Neurogenesis in neurological and psychiatric diseases and brain injury: from bench to bedside.

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Contents lists available at ScienceDirect

Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio

Neurogenesis in neurological and psychiatric diseases and brain injury: From bench to bedside Linhui Ruan a,b,1, Benson Wui-Man Lau c,1, Jixian Wang b, Lijie Huang a,b, Qichuan ZhuGe a, Brian Wang b, Kunlin Jin a,b,*, Kwok-Fai So d,e,f,g,** a

Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, TX 76107, USA Department of Rehabilitation Science, The Hong Kong Polytechnic University, Hong Kong, PR China d Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, PR China e The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, PR China f Research Centre of Heart, Brain, Hormone and Healthy Aging, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, PR China g GMH Institute of CNS Regeneration, Jinan University, Guangzhou, PR China b c

A R T I C L E I N F O

A B S T R A C T

Article history: Received 6 October 2013 Received in revised form 8 December 2013 Accepted 12 December 2013 Available online xxx

Researchers who have uncovered the presence of stem cells in an adult’s central nervous system have not only challenged the dogma that new neurons cannot be generated during adulthood, but also shed light on the etiology and disease mechanisms underlying many neurological and psychiatric disorders. Brain trauma, neurodegenerative diseases, and psychiatric disorders pose enormous burdens at both personal and societal levels. Although medications for these disorders are widely used, the treatment mechanisms underlying the illnesses remain largely elusive. In the past decade, an increasing amount of evidence indicate that adult neurogenesis (i.e. generating new CNS neurons during adulthood) may be involved in the pathology of different CNS disorders, and thus neurogenesis may be a potential target area for treatments. Although new neurons were shown to be a major player in mediating treatment efficacy of neurological and psychotropic drugs on cognitive functions, it is still debatable if the altered production of new neurons can cause the disorders. This review hence seeks to discuss pre and current clinical studies that demonstrate the functional impact adult neurogenesis have on neurological and psychiatric illnesses while examining the related underlying disease mechanisms. ß 2014 Published by Elsevier Ltd.

Keywords: Neurogenesis Neurodegenerative diseases Psychiatric disorders Stroke Regulation

Abbreviations: 6-OHDA, 6-hydroxydopamine; 7-OH-DPAT, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin; AD, Alzheimer’s disease; ADAM, a disintegrin and metalloproteinase; APH-1, anterior pharynx-defective 1; ApoE4, apolipoprotein E e4 allele; APP, amyloid precursor protein; Ab, amyloid-b protein; BDNF, brain-derived neurotrophic factor; CAG, cytosine–adenine–guanine; CCI, controlled cortical impact; CNS, central nervous system; CREB, cAMP-response element binding protein; D1L, D1-like; D2L, D2like; DCX, doublecortin; DG, dentate gyrus; Dll4, delta-like 4; ECT, electroconvulsive therapy; GCL, granule cell layer; anti-GFAP, anti-glial fibrillary acidic protein; HB-EGF, heparin binding EGF; HD, Huntington’s disease; HPA, hypothalamic–pituitary–adrenal; LB, Lewy bodies; LFP, lateral fluid percussion; LGF, liver growth factors; LN, Lewy neuritis; LPS, lipopolysaccharide; MAM, methylazoxymethanol acetate; MAOIs, monoamine oxidase inhibitors; MCAO, middle cerebral artery occlusion; MLK2, mixedlineage kinase 2; MPTP, methyl-4-phenyl-1,2,3,6-tetrahydropyridine; mTOR, mammalian target of rapamycin; NeuroD, a transcription factor also known as Beta2; NFT, neurofibrillary tangles; NPAS3, neuronal PAS domain-containing protein 3; NPAS3, neuronal PAS domain-containing protein 3; NRG1, neuregulin 1; NRSE, neuron-restrictive silencer element; NRSF, neuron-restrictive silencer factor; NSCs, neural stem cells; OB, olfactory bulb; PCNA, proliferating cell nuclear antigen; PD, Parkinson’s disease; PDGF, platelet-derived growth factors; PEN-2, presenilin enhancer 2; polyI:C, polyriboinosinic-polyribocytidilic acid; PPv, posterior periventricular area; PS1, presenilins 1; PS2, presenilins 2; PSA-NCAM, polysialylated neural adhesion molecules; PTSD, post-traumatic stress disorder; REST, repressor-element-1 transcription factor; RMS, rostral migratory stream; sAPP, secreted form of APP; SEL, subependymal later; SGZ, subgranular zone; SN, substantia nigra; SNRIs, selective norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; SVZ, subventricular zone; TAPs, transient amplifying progenitors; TBI, traumatic brain injury; TCAs, tricyclic antidepressants; TGF-a, transforming growth factor a; VEGF, vascular endothelial growth factor. * Corresponding author at: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA. Tel.: +1 817 735 2579; fax: +1 817 73504080. ** Corresponding author at: Department of Ophthalmology, The University of Hong Kong, Room L1-55, 21 Sassoon Road, Pokfulam, Hong Kong SAR, PR China. E-mail addresses: [email protected] (L. Ruan), [email protected] (K. Jin), [email protected] (K.-F. So). 1 These authors are co-first authors. 0301-0082/$ – see front matter ß 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.pneurobio.2013.12.006

Please cite this article in press as: Ruan, L., et al., Neurogenesis in neurological and psychiatric diseases and brain injury: From bench to bedside. Prog. Neurobiol. (2014), http://dx.doi.org/10.1016/j.pneurobio.2013.12.006

