels and steroid signaling brought on by stress or aging lead to a decrease in both the proliferation of progenitor cells and the differentiation of newborn neurons into mature neurons. Alterations in neurogenesis have been observed in a wide variety of conditions, including depression, contextual memory, pattern separation, AD, Down’s syndrome, and stress. Antidepressants have been proposed to treat depression indirectly by promoting hippocampus neurogenesis in addition to directly raising monoamine levels in synapses. A progressive decrease in the number of doublecortin-positive newborn neurons is seen in the DG of AD patients compared to healthy controls. This reduction first appeared before amyloid β deposition and neurofibrillary tangles in the hippocampus (Redell et al., 2020; Table 1). The impact of various diseases on adult neurogenesis has been extensively discussed in previous studies (for detailed review see Liu and Song, 2016; Lim et al., 2018; Marchetti et al., 2020; and Wakhloo et al., 2022).

Table 1.

Neurodegenerative diseases and neurogenesis

Disease	Neurogenesis in specific brain regions
	Subventricular zone (olfactory bulb)	Subgranular zone (hippocampus)
Alzheimer’s disease	↑Proliferation	Unknown
Huntington’s disease	↑Proliferation	↓Proliferation
Parkinson’s disease	↓Proliferation & survival	↓Proliferation
Seizure	↑Proliferation & survival	↑Proliferation & survival
Ischemia	↑Proliferation & survival	↑Proliferation & survival

Data were from Abrous et al. (2005) and Ming and Song (2011).

Extracellular Factors Influencing Neurogenesis

Impact of physical activity

Exercise enhances cognition, reduces amyloid β burden, and raises levels of BDNF, interleukin 6, fibronectin type III domain-containing protein-5, as well as synaptic markers in the AD model (Choi et al., 2018). Exercise causes adult hippocampus neurogenesis in the AD model, which enhances cognition, reduces amyloid β burden, and raises levels of BDNF, interleukin 6, fibronectin type III domain-containing protein-5, as well as synaptic markers (Choi et al., 2018). Exercise causes changes in the systemic environment that lead to the activation of dormant hippocampal NPCs and their subsequent recruitment into the neurogenic trajectory. This activation of selenoprotein P and its receptor low-density lipoprotein receptor-related protein 8 is the major cause of hippocampal neurogenesis (Leiter et al., 2022).

Additionally, distinct neuronal cohorts formed by exercise quickly integrate into the aging brain, leading the advantages of running to increase and broaden network assembly prompted by neurogenesis. These networks are probably more complex than those developed in a sedentary mouse because new neurons integrate faster and more effectively (Trinchero et al., 2019). A thorough meta-analysis also shows that 45–60 minutes of moderate-intensity physical activity can significantly enhance cognitive abilities in people over 50 years old (Lei et al., 2019).

It’s interesting to note that increased SVZ neurogenesis in swimming rats results from increased nerve growth factor (Chae et al., 2014). In stroke-prone spontaneously hypertensive rats, the direct impact of exercise on inducing hypothalamic neurogenesis was examined. The results showed that long-term voluntary exercise decreased systolic blood pressure, increased food intake, and body weight, leading to an improvement in survival rate as compared to sedentary animals. An increase in total levels of cell proliferation and adult neurogenesis was evident in the ARC and median eminence in both stroke-prone spontaneously hypertensive and wild-type rats (Niwa et al., 2016).

The pro-neurogenic effects of running are mediated by vascular endothelial growth factor and insulin-like growth factor (IGF)-1. By activating the receptor tyrosine kinase on endothelial cells, vascular endothelial growth factor causes angiogenesis. Mice showed higher levels of IGF-1 in their blood and hippocampus an hour after jogging. Exercise effects are absent in IGF-1 null mice and anti-IGF injection into the hippocampal region reduces the improvement in spatial recall induced by exercise, confirming that IGF-1 interacts with BDNF to regulate a number of aspects of running-dependent cognitive improvements (for detail see Saraulli et al., 2017 and Schoenfeld and Swanson, 2021).

