**Preface to "Induced Impairment of Neurogenesis and Brain Diseases"**

The impairment of neurogenesis may be induced after pre- and post-natal chemical and biological toxin, alcohol, or radiation exposure, drug treatment, hormone imbalances, stress, pain, hypoxia, brain trauma, malnutrition, and aging. It also occurs as a result of genetic disorders such as Down syndrome (DS), autism, fragile X syndrome (FXS), neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, and Huntington's disease (HD), and neuropsychiatric disorders such as depression and schizophrenia. However, the causal relationship between the impairment of neurogenesis and neurological and neuropsychiatric disorders remains unknown. In this Special Issue entitled "Induced Impairment of Neurogenesis and Brain Diseases", original animal or cell experimental research and review papers were combined to discuss different causes of the impairment of neurogenesis, relevant neurobehavioral changes, molecular mechanisms, and therapeutic approaches. The aim is to update researchers and clinicians about the complexity of the development of the impairment of neurogenesis, the importance of the involvement of the impairment of neurogenesis in neurological and neuropsychiatric disorders, and to provide some clues for designing novel therapeutic approaches by targeting the impairment of neurogenesis to effectively prevent or treat different genetic, neurological, and neuropsychological disorders.

In a mouse radiation exposure model, Wang et al. revealed that early-life (postnatal day 3) irradiation induced hypoplasia and the impairment of neurogenesis in the dentate gyrus and adult depression, which were mediated by the microRNA-34a-5p/T-cell intracytoplasmic antigen-1 pathway [1]. In their review, Wang et al. described the effects of irradiation on the aging of different types of brain cells, including neurons, microglia, astrocytes, and cerebral endothelial cells, and the relevant molecular mechanisms, and highlighted how radiation-induced senescence in different cell types might lead to the brain aging and the subsequent development of various neurological and neuropsychological disorders [2]. Boyd et al. reviewed the control of neuroinflammation through radiation-induced microglial changes, and summarized the impacts of ionizing radiation on healthy brains by altering microglial function states, and low-dose ionizing radiation on neurodegenerative diseases [2].

In mutant animal models, Wang et al. investigated the biological functions of MCPH1's central domain, by constructing a mouse model which lacked the central domain of MCPH1 by deleting its exon 8 (designated as Mcph1-∆e8). Mcph1-∆e8 mice exhibited a reduced brain size and thinner cortex, likely caused by a compromised self-renewal capacity and the premature differentiation of Mcph1-∆e8 neuroprogenitors during corticogenesis [4]. Chithanathan et al. demonstrated the cell-specific function of miR-146b in the neuronal and astroglial organization of the mouse brain. In miR146b-/- mice, there was a higher density of neurons in the frontal cortex and enhanced hippocampal neurogenesis. No microglial activation or neuroinflammation was observed in miR146b-/- mice. At molecular level, they demonstrated that miR-146b deficiency was associated with the elevated expression of glial-cell-line-derived neurotrophic factor (Gdnf) mRNA, which might be related to hippocampal neurogenesis [5]. Sun et al. found that TRIM32 deficiency impaired the generation of pyramidal neurons in the developing cerebral cortex, leading to a smaller brain size. Reduced Notch signaling may be involved in the TRIM32-deficiency-induced impairment of pyramidal neurogenesis [6].

Neurogenesis is also regulated epigenetically. Blanco-Luquin et al. reported that Aβ-treated human neural progenitor cells (NPCs) exhibited transient decreases in mRNA expression for SEPT5-GP1BB and NXN and an increase in DNA methylation for NXN, suggesting that NXN gene epigenetic changes may be involved in the impairment of hippocampal neurogenesis in Alzheimer's disease [7]. Maria Guerra et al. reported that SMG6 regulated cell fate in a cell-type-specific manner and was more important for neuroprogenitors originating from the ganglionic eminence (GE) than for progenitors from the cortex. N6-methyladenosine (m6A), the most abundant modification in messenger RNAs (mRNAs), was deposited by methyltransferases ("writers") Mettl3 and Mettl14 and erased by demethylases ("erasers") Fto and Alkbh5. m6A can be recognized by m6A-binding proteins ("readers"), such as Yth domain family proteins (Ythdfs) and Yth domain-containing protein 1 (Ythdc1) [8]. Shu et al. summarized the current knowledge about the roles of m6A machinery, including writers, erasers, and readers, in regulating gene expression, and the function of m6A in neurodevelopment and neurodegeneration; perspectives for studying m6A methylation were also provided [9].

Ghrelin [10] and TGF-β/Smad signaling [11] are also involved in neurogenesis. In cultured cerebral cortex neurons, cerebellar granule neurons, and organotypic cerebral cortex slices from rat brains to hypoxia, Stoyanova et al. found that ghrelin stimulates neurogenic factors for the protection of neurons in a GHSR1-dependent manner in non-neurogenic brain areas such as the cerebral cortex after exposure to hypoxia [10]. Hiew et al. reviewed TGF-β/Smad signaling in neurogenesis and its implications for neuropsychiatric diseases, and suggested that TGF-β/Smad signaling was an important regulator of stress response and was implicated in the behavioral outcomes of mood disorders [11].