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Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurogenesis and neurological diseases . . . . . . . . . . . . . . . . . . . . . . . Neurogenesis and brain injuries. . . . . . . . . . . . . . . . . . . . . . . . 2.1. Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. 2.1.2. Brain trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurogenesis and neurodegenerative diseases . . . . . . . . . . . . 2.2. Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Huntington’s disease . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3. Neurogenesis and psychiatric illnesses . . . . . . . . . . . . . . . . . . . . . . . . Neurogenesis and clinical depression . . . . . . . . . . . . . . . . . . . 3.1. Neurogenesis and anxiety disorders . . . . . . . . . . . . . . . . . . . . 3.2. Neurogenesis and schizophrenia . . . . . . . . . . . . . . . . . . . . . . . 3.3. Regulation of stroke-induced neurogenesis . . . . . . . . . . . . . . . . . . . . Notch signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Shh signaling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Wnt signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Neurotrophic factor and growth factors . . . . . . . . . . . . . . . . . 4.4. BDNF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.1. FGF-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.2. 4.4.3. EGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IGF-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.4. VEGF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.5. Neurotransmitters. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. 4.6. Transcriptional factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulation of AD-induced neurogenesis . . . . . . . . . . . . . . . . . . . . . . . Regulation of PD-induced neurogenesis . . . . . . . . . . . . . . . . . . . . . . . Regulation of HD-induced neurogenesis. . . . . . . . . . . . . . . . . . . . . . . 7.1. Decreased neurotrophic factor and growth factor expression Neurotransmission deficits . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Dysregulation of transcriptional factor . . . . . . . . . . . . . . . . . . 7.3. Mitochondrial deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Regulation of neurogenesis in psychiatric illnesses . . . . . . . . . . . . . . Clinical implication of neurogenesis in psychiatric illnesses . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Adult neurogenesis is known as generating newly functional neurons from neural precursor cells resulting in the addition or replacement of neurons in the CNS of adult mammals under physiological and pathological conditions (Ming and Song, 2011; Lindsey and Tropepe, 2006). Traditionally, new neurons were thought to only be produced in the pre- and early post-natal periods, and this ability was said to be markedly diminished in the adult CNS. This view was first challenged by the findings of Altman et al. in the 1960s, which showed that the subgranular zone (SGZ) of the hippocampus, a limbic system constituent responsible for memory formation, could generate new neurons (Altman and Das, 1965). This finding was echoed by a later study that used canaries as an animal model (Paton et al., 1985). New interneurons were found in the hyperstriatum ventralis and pars caudalis of adult canaries, which may partially explain how canaries can learn different songs. Moreover, additional studies confirmed that the adult humans’, rodents’ and primates’ brains could indeed generate new neurons (Kirschenbaum et al., 1994; Eriksson et al., 1998; Kukekov et al., 1999; Pincus et al., 1998). Neural stem cells (NSCs) and neural progenitor cells (NPCs) residing in the subventricular zone (SVZ), subgranular zone (SGZ), and the posterior periventricular area (PPv) are said to be able to produce newly functional neurons and glia throughout a mammal’s lifetime (Alvarez-Buylla et al., 2002).

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Adult neurogenesis in an adult mammal’s CNS mainly occurs in two neurogenic regions namely the: (1) SVZ and (2) region within the dentate gyrus (DG) of the hippocampus known as the SGZ (Fig. 1) (Semple et al., 2013; Curtis et al., 2007a; Sanai et al., 2004). Apart from these two regions, there is increasing evidence demonstrating the presence of neurogenesis in regions of the brain such as the cerebral cortex, thalamus, hypothalamus, striatum, and septum (Pencea et al., 2001). Neurogenesis is a process that consists of four stages, namely, cell proliferation, cell migration, differentiation, and integration into a circuit. After proceeding through these stages, the neurons are incorporated into the mature brain (Ming and Song, 2011). In the SGZ, radial glia-like cells act as the source of continuous cell proliferation. After cell division, the progenitor cells lose a certain degree of ‘‘stemness’’ and become migrating neuroblasts that then migrate to the outer granule cell layer (GCL). In the GCL, the immature neurons differentiate into dentate granule neurons and their dendrites extend to the molecular layer of the DG. The new neurons then integrate into the existing hippocampal tri-synaptic circuitry by establishing synapses in the molecular layer with other neurons. In the SVZ, the developmental origin of NSCs is embryonic radial glia, which gives rise to neurons, oligodendrocytes, and astrocytes (Merkle et al., 2004). NSCs found along the lateral wall of the lateral ventricles produce immature neurons that aggregate and form a chain of neuroblasts that, in turn, forms a restricted migration


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Fig. 1. Dentate gyrus and subventricular zone (SVZ) as neurogenic regions in mammalian brain. Sagittal section showing the two anatomically distinctive regions. Proliferation of neural precursor cells (C cells) takes place at SVZ, followed by migration of transiently migrating neuroblasts (A cells). After reaching the olfactory bulb (OB), the neuroblasts differentiate into periglomerular neurons and granule cells. Integration into the existing OB circuitry renders functional significance to the new neurons. In the dentate gyrus (DG), the newborn neural precursors migrate through a short distance and then differentiate into immature neurons. Hp, hippocampus.

