**2. Adult neurogenesis**

#### **2.1. Hippocampal neurogenesis**

NPCs in the SGZ become neurons of the granular cell layer of the dentate gyrus in the hip‐ pocampus. In the SGZ, the most immature NPCs (Type 1) are radial and horizontal NPCs that transition to intermediate progenitors (type-2a, 2b and 3) and then to immature granule neurons which become dentate granular neurons. These then make large mossy fibre projec‐ tions with CA3 pyramidal neurons [4].

in the SVZ and SGZ can obstruct this cascade [21-23]. Inhibition of the BMP pathway increases neurogenesis initially, however it results in depletion of the NSC pool leading to decreased neurogenesis [24]. In the dentate gyrus, the RNA-binding protein FXR2 regulates neurogene‐ sis by reducing the stability of noggin mRNA leading to an increased activation of the BMP pathway [25]. Proliferation in the SVZ is under epigenetic control via histone HZAX phoso‐

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Proneural proteins, basic-helix-loop-helix (bHLH) transcription factors also control neuronal fate commitment of NPCs. Type C cells of the SVZ fated to become GABAergic interneurons in the olfactory bulb express *Ascl1* [27]. *Ngn2* and *Tbr2* are expressed in dorsal SVZ progeni‐ tors that become glutamatergic juxtaglomerular neurons [28], while *Sp8* is required for par‐ valbumin-expressing interneurons in the olfactory bulb [29]. In the SGZ, *Neurog2* and *Tbr2* are expressed in NPCs destined to become glutamatergic neurons in the hippocampus [27,

Neurotrophic growth factors have been studied extensively in the SVZ. Many, including, epidermal growth factor (EGF), transforming growth factor (TGF), and vascular endothelial growth factor (VEGF) can augment SVZ progenitor proliferation and migration of newly de‐ rived cells into structures beside the lateral ventricles; however these cells primarily differ‐ entiate into oligodendrocytes [33-36]. Fibroblast growth factor-2 (FGF-2) signalling promotes proliferation in both the SVZ and SGZ [37-39]. FGF-2 and TGF synthesis and secretion can be augmented by ATP, which can increase proliferation, and provide a potential explanation for the reduced neurogenesis in purinergic receptor knockout mice (P2Y1) [40, 41]. Other factors also play a role in neurogenesis, including neuregulin-1, which has been implicated in dentate gyrus neurogenesis in addition to having antidepressant effects [42] and Growth Hormone (GH) which augments EGF and FGF2-induced proliferation [43]. Growth factor signalling often leads to activation of Akt through phosphoinositide-3 kinase (PI-3K); one negative regulator of this pathway is the phosphatase and tumour suppressor PTEN, which has a role in regulating neurogenesis as demonstrated by increased proliferation and differ‐ entiation in mutant mice [44]. Furthermore, IGF-2 also regulates proliferation in the dentate

The gp130-associated cytokines, ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), activate Janus kinase (JAK/signal transducer of transcription 3 (STAT3)), mito‐ gen activated protein (MAP) kinase and PI-3K/Akt pathways following ligand binding. These cytokines have been shown to regulate NSC proliferation and differentiation [46-49]. Specifically in the dentate gyrus, the activation of STAT3 from CNTF appears to be essential for the formation and maintenance of the NSCs [50]. The role of the JAK/STAT pathway will be discussed in more detail later. The MAPK pathway is important for neurogenesis as dem‐ onstrated by conditional knockdown of extracellular signal-related kinase 5 (ERK5) which limits neuronal differentiation and neurogenesis resulting in impaired contextual fear ex‐

Other molecules shown to have a role in controlling neuronal differentiation include Prese‐ nilin-1 (PS1), which is the catalytic core of the aspartyl protease gamma-secretase. Reduction of PS1 enhances differentiation, primarily through its transducers the EGF receptor and β-

phorylation which can limit proliferation and overall neurogenesis [26].

30, 31], while over-expression of *Ascl1* produces oligodendrocytes [32].

gyrus in an Akt-dependent manner [45].

tinction and remote fear memory [51, 52].

#### **2.2. SVZ neurogenesis**

The SVZ produces NPCs that form neuroblasts which migrate along the rostral migratory stream and become neurons in the olfactory bulb. These new neurons primarily become GA‐ BAergic granule neurons that provide lateral inhibition between mitral and tufted cells. A mi‐ nority of the new neurons become periglomerular neurons that are involved in lateral inhibition between glomeruli, and a small number of these cells are dopaminergic. Similar to the SGZ, there is a progression of NPC development in the SVZ. Slowly proliferating astro‐ cytes in the SVZ (Type B cells) are the NSCs and these generate the highly proliferative transitamplifying Type C cells. These then generate post-mitotic neuroblasts (the Type A cells) destined for the olfactory bulb via migration along the rostral migratory stream (RMS) [5-7].