Role of diet in neurogenesis

Dietary intake is thought to alter behavior and can affect adult neurogenesis and cognitive performance (Murphy et al., 2014; Table 2). In comparison to mice fed soft textured food containing the equivalent calories, animals fed a hard diet showed increased neurogenesis rates and proliferation in the hippocampus. Along with proliferation, hard-textured feeding was linked to improved neurogenesis and the restoration of decreased olfactory function brought on by soft diet feeding (Utsugi et al., 2014).

Table 2.

Effect of extrinsic and intrinsic regulators on neurogenesis

Regulator	Neurogenesis	Brain region	References
Intrinsic factors
Neurotransmitter
Glutamate	↑	SGZ	Sibbe and Kulik, 2017; Song et al., 2017b; Matsubara et al., 2021
Gamma-aminobutyric acid	↑	SGZ
Acetylcholine	↑	SGZ
Dopamine	↑	SZV
Serotonin	↑	SGZ
Trophic factor
Fibroblast growth factor	↑	SGZ	Abdissa et al., 2020
Epidermal growth factor	↑	SVZ
Brain-derived neurotrophic factor	↑	SVZ, SGZ	Ferreira et al., 2018
Ciliary neurotrophic factor	↑	Hypothalamus, SGZ	Ding et al., 2013; Purser et al., 2013; Pasquin et al., 2015
Hormones
Testosterone and dihydrotestosterone	↑	SGZ	Duarte-Guterman et al., 2019; Spritzer and Roy, 2020
Glucocorticoids	↑	SGZ	Schoenfeld and Gould, 2012
Thyroid hormone	↑	SGZ, SVZ	Kapoor et al., 2015; Fanibunda et al., 2018
Ghrelin	↑	SGZ	Kent et al., 2015
Transcription factor
Sox21	↑	SGZ	Stergiopoulos et al., 2014
Sox4 and Sox11 repression	↑	SGZ	Mu et al., 2012
SoxC	↑	SGZ, SVZ	Beckervordersandforth et al., 2015
Gene/pathway
Ascl1	↑	SGZ, SVZ	Soares et al., 2022
Tlx	↑	SGZ	Lucassen et al., 2019
Prox1	↑	SGZ	Stergiopoulos et al., 2014
CcnD1, CcnD2	↑	SGZ	Urbán and Guillemot, 2014
Tbr2	↑	SGZ	Urbán and Guillemot, 2014
Over expression of Notch3	↓	SGZ	Ehret et al., 2021
Bone morphogenetic proteins	↑	SGZ	Jensen et al., 2021
Other factors
Aging	↓	SGZ	Simen et al., 2011; Sartori et al., 2012; Franceschi and Campisi, 2014; Seib and Martin-Villalba, 2015; Poulose et al., 2017
Extrinsic factors
Exercise
Physical activity	↑	SVZ	Chae et al., 2014; Niwa et al., 2016
Sleep
Insomnia	↓	SGZ, SVZ	Mueller et al., 2015
Sexual activity
Sex	↑	SGZ	Leal-Galicia et al., 2019
Diet
LMN diet	↑	SGZ, SVZ	Valente et al., 2009
High-fat and refined sugar diets	↓	SGZ	Poulose et al., 2017
Vitamin D	↑	SGZ	Morello et al., 2018
Vitamin A	↑	SVZ	Oyarce et al., 2014
Vitamin C	↑	SVZ
Curcumin	↑	SGZ	Li et al., 2019
Flavonoids	↑	SGZ	Cichon et al., 2020
Environmental factor
Exposure to dim light at night	↓	SGZ	Walker et al., 2020
Chronic, traumatic stress, depression	↓	SGZ	Loi et al., 2014; Abdissa et al., 2020; Surget and Belzung, 2022

LMN diet: Riches in both polyphenols found in teas, wine, olive oil, nuts, fruits, and veggies; SGZ: subgranular zone; Sox: SRY-box; SVZ: subventricular zone.