pathway toward the olfactory bulb (OB). This restricted route is known as rostral migratory stream (RMS) (Corotto et al., 1993; Curtis et al., 2007b; Lois and Alvarez-Buylla, 1994). Upon arriving at the OB, these neuroblasts differentiate into two types of neurons: periglomerular neurons and granule cells (Whitman and Greer, 2009). With synaptic connections to other mature neurons such as the mitral cells, the new interneurons are then functionally integrated into the OB. Under normal physiological conditions, the majority of the NPCs become neurons in the DG & OB although they may also differentiate into other cell types (DeCarolis and Eisch, 2010). Precursor cells in the SVZ include: (1) proliferating type A cells (neuroblasts), (2) slowly proliferating type B1 and B2 cells (astrocytes) that show self-renewal properties in the CNS (Alvarez-Buylla and Garcia-Verdugo, 2002), and (3) actively proliferating type C cells transient amplifying progenitors (TAPs). Type A cells have the ultrastructure of migrating neuronal precursors and are arranged as chains parallel to the walls of the ventricle and ensheathed by two ultrastructurally distinct astrocytes (type B1 and B2). Type A and B2 – but not B1 – cells incorporate 3H-thymidine. The most actively dividing cells in the SVZ correspond to type C cells, which have immature ultrastructural characteristics, are present throughout the SVZ (Doetsch et al., 1997), and form clusters that are associated with type A cells. The successive stages of NSCs’ differentiation are as follows: type B, to type C, and finally to type A. There are certain protein markers that can discriminate different types of cells. Polysialylated neural adhesion molecules (PSA-NCAM) found on the surface of neural cells play a significant role in regulating neurogenesis (Bonfanti and Theodosis, 1994). Doublecortin (DCX), a microtubule-associated protein, is highly expressed in Type A cells (Karl et al., 2005) and migrating and

differentiating neurons (des Portes et al., 1998; Francis et al., 1999). In addition, Type A cells can also be recognized by other markers such as bIII tubulin (TuJ1) and Hu. Types B and C cells on the other hand, do not express PSA-NCAM, DCX, and TuJ1. In particular, type B cells are more likely to express glial fibrillary acidic protein (GFAP) than vimentin. One uniting characteristic amongst these three cell types is that they all express nestin. In the SGZ, there are two types of NPCs: GFAP-positive and GFAP-negative cells that can be discriminated by electron and confocal microscopy (Seri et al., 2001). Type 1 cells (GFAP-positive) have darkly stained organelles, polyribosomes, but lightly stained mitochondria, and they are positive for nestin, GFAP, Blbp, Glast, and SOX2 (Fukuda et al., 2003; Suh et al., 2007). Recent studies using inducible Cre-recombinase driven by a variety of promoters including Glia GFAP, nestin, and GLAST have provided evidence substantiating that type 1 cells are the primary NSCs in the adult brain (Dhaliwal and Lagace, 2011). Type 2 cells, also called nonradial precursor cells, display a more horizontal morphology with very short processes. These express GFAP but not nestin or Sox 2 (Fukuda et al., 2003). Type 2 cells can be further classified based on the existence of pro-neuronal transcription factors: (1) Type 2a cells express Mash1, and (2) Type 2b cells express Prox1 and Neurod1 (Lugert et al., 2010). Type 2b cells, the intermediate cell type between NSCs and neuroblasts, are the TAPs in the SGZ. To understand the functional and behavioral roles of adult neurogenesis, three components should be considered: the cellular substrate, network, and system (Kempermann et al., 2004). For functional understanding of the newly produced cells at the system level, ablation of neurogenesis by different techniques is usually employed. Shors et al. (2001) used the cytostatic toxin methylazoxymethanol acetate (MAM) to suppress hippocampal neurogenesis, and showed that the formation


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of hippocampal-dependent trace memories, which refers to the association of different events occurring at different times, was decreased when the neurogenesis was suppressed. When neurogenesis is recovered, the impairment in forming traces memories ceased. Later studies suggested another function of neurogenesis in mediating anxiety and depression-like behaviors, which are discussed later in this review. The function of neurogenesis in the SVZ was elusive until recent findings suggested that new neurons might be related to reproductive behaviors. Rodents rely heavily on olfaction for reproduction by receiving olfactory and pheromone signals in the surrounding environment to identify potential mates. Because the OB continuously receives a supply of new neurons from the SVZ, it has been suggested that neurogenesis may be important for identifying potential mates. Indeed, Mak et al. (2007) showed that under normal conditions, neurogenesis in the SVZ was upregulated in female mice upon exposure to pheromones of their male counterparts. The increase in neurogenesis was associated with their ability to select the dominant male as their preferred mate. When neurogenesis was blocked, the preference for a stronger mate was abolished. These results suggest that neurogenesis in the SVZ may be important for the female rodents to choose dominant mates, which may increase their chances for producing offspring with a better genetic make-up as well as selecting a mate with a desirable phenotype to protect the offspring. Interestingly, a later study showed that neurogenesis in the SVZ enabled paternal recognition of the pups thereby demonstrating that new neurons are involved in forming recognition memory between the parents and offspring (Mak and Weiss, 2010). When male rats were treated with stress hormone corticosterone, not only neurogenesis was suppressed, sexual behavior was decreased as well. Consistent with this finding, when neurogenesis was blocked by cytosine arabinoside, a cytostat, sexual behavior was also impaired. These findings suggest a role for neurogenesis in the SVZ in the successful reproduction of rodents and, correspondingly, that neurogenesis in the two neurogenic regions may have a distinct role in behavior. Although neurogenesis is presumed to take place in the two neurogenic regions, recent reports suggest that adult neurogenesis may be found in other CNS regions, such as the amygdala and neocortex (Dayer et al., 2005; Fowler et al., 2008; Lieberwirth et al., 2012a; Okuda et al., 2009). The potential for generating functional neurons in these regions is still a matter of debate. However, because of the functional and behavioral significance of these regions in different behaviors such as social interaction, learning, memory, and reproductive behaviors (Fowler et al., 2008), it is feasible that the new neurons may mediate the above behaviors. For instance, the amygdala is a prominent structure that could be further divided into several nuclei in which each of these structures is responsive to physiological or environmental stimuli (e.g. stress) and contributes to the emotional process and social interaction of individuals. By considering the functions exerted by the new neurons in the hippocampus and SVZ, the new cells in amygdala, whether destined to be neurons or glia, may affect the behavioral phenotype and possibly the pathophysiology of mood disorders (Ferguson et al., 2002; Mercadante et al., 2008; Wang et al., 2006). In the amygdala, altered neurogenesis has been a suggested cause for autism (Mercadante et al., 2008). A major characteristic of autistic patients is the refusal to establish social interaction with others (Mercadante et al., 2008; Silverman et al., 2012), which may be associated with amygdala function. Imaging studies have shown that the volume of the amygdala in autistic patients was decreased (Munson et al., 2006), and this may be due to the suppressed cell proliferating rate and decreased dendritic arborization (Howard et al., 2000; Mercadante et al., 2008).

