**5.1 Stages of adult neurogenesis**

The process of adult neurogenesis occurs in stages viz. maintenance of neural stem/progenitor cells [NPC] and proliferation of NPC, fate specification/commitment, differentiation, maturation, survival of immature neurons, and integration into neural circuitry. The defining abilities of NPC are self-replication and multipotency, that is, the ability to differentiate into multiple lineages of cells and in this case neurons, astrocytes, and oligodendrocytes [48]. There are different types of neural progenitor cells in SGZ and SVZ. Type-1 cells in SGZ, B-cells in SVZ, and radial glia-like cells in SGZ and SVZ are largely quiescent cells, which are similar to radial glia cells found during embryonic development and have a morphology similar to mature astrocytes. Type-2 cells in SGZ and C-cells in SVZ are small roundish cells that are highly proliferative, and they give rise to type-3 cells in SGZ and A-cells in SVZ which represent committed neuroblasts. The type-1/B-cells

are multipotent and have unlimited self-renewal capacity which get activated by various factors and multiply to form highly proliferative transient intermediate progenitor cells [TIP] in the SGZ. In SVZ, the transit-amplifying cells [TAC] [type-2/C-cells] has the ability to differentiate into neurons. These divide to form neuroblasts or immature neurons [type-3/A-cells] which proceed to neuronal differentiation and forms newborn neurons that mature and get integrated into neural circuitry in the brain. It is pertinent to know that many of the newborn neurons perish and only 15–30% of immature neurons survive the maturation process. There are various factors that regulate this step and thereby the process of adult neurogenesis [49–51].

In SGZ, the NPCs form granule cells which are the principal excitatory cells of the dentate gyrus. Their axons form the mossy fibres extending to the CA3 region and their dendrites are in the molecular layer which receives connections from the entorhinal cortex. Immature neurons that are less than a week-old start to have neurite outgrowth and by one- or two-weeks axons can be observed in the hilus, and dendrites start to extend to the molecular layer without spines which being developed by around the 16th day. By 17 days, functional connections are formed by the axons [mossy fibres] with the CA3 pyramidal neurons [52]. They release glutamate as the neurotransmitter. After around 1 week of birth, the newborn granule cells receive GABAergic inputs and after 2 weeks receive glutamatergic inputs [53]. These immature neurons exhibit enhanced excitability by virtue of high input resistance and subthreshold calcium ion conductance which enables them to develop action potential with less excitatory currents. They also have a low threshold for induction of LTP [long-term potentiation] [54, 55]. Between 3 weeks and 2 months, there occurs a gradual increase in spine formation, dendritic arborisation and connection, boutons on CA3 neurons, and maturation of mossy fibres. By less than 2 months, the newborn neurons become functionally indistinguishable from fully mature granule cells [52].


**Table 3.**

*List of intrinsic factors that affect adult neurogenesis.*

*Does COVID-19 Affect Adult Neurogenesis? A Neurochemical Perspective DOI: http://dx.doi.org/10.5772/intechopen.101179*

In SVZ, restricted neural progenitor cells migrate along scaffolds maintained by specialised astrocytes via the rostral migratory stream [RMS] to reach the olfactory bulb. By 15–30 days, they differentiate into two types of interneurons, GABAergic granule neurons [95%] and GABA or dopaminergic periglomerular neurons [5%]. The newborn GABAergic granule neurons can become cells with dendrites that do not cross beyond the mitral cell layer and those with non-spiny dendrites that extend till the external plexiform layer. These interneurons mature and get integrated into olfactory network and start responding to olfactory signals [52].

There are various factors that regulate neurogenesis. These include intrinsic niche-derived intrinsic mechanisms and extrinsic systemic factors. The intrinsic factors that regulate adult neurogenesis are given in **Table 3**. There are extrinsic environmental cues and systemic factors that can positively and negatively affect adult neurogenesis like physical exercise, dietary intake, olfactory/hippocampaldependent learning, environmental enrichment, ageing, stress, alcohol abuse, and certain inflammatory conditions [46, 56–59].