HFD upregulates the percentage of proopiomelanocortin neurons, as well as neurogenesis and physical exercise, enhance cell proliferation in the adult arcuate nucleus (Klein et al., 2019). The increased expression of mitochondrial biogenesis markers and decreased mitochondrial reactive oxygen species scavengers in the neurogenic niches show that this mitochondrial stress-dependent pathway is involved in mediating dietary changes in adult neurogenesis of high-fat, choline-deficient-fed mice (Ribeiro et al., 2020).

Polyphenols have gained attention due to the presence of potent compounds that can be used as dietary supplements (Poulose et al., 2017). Owing to their known antioxidant and anti-inflammatory properties, polyphenols and polyphenol-rich foods can be used to increase neurogenesis. Berry fruit can improve cognition in both animals and humans (Whyte and Williams, 2015; Whyte et al., 2016; Miller et al., 2018). The use of strawberries increases the survival of the DG’s progenitor cells (Shukitt-Hale et al., 2015). Administration of caffeine dramatically reverted the effects of oxygen stress on hippocampal neuronal development. The transcription of neural mediators of maturing and matured neurons was interestingly reduced by coffee under normoxia. Caffeine was administered early and demonstrated neuroprotective qualities in the newborn rat oxygen toxicity model, modulating hyperoxia-induced reduced neurogenesis in the hippocampus (Heise et al., 2023).

Stem cell therapy

Stem cell therapy acts as an intensive approach to replace the neurons that have been lost due to any injury or neurodegeneration. Mesenchymal stem cells encourage neurogenesis in the hippocampus and improve cognitive abilities (Yang et al., 2013; Oh et al., 2015). These cells express IGF-1, nerve growth factor, and BDNF which directly regulate hippocampal neurogenesis (Rita and Animesh, 2016). Furthermore, enhanced Wntβ/catenin signaling results in neurogenesis in mice who receive an IV injection of mesenchymal stem cells in the AD model (Oh et al., 2015). Several clinical trials are being conducted to evaluate the efficacy and safety of mesenchymal stem cell therapy (Duncan and Valenzuela, 2017).

Chronic stress

Hypothalamo-pituitary-adrenal axis mediates stress response through increased secretion of glucocorticoids. Adrenalectomies lead to impair neurogenesis and cause excessive release of glucocorticoid (Lehmann et al., 2013). In vitro analysis shows that persistent glucocorticoid therapy inhibits neurogenesis (Hodes et al., 2010; Hill et al., 2015).

Chronic stress exposure resulted in a general decline in the formation of adult-born neural cells and, more particularly, in a region-specific decline in the survival of adult-born neurons at the supra pyramidal blade (Alves et al., 2018). It significantly reduces hippocampal neurogenesis, having an impact on both the early stage of neurogenesis (cell multiplication) and the later stages, such as neuronal survival and integration into the DG circuitry (Eliwa et al., 2021; Figure 5).

Figure 5.

Role of extracellular factors in mediating neurogenesis.

Created with BioRender.com.

Conclusion

The overview of the fundamental differences in embryonic and adult neurogenesis gives us the understanding to improve neuron development in the adult brain. It may be possible to explain this gap by targeting signaling molecules such as Notch, Wnt, BMPs, mTOR, Akt, Ephrin, MAPK, and Shh. These molecules regulate NSC proliferation by either directly or indirectly activating them. The idea that the adult brain is capable of neurogenesis in old age gives us hope that the process might be used to repair brain damage by regulating the NSC proliferation. It will be materialized once we have control over the crucial checkpoints to prevent tumorigenesis which can turn out to be a curse rather than a blessing or a sign of hope.

Due to a dearth of research, the main limitations of this study raise the question of whether adult neurogenesis is a valid hope or a myth. Although we have reviewed this topic using various keywords and search engines, we have noticed a scarcity of recent studies. Apart from research articles, we also rely on the work that has been discussed in reviews.