Morphological changes may be related to an abnormal GABA signaling system (Mercadante et al., 2008), which affects the ability to learn new experiences. All in all, morphological changes seen in the amygdala are associated with autistic behavior at a theoretical level. The neocortex is another region in which several research groups have detected neurogenesis. New neurons were found in the cortex of monkeys. Gould et al. (1999) suggested that cortical migration of these new neurons originated from the SVZ. Other studies suggested that the new neurons could be found in the cortex under pathological conditions such as a cerebrovascular event (Arvidsson et al., 2002; Leker et al., 2007). Using transgenic technologies, the new cells were shown to migrate toward other cortical layers and differentiate into GABAergic neurons (Ohira et al., 2010). However, unless functional significance of neurogenesis in the cortex is explored, it will remain only a speculation.

2. Neurogenesis and neurological diseases Neurological diseases and brain injuries induce a progressive cascade of related events that contribute to inflammatory responses, neuronal death, brain edema, axonal injury, excitotoxicity, radical-mediated damage, mitochondrial dysfunction, and dysregulation of calcium homeostasis (McColl et al., 2008). Although repair mechanisms in the adult CNS are thought to be extremely limited, current experimental paradigms have expanded to evaluate the response of endogenous neurogenesis to cerebral diseases. Recently, reports have asserted that newborn neurons are capable of repairing and remodeling after brain injury. These newborn neurons are critically important for brain development and maintenance in both the embryonic and adult brains. Alterations to the development of, and maintenance in, the brain are observed in neurological diseases. This section aims to summarize neurogenesis in response to brain injuries in the adult mammalian brain as well as to evaluate current progress toward potential clinical therapies targeting neurogenesis. 2.1. Neurogenesis and brain injuries 2.1.1. Stroke Reports have seen the induction of neurogenesis by physiological factors like growth factors and pathological conditions such as ischemic stroke. Previous studies in rodents have shown that stroke induced the proliferation of endogenous NSCs generating from the SVZ (in cases of focal ischemia) (Jin et al., 2001; Arvidsson et al., 2002; Parent et al., 2002; Zhang et al., 2001) as well as the SGZ (in global ischemia) (Liu et al., 1998). These newborn cells are capable of migrating into damaged brain regions (Jin et al., 2003), expressing phenotypic and region-specific markers of mature neurons like cAMP-regulated phosphoprotein-32, calbindin, and dopamine (Arvidsson et al., 2002), and even forming synapses (Yamashita et al., 2006). It has been shown that bilateral proliferation begins as early as 48 h after transient focal ischemia in both the SVZ and DG. It then peaks at about one to two weeks before returning to sham levels three to four weeks later (Jin et al., 2001). Many other studies have also observed significant increases in proliferation of progenitors in both the DG and SVZ following middle cerebral artery occlusion (MCAO). For example, Jin et al. (2003) observed that newborn cells in the SVZ could migrate to ischemic areas like the cortex and striatum, and this process may last for four months or more after stroke (Thored et al., 2006). In addition to rodents, studies have also reported neurogenesis occurring in primates and humans. For example, reports have seen the occurrence of neurogenesis in the cortex of adult primates (Gould et al., 1999), and brain tissue from stroke patients provided