The influence of the gut microbiota on neurogenesis and the possible underlying mechanisms were reviewed by Sarubbo et al., and the potential implications of the emerging knowledge for the fight against neurodegeneration and brain aging through the gut microbiota were also provided [12]. Yow et al. systematically reviewed the therapeutic potential of complementary and alternative medicines in peripheral nerve regeneration [13].

Funding: This research was supported by the National Research Foundation of Singapore.

Acknowledgments: I would like to thank all the authors for their contribution to this Special Issue. I am grateful for all of the support that I have received from the *Cells* editorial staff.

Conflicts of Interest: The authors declare no conflicts of interest.

#### References

1. Wang, H., Ma, Z.W., Shen, H.Y., Wu, Z.J., Liu, L., Ren, B., Wong, P.Y., Sethi, G., Tang, F. Early life irradiation-induced hypoplasia and impairment of neurogenesis in the dentate gyrus and adult depression are mediated by microrna-34a-5p/t-cell intracytoplasmic antigen-1 pathway. Cells 2021, 10(9). doi:10.3390/cells10092476.

2. Wang, Q. Q., Yin, G., Huang, J.R., Xi, S. J., Qian, F., Lee, R. X., Peng, X.C., Tang, F. R. Ionizing radiation-induced brain cell aging and the potential underlying molecular mechanisms. Cells 2021, 10(12), doi:10.3390/cells10123570.

3. Boyd, A., Byrne, S., Middleton, R.J., Banati, R.B., Liu G.J. Control of Neuroinflammation through Radiation-Induced Microglial Changes. Cells 2021, 10(9), 2381; doi:10.3390/cells10092381.

4. Wang, Y.R., Zong, W., Sun, W.L., Chen, C.Y., Wang, Z.Q., Li, T.L., The Central Domain of MCPH1 Controls Development of the Cerebral Cortex and Gonads in Mice. Cells 2022, 11(17), 2715; doi:10.3390/cells11172715.

5. Chithanathan, K., Somelar, K., Jurgenson, M., ¨ Zarkovskaja, T., Periyasamy, K., Yan, L., ˇ Nathaniel Magilnick, N., Boldin, M.P., Rebane, A., Tian, L., and Zharkovsky, A. Enhanced Cognition and Neurogenesis in miR-146b Deficient Mice. Cells 2022, 11(13), 2002; doi:10.3390/cells11132002.

6. Sun, Y.Y., Chen, W.J., Huang, Z.P., Yang, G., Wu, M.L., Xu, D.E., Yang, W.L., Luo, Y.C., Xiao, Z.C., Xu, R.X., Ma, Q.H. TRIM32 Deficiency Impairs the Generation of Pyramidal Neurons in Developing Cerebral Cortex. Cells 2022, 11(3), 449; doi:10.3390/cells11030449.

7. Blanco-Luquin, I., Acha, B., Urdanoz-Casado, A., G ´ omez-Orte, E., Roldan, M., ´ Perez-Rodr ´ ´ıguez, D.R., Juan Cabello, J., Mendioroz, M. NXN Gene Epigenetic Changes in an Adult Neurogenesis Model of Alzheimer's Disease. Cells 2022, 11(7), 1069; doi:10.3390/cells11071069.

8. Maria Guerra, G., May, D., Kroll, T., Koch, P., Groth, M., Zhao-Qi Wang, Z.Q., Li T.L., Grigaravicius, P. Cell Type-Specific Role of RNA Nuclease SMG6 in Neurogenesis. Cells 2021, 10(12), ˇ 3365; doi:10.3390/cells10123365.

9. Shu, L.Q., Huang, X.L., Cheng, X.J., Li, X.K. Emerging Roles of N6-Methyladenosine Modification in Neurodevelopment and Neurodegeneration. Cells 2021, 10(10), 2694; doi:10.3390/cells10102694.

10. Stoyanova, I.I., Klymenko, A., Willms, J., Doeppner, T.R., Anton B. Tonchev, A.B., Lutz, D. Ghrelin Regulates Expression of the Transcription Factor Pax6 in Hypoxic Brain Progenitor Cells and Neurons. Cells 2022, 11(5), 782; doi:10.3390/cells11050782.

11. Hiew, L.F., Poon, C.H., You H.Z., Lim, L.W. TGF-β/Smad Signalling in Neurogenesis: Implications for Neuropsychiatric Diseases. Cells 2021, 10(6), 1382; doi:10.3390/cells10061382.

12. Sarubbo, F., Cavallucci, V., and Pani, G. The Influence of Gut Microbiota on Neurogenesis: Evidence and Hopes. Cells 2022, 11(3), 382; doi:10.3390/cells11030382.

13. Yow, Y.Y., Goh, T.K., Nyiew, K.Y., Lim, L.W., Phang, S.M., Lim, S.H., Ratnayeke, S., Wong, K.H. Therapeutic Potential of Complementary and Alternative Medicines in Peripheral Nerve Regeneration: A Systematic Review. Cells 2021, 10(9), 2194; doi:10.3390/cells10092194.

> **FengRu Tang** *Editor*
