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The olfactory bulb (OB) is one of the primary sites of adult neurogenesis. Neural stem cells (NSCs) found in the subventricular zone (SVZ) of the lateral ventricles produce neuronal progenitor cells (NPC) that migrate to the OB via the rostral migratory stream (RMS), guided by glial cells and complex signaling pathways². Upon reaching the olfactory bulb, neuroblasts differentiate into mature neurons, with granule cells integrating into the granule cell layer and periglomerular cells integrating into the glomerular layer. The stages of neurogenesis in the OB include precursor cell stages, migration, differentiation, and postmitotic stages. Initially, neural stem cells in the SVZ divide to produce temporary amplifying progenitor cells, which further divide to generate neuroblasts or immature neurons. These neuroblasts then migrate along the RMS to the OB, guided by glial cells and complex signaling pathways. Upon reaching the olfactory bulb, neuroblasts differentiate into mature neurons, with granule cells integrating into the granule cell layer and periglomerular cells integrating into the glomerular layer. In the postmitotic stages, newly differentiated neurons extend their dendrites and axons, forming synaptic connections with existing neural circuits, which is crucial for the functional plasticity of the OB³.

The hippocampus, especially the dentate gyrus, is crucial for adult neurogenesis. Neural stem cells located in the subgranular zone (SGZ) of the dentate gyrus create new granule cells that play a significant role in learning and memory. It begins with radial glia-like cells, which serve as neural stem cells in the SGZ⁴. Radial glia-like precursor cells give rise to intermediate progenitor cells, which differentiate into neuroblasts. The neuroblasts migrate a short distance to the granule cell layer of the dentate gyrus. Once they reach their destination, they develop into granule cells, extending their dendrites into the molecular layer and their axons towards the CA3 region of the hippocampus. Newly formed granule cells undergo a maturation process that enhances their synaptic plasticity. This period of increased plasticity is vital for incorporating new neurons into the existing hippocampal circuits.

Neuronal lineage pathways are diverse and are characterized by specific proteins that serve as markers for various cell types. For example, GFAP is a marker for astrocytes, while SOX2 and Nestin indicate the presence of neural stem cells. PAX6 plays a critical role in neurogenesis and marks neural progenitors. BLBP (Brain Lipid-Binding Protein) is associated with radial glial cells. Gli1 also marks neural progenitors and is involved in the Hedgehog signaling pathway. Nkx2.1 is specific to basal forebrain neurons, which are necessary for cognitive functions. These markers are essential for identifying and studying the development and differentiation of different neuronal cell types⁵.

At the molecular level, adult neurogenesis entails a series of strictly regulated events, including cell proliferation, differentiation, migration, and synaptic integration. Key signaling pathways, such as Notch, Wnt, and Sonic Hedgehog (Shh), are critical in regulating these processes^6,7. Neural stem cells differentiate into specific neuronal subtypes by expressing transcription factors and signaling molecules. For example, NeuroD1 (Neuronal Differentiation 1) and Prox1 (Prospero Homeobox 1) operate by differentiating granule cells in the hippocampus⁸. Chemokines, growth factors, and cell adhesion molecules guide the migration of neuroblasts. In the OB, neuroblasts migrate along the RMS in a chain-like formation facilitated by interactions with glial cells. New neurons contribute to olfactory discrimination and adaptation in the olfactory bulb. Conversely, new neurons in the hippocampus play roles in memory formation, spatial navigation, and mood regulation. Integrating new neurons into existing circuits involves the formation of synaptic connections and establishing functional networks, which are essential for maintaining brain plasticity and cognitive function.

Adult neurogenesis has significant implications for brain health and disease. Enhanced neurogenesis is associated with improved cognitive function, whilst impaired neurogenesis is linked to numerous neurological and psychiatric disorders, such as depression, schizophrenia, and addiction⁹. Antidepressant treatments, including selective serotonin reuptake inhibitors (SSRIs), have been demonstrated to enhance neurogenesis, suggesting a potential mechanism for their therapeutic effects. In addition, increased neurogenesis in the hippocampus is associated with improved memory acquisition, memory formation, and maintenance¹⁰. Approaches to enhance neurogenesis, such as physical exercise and cognitive stimulation, have improved cognitive function in aging and neurodegenerative disorders. Understanding the mechanisms of adult neurogenesis unfolds opportunities for developing regenerative therapies for brain injuries and neurodegenerative conditions. Therefore, promoting neurogenesis could potentially aid in the recovery of mental and motor functions following brain damage.

References

1.    Kempermann, G., Song, H. & Gage, F.H. Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol 7, a018812 (2015).

2.    Lledo, P.M. & Valley, M. Adult olfactory bulb neurogenesis.  Cold Spring Harb Perspect Biol  8, a018945 (2016).

3.    Nissant, A., Bardy, C., Katagiri, H.  et al.  Adult neurogenesis promotes synaptic plasticity in the olfactory bulb.  Nat Neurosci  12, 728–730 (2009).

4.    Toda, T., Parylak, S.L., Linker, S.B.  et al.  The role of adult hippocampal neurogenesis in brain health and disease.  Mol Psychiatry  24, 67–87 (2019).

5.    Ming, G.L. & Song, H. Adult neurogenesis in the mammalian brain: significant answers and significant questions.  Neuron  70, 687–702 (2011).

6.    Antonelli, F., Casciati, A. & Pazzaglia, S. Sonic hedgehog signaling controls dentate gyrus patterning and adult neurogenesis in the hippocampus.  Neural Regen Res  14, 59–61 (2019).

7.    Arredondo, S.B., Valenzuela-Bezanilla, D., Mardones, M.D. & Varela-Nallar, L. Role of Wnt signaling in adult hippocampal neurogenesis in health and disease.  Front Cell Dev Biol  8, 860 (2020).

8.    Gao, Z., Ure, K., Ables, J.L., Lagace, D.C., Nave, K.A., Goebbels, S., Eisch, A.J. & Hsieh, J. Neurod1 is essential for the survival and maturation of adult-born neurons.  Nat Neurosci  12, 1090–1092 (2009).

9.    Kang, E., Wen, Z., Song, H., Christian, K.M. & Ming, G.L. Adult neurogenesis and psychiatric disorders.  Cold Spring Harb Perspect Biol  8, a019026 (2016).

10. Yau, S.Y., Li, A. & So, K.F. Involvement of adult hippocampal neurogenesis in learning and forgetting.  Neural Plast  2015, 717958 (2015).