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evidence that neurogenesis occurs in ischemic stroke (Jin et al., 2006). Many researchers have investigated the fate of neuroblasts after focal ischemia. Thored et al. (2009) reported that for up to a year after ischemia, neuroblasts in the SVZ could migrate to injured areas like the striatum. This opened up the possibility of the SVZ being a steady reservoir of newborn neurons thus offering an extensive window of opportunity for therapeutic action. Liu et al. labeled SVZ progenitors using retroviral reporters prior to the availability of stroke models in adult rats. They observed that the majority of newborn neurons have differentiated to calretininexpressing interneurons (Doh-ura et al., 1999). In the DG, the newly proliferated progenitors either died or migrated into the GCL. Most of the cells that migrated to the DG differentiated into neurons expressing calbindin or NeuN within three to four weeks after ischemia. Out of those cells that differentiated, about 10–20% differentiated into astrocytes expressing GFAP in both the hippocampal hilus and the GCL (Komitova et al., 2002). A number of proliferating cells from the PPv and the ipsilateral SVZ were seen migrating into the penumbral cortex and corpus callosum, but most of them did not differentiate into mature neurons at later time points (Lichtenwalner and Parent, 2006). This suggests that the damaged cortex lacks the necessary signals to induce differentiation or even support neuronal survival. Several studies have also shown that global ischemia induced a tenfold increase in SGZ progenitor proliferation of mice, rats, humans, gerbils, and monkeys (Takagi et al., 1999; Iwai et al., 2001; Yagita et al., 2001; Kee et al., 2001; Schmidt and Reymann, 2002; Jin et al., 2006; Tonchev et al., 2005). These progenitors express immature neuronal markers like Nestin, PSA-NCAM, bIII tubulin, amongst many others, and are known to migrate from the SGZ, by way of the RMS, and ending at the OB. Nakatomi’s group also showed that the new neurons migrating to the CA1 from the PPv could repair damage to the hippocampus (Nakatomi et al., 2002). A more recent study by Bendel et al. (2005) demonstrated that the recovery of memory functions and spatial learning in adult rats could be achieved by repopulating CA1 neurons after a global ischemic event. Echoing that, the gerbil brain also showed an increase in hippocampal neurogenesis (Takagi et al., 1999; Iwai et al., 2001; Yagita et al., 2001; Kee et al., 2001; Schmidt and Reymann, 2002; Jin et al., 2006; Tonchev et al., 2005). Liu et al., too, observed a similar phenomenon in the dentate SGZ one to two weeks after 10 min of bilateral occlusions of the common carotid artery in gerbils. Interestingly, a global ischemic event lasting 2 min did not cause a significant increase in neurogenesis (Liu et al., 1998), thus indicating that the neurogenesis induced by global-ischemia is affected by the duration of the event. Tanaka and colleagues injected a retroviral vector expressing EGFP into the DG of Mongolian gerbils 48 h before global ischemia. At 30 days after injury, they found that progenitor cells proliferated and were seen migrating to the GCL. These cells expressed developing neuronal markers like DCX and PSA-NCAM, and upon differentiation into mature granule cells, they expressed neuronal nuclei or calbindin (Tanaka et al., 2004). Although neurogenesis after cerebral ischemia is well documented, whether or not the small number of surviving newborn neurons are able to integrate appropriately by replacing lost cells in order to improve functional recovery remains unclear. There is evidence that supports the theory of newborn neurons integrating into the injured striatum after migration (Yamashita et al., 2006). Therein lies the question of whether the migrated cells can actually make the necessary connections for proper integration. Wang et al. showed that administration of erythropoietin 24 h after stroke enhanced neurogenesis and improved neurological function (Wang et al., 2004b), suggesting that neurogenesis may be correlated with neurological functional recovery. Other groups

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demonstrated that a variety of neurotrophic factors, including VEGF, as well as drugs like sildenafil (Sun et al., 2003; Zhang et al., 2006) along with exogenously transplanted mesenchymal stem cells and NSCs (Tang et al., 2013; Jin et al., 2010), could also increase neurogenesis after cerebral ischemia, and that this was accompanied with improved behavioral recovery. However, whether the ischemia-induced new cells can become functional neurons remains unknown. Hou et al. stereotaxically injected an EGFP gene-bearing retrovirus into the lateral ventricle 24 h before MCAO to label the dividing progenitors. They found that newborn neurons could anatomically form neuronal polarity and synapses with preexisting neurons. In addition, patch clamp recording showed that newborn neurons displayed functional electrophysiological properties (Hou et al., 2008). Thus, this study directly demonstrated that ischemia-induced neurons are electrophysiologically functional. Recently, Wang et al. also showed that conditional inhibition of neurogenesis via specific knockout of DCX in a mouse model of stroke impaired long-term functional recovery (Wang et al., 2012), indicating that endogenous neurogenesis is critical for functional recovery after stroke. 2.1.2. Brain trauma In patients with traumatic brain injury (TBI), neuronal loss is focal and diffuse and often occurs by necrotic and apoptotic mechanisms (Smith et al., 2000). Among the diffuse sites of injury, the hippocampus is known to be damaged frequently in humans (Kotapka et al., 1992), and that is associated with deficits in learning and memory, which are the hallmarks of TBI. Significant recovery occurs following TBI, and neurogenesis is thought of as one potential contributor to that recovery. This raised hopes that TBI-induced neurogenesis may function to replace damaged neurons, contribute to the repair of neuronal circuits, and improve neurological recovery in patients with TBI. Employing the two most relevant and frequently used experimental TBI models, the lateral fluid percussion (LFP) and controlled cortical impact (CCI) injury models, Rice et al. (2003) found that neurogenesis increased three- to four-fold beginning as early as two days post-injury. New cells expressing neuronal markers after appropriate maturation periods increased significantly, thus suggesting that injury-induced proliferation in the DG is primarily neurogenic, rather than a reactive gliosis, in nature (Sun et al., 2005). However, the results reported are by and large correlational and consequently do not give a true sense of whether neurogenesis after TBI is aiding the recovery of learning and memory functions (Leuner et al., 2006). Newly born neurons in the CA regions have not been found to migrate, thus raising the possibility that some newborn neurons in the hippocampus may have been derived from the nearby SVZ. Experimental TBI induces an increase in SVZ proliferation in some studies, followed by recruitment of NPCs to the injured cortex (Chirumamilla et al., 2002; Chen et al., 2003). In addition, some groups reported a two- to four-fold increase in neuroblasts available for subsequent migration up to 14 days after injury (Lu et al., 2003; Ramaswamy et al., 2005). After TBI, cells can be detected with antibodies recognizing neuronal markers like DCX or Hu along with BrdU to observe their expression in the striatum, cortex, and corpus callosum. As early as three days after TBI, BrdU/DCX-positive cells were to shown to migrate to the injury site (Ramaswamy et al., 2005) whereas BrdU/ Hu-positive cells were observed in the striatum as well as the cortex at 42 days following TBI (Lu et al., 2003). Additionally, treatment with 3,3-bis(aminoethyl)-1-hydroxy-2-2-oxo-1-triazene otherwise known as DETA NONOate, resulted in a threefold increase in SVZ proliferation at 14 days post-TBI, whereas at 42 days post-TBI, a twofold increase was observed with respect to the


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number of cells positive for BrdU/Hu present in the striatum, cortex, and corpus callosum. This suggests that the increase in the number of neuroblasts that migrate to the injury is dependent upon augmentation of SVZ proliferation (Lu et al., 2003). Ramaswamy et al. (2005) injected fluorescent microspheres intraventricularly to label BrdU-positive subventricular cells and found that the progenitors migrated from the SVZ throughout the corpus callosum to the cortex surrounding the site of a contusion from cortical impact. In the SVZ, corpus callosum, striatum, and cortex, many of these cells were also positive for DCX at three days after TBI, suggesting that neuroblasts can be redirected from the SVZ by injury-specific extracellular signaling pathways. Whether neuroblasts can replace neurons lost in TBI remains to be determined. In the OB of rodents, 90% of neuroblasts differentiate into GABAergic interneurons, whereas the remaining neuroblasts become dopaminergic periglomerular interneurons. This fact demonstrates that NPCs in the SVZ differentiate into neuronal phenotype. Richardson et al. provided evidence for the plasticity of SVZ NPCs by demonstrating their differentiation to calbindinexpressing neurons after transplantation to the DG (Richardson et al., 2005). All in all, the data from the studies cited above show the potential for directing the phenotypic differentiation of NPCs that migrate to sites of injury. As previously mentioned, newborn cells at injured sites may migrate from the SVZ, but there is also evidence for the activation of latent NPCs in the cortex of mammalian brain after TBI. Macklis et al. suggested the possibility that after targeted neuronal death, endogenous neural precursors from the cortex itself can differentiate into corticothalamic neurons and survive for long periods to form the necessary long-distance connections in adult mice (Magavi et al., 2000). In humans, there is still no substantial evidence showing that NPCs are indeed present in the nongerminal cortex. It has thus far been restricted to the isolation of cells from surgically resected tissue. Richardson et al. (2006) have reported the isolation of putative neuroblasts from neocortical tissue surgically resected from patients with TBI. Previously, Arsenijevic et al. (2001) also isolated neurosphere-generating cells from similar cortical tissue. After CCI injury in rodents, the formation of neurospheres from neocortical cells has also been observed but only when injured tissue was isolated at 3 days post-injury, which corresponded to a peak in nestin expression in the pericontusional cortex (Itoh et al., 2005). Induction of nestin expression in the cortex adjacent to the CCI injury has also been reported at seven days after injury, supporting the possibility that resident NPCs are activated in the cortex after trauma (Kernie et al., 2001). Therefore, in order to ascertain the presence of NSCs residing in the cortex, more time and effort needs to be devoted to this area. Despite the previously discussed evidence for the increase in new neurons in the hippocampus, there also lies the question of whether enhancing proliferation can possibly improve functional outcome. A few reports have demonstrated the use of pharmacological agents that induce increased neurogenesis following TBI to improve functional outcome. Kleindienst et al. (2005) showed that S100B could improve cognitive recovery in addition to an increased number of DG neurons. Lu et al. (2007) treated rats after traumatic brain injury with statins and found that neurogenesis in the DG increased and spatial learning improved after treatment. Sun et al. (2009b) infused FGF-2 intraventricularly for 7 days immediately following TBI and found that injured animals infused with bFGF displayed significantly enhanced neurogenesis in the SVZ and DG and exhibited significant cognitive improvement. Lu et al. (2005) also administered erythropoietin 14 days after CCI injury and found that newborn cells in GCL of the ipsi- and contra-lateral DG produced a significant percentage of increase of

differentiated mature neurons, which was accompanied by improved behavioral outcome. Additionally, Xiong and colleagues showed that recombinant treatment of mice with TBI with human erythropoietin dramatically decreased the number of dead cells in the DG and the volume of the cortical lesion after TBI. This led to increased recovery of spatial learning ability and sensorimotor function (Xiong et al., 2008). Although the improvements in functional outcome may be attributed to the neuroprotection provided by these growth factors, these data strongly suggest the possibility that improved behavioral recovery is associated with neurogenesis. 2.2. Neurogenesis and neurodegenerative diseases 2.2.1. Alzheimer’s disease In 1906, Alois Alzheimer first described Alzheimer’s disease (AD) which is now regarded as the most common cause of senile dementia (Berchtold and Cotman, 1998). The neuropathological hallmarks of AD include senile plaques (deposits of amyloid-b protein (Ab) and neurofibrillary tangles (NFT) (Hardy and Selkoe, 2002; Selkoe, 2001). Ab is produced upon proteolysis of the amyloid precursor protein (APP) by the cleavage of a-, b- and gsecretases. Three members of a disintegrin and metalloproteinase (ADAM) family (ADAM9, ADAM10, and ADAM17) are regarded as a-secretases (Allinson et al., 2003). Beta-site APP-cleaving enzyme (BACE) is a transmembrane aspartic protease and is regarded as a b-secretase(Vassar et al., 1999). The g-secretases, on the other hand, are made up of presenilins 1 and 2 (PS1 and PS2), anterior pharynx-defective 1 (APH-1), nicastrin, and presenilin enhancer 2 (PEN-2) (Steiner et al., 2002; Wolfe et al., 1999; Yu et al., 2000). Patients with AD present a loss of cognitive functions and progressive dementia, but motor functions are by and large spared. In the early stages of AD, the hippocampus is among the first area to be affected, due to the accumulation of plaques and tangles in hippocampal neurons. Since the hippocampus is mainly involved in the formation of memory and learning processes, many patients with AD exhibit symptoms affecting learning and memory in addition to spatial and temporal orientation. The primary site of Ab hippocampal accumulation is touted to be a possible link between AD and adult neurogenesis. Theoretically, changes in adult neurogenesis can be induced by any pathological change involving the hippocampus. Suffice to say, both the accumulation of Ab, as well as deteriorating neurons, may indeed affect neurogenesis. An in vitro study demonstrated that Ab disrupts the differentiation of neuronal cells (Haughey et al., 2002). In vivo studies by Chevallier et al. (2005) demonstrated that PS1 mutations in mice impaired neurogenesis via abnormal betacatenin signaling pathway. Wang et al. (2004c) used the PS1M146V knock-in mice, and found that impaired hippocampus-dependent associative learning was correlated with reduced adult neurogenesis in the dentate gyrus. Feng’s group revealed that mice displayed a pronounced deficiency in the DG in regard to enrichment-induced neurogenesis after conditional knockout of PS1. However, this reduction in neurogenesis did not result in learning deficits, thus indicating that newly formed neurons are not required for memory formation (Feng et al., 2001). The triple transgenic mouse (3 tg-AD), which has three mutant genes (APP, PSEN1, and tau), is developed recently. These mice exhibits temporal- and region-specific deposition of Ab (Oddo et al., 2003). In this model, neurogenesis begins to decrease at nine months of age, and this is accompanied by an increase in the amount of Ab plaque and the number of hippocampal neurons containing Ab (Rodriguez et al., 2008). Several other groups also have found a reduction in neurogenesis in the DG and SVZ using this transgenic model of AD (Wang et al., 2004c; Lim et al., 2011; Fedele et al., 2011).


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In contrast to previously discussed work, several studies have reported that adult neurogenesis was possibly enhanced by an ADlike pathology. For example, Jin et al. reported increased neurogenesis in PDGF-APP (Sw, Ind) mice, which express the Swedish and Indiana mutation in APP. His group found increases in BrdU incorporation and in immature neuronal markers even before Ab deposits and neuronal loss in the DG and SVZ were detected (Jin et al., 2004c). Jin’s group also reported that in patients with AD, increased neurogenesis in the hippocampus was evident (Jin et al., 2004a). These findings are supported by previous studies regarding an increase in the expression of cell-cycle-associated molecules in AD (Nagy et al., 1997). Despite decades of fervent research, the functions of adult neurogenesis in patients with AD and associated animal models remain unclear. Upon discovering neurogenesis in postnatal rat hippocampi, it was suggested that newborn neurons are exceedingly important for learning and memory (Guidi et al., 2005). However, the relationship between neurogenesis and cognitive improvement is still poorly understood. In one study by Arendash et al., Ab plaque was abundant in 16 month-old APP transgenic mice overexpressing K670N and M671L, the Swedish double mutation. Interestingly, mice housed in an enriched environment for four months exhibited improvements in their learning and memory abilities. This corresponded to an increase in hippocampal neurogenesis and specific neurotrophic factors, but failed to reduce the plaque load (Arendash et al., 2004). On the other hand, Jankowsky and colleagues demonstrated that an enriched environment exacerbated the Ab plaque load in mice with both APP and PS1 mutations. However, the animals were not tested for cognitive performance (Jankowsky et al., 2003). Thus, it is difficult to directly compare these two studies, as they differ in the animal model used as well as the age and gender of the animals. Bolognin et al. recently developed the I2NTF-CTF rat, which exhibits reduced brain PP2A activity, decreased neuronal plasticity, abnormal hyperphosphorylation and aggregation of Tau, and impaired spatial reference and working memories. The group found that by increasing neurogenesis in the DG via peptide 6, neurodegeneration along with cognitive deficits in I2NTF-CTF animals were rescued (Bolognin et al., 2012). This suggests that neurogenesis in the DG is beneficial for improving spatial reference and working memory. However, Russo et al. found that when Ab (1–42) injected rats were treated with a new TNF-a synthesis inhibitor, 3,60 -dithiothalidomide, memory impairment and neurogenesis were reduced (Russo et al., 2012), thus suggesting neurogenesis is not associated with memory improvement. As the correlation between neurogenesis and behavioral outcome in AD is obviously lacking, this lends itself to another area of AD research that needs to be looked into more intently. 2.2.2. Parkinson’s disease Parkinson’s disease (PD) is a longstanding progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN). The neuropathological characteristics are Lewy bodies (LB) and Lewy neuritis (LN) (Goedert, 2001). LB and LN contain the fibrillar and misfolded protein a-synuclein protein (a-syn), deposits of which are significant in PD (Dauer and Przedborski, 2003). To study the pathophysiology of PD, a number of animal models have been developed. These include those produced with a neurotoxin, such as 6-hydroxydopamine (6-OHDA) or methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), or a viral vector, as well as transgenic animal models, like the a-synuclein transgenic mice (Geraerts et al., 2007). Adult SN neurogenesis has been discussed extensively in PD, but not without controversy. Zhao and colleagues observed that neurons in the dopaminergic projection that are lost in PD can be

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regenerated from stem cells, and the rate at which nigral BrdU/THpositive neurons are generated is enhanced after an MPTP-induced lesion of the SN. These newborn DA neurons project into the striatum and are integrated into synaptic circuits (Zhao et al., 2003). Another study found that there is a population of actively dividing NPCs in the adult SN, and that these can generate new mature glial cells instead of neurons. However, these cells will differentiate into new neurons immediately after removal from the SN and subsequent transplantation into the adult hippocampus when exposed to appropriate environmental signals (Lie et al., 2002). Other studies have reported the presence of SN cell proliferation but without differentiating into DA neurons in 6OHDA-induced lesioned rats, and MPTP-induced lesioned mice(Kay and Blum, 2000; Mao et al., 2001). However, after isolating and transplanting these cells in a neurogenic environment like the DG, 20% of these cells were found to have differentiated into mature neurons (Lie et al., 2002), thus suggesting that different environmental factors could influence the fates of these cells. Interestingly, other studies failed to provide evidence involving dopaminergic neurogenesis in adult SN. A study using markers for dividing cells, BrdU and TH, showed negative results with respect to the production of new DA neurons in the SN in rodent models of PD, even after treatment with growth factor. Additionally, no NSCs from SVZ were found migrating to the SN, thus suggesting that newly generated dopaminergic neurons are extremely unlikely to be generated in the adult mammalian SN (Frielingsdorf et al., 2004). Kay and Blum (2000) explored the fate of proliferative cells in the SN after MPTP-induced brain lesions and found that most BrdU+ cells in the SN did not express markers for microglia, astrocytes, or oligodendrocytes. Cooper et al. investigated the neurogenic, behavioral, and cell proliferative effects of transforming growth factor a (TGF-a) in a 6-OHDA model of PD, and found that progenitor cells recruited by TGF-a proliferated and migrated but did not differentiate into midbrain DA-like neurons (Cooper and Isacson, 2004). Moreover, intraventricular infusions of brainderived neurotrophic factor (BDNF), liver growth factors (LGF), and platelet-derived growth factors (PDGF) were deemed ineffective in the generation of BrdU/TH positive neurons in the SN of adult rats with and without 6-OHDA lesions (Reimers et al., 2006; Mohapel et al., 2005; Frielingsdorf et al., 2004). 2.2.3. Huntington’s disease Huntington’s disease (HD) is a detrimental autosomal dominant neurodegenerative disorder caused and characterized by cytosine– adenine–guanine (CAG) repeated expansions within the huntingtin protein-encoding gene. HD results primarily from the loss of GABA medium spiny projection neurons in the caudate nucleus, in addition to deterioration of specific populations of striatal interneurons (Li and Li, 2004). The clinical symptoms of HD involve cognitive decline, bradykinesia, psychiatric syndromes, and more importantly, progressive involuntary choreatic movements (Walker, 2007). Impaired olfactory function has also been observed in both presymptomatic HD gene carriers and in patients with HD (Mochel et al., 2007). A number of groups have reported decreased proliferation in DG NPCs of the rat model for HD. Lazic et al. (2004) showed that hippocampal cell proliferation was similar in younger asymptomatic R6/1 mice (5 weeks) and wild type controls, but that older R6/1 mice (20 weeks) had significantly fewer BrdU cells than did controls. This phenomenon was also seen in the R6/2 mouse model of HD and was accompanied by a reduction in NeuroD1 versus wild-type controls (Fedele et al., 2011; Gil et al., 2005). Actively proliferating cells were reduced in both the mouse models, and were accompanied by a dramatic decrease in PSA-NCAM (van der Borght and Brundin, 2007). In the transgenic YAC128 mouse model of HD, significant decreases of DG neuronal proliferation were


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found, which persisted through the entire progression of this disease (Simpson et al., 2011). However, the SVZ did not show any significant differences pertaining to cell proliferation and differentiation (Gil et al., 2005; Lazic et al., 2006; Simpson et al., 2011). In contrast to the reduced proliferation of NPCs in the DG, proliferation in the SVZ was found to be unchanged in R6/2 mice (Phillips et al., 2005). Kohl et al. (2010) showed that the hostile huntingtin-associated microenvironment in the OB interferes with the survival and integration of new mature neurons, which resulted in a decrease in newborn neurons. In the brains of humans with HD, Curis et al. reported a significant increase in cell proliferation in the subependymal later (SEL) adjacent to the caudate nucleus by using the neuronal marker bIII-tubuliun, the cell cycle marker proliferating cell nuclear antigen (PCNA), and the glial cell marker GFAP. Of note, PCNA+ cells were shown to coexpress bIII-tubulin or GFAP, thus showing the generation of neurons or glial cells in the SEL of the HD human brains (Curtis et al., 2003). 3. Neurogenesis and psychiatric illnesses The ‘‘neurogenesis of depression’’ has now extended to other psychiatric illnesses such as schizophrenia and anxiety disorders (Fig. 2). The following sections will examine the evidence that supports the linkage between neurogenesis and psychiatric illnesses. We hope to provide a better understanding of the roles of neurogenesis in the pathophysiologies of severe mental illnesses. 3.1. Neurogenesis and clinical depression After the discovery that antidepressants were pro-neurogenic, clinical depression was the first psychiatric disorder to be linked to neurogenesis (Malberg et al., 2000). Intensive investigations of this association have been carried out in the past decade, but this still remains a matter of debate. The potential role of decreased neurogenesis in clinical depression has been supported by different lines of evidence.

First, several animal studies demonstrated that neurogenesis is under negative regulation by stress, which is widely recognized as a predisposing factor of mood disorders and a potential exacerbating factor of psychiatric illnesses (Gould et al., 1997). The convergence of different measures to induce stress is the stress hormone corticosterone, which is the key mediator of depression and anxiety-like behaviors (Murray et al., 2008). Suppressed neurogenesis, especially cell survival and cell proliferation, were usually found in animal models of clinical depression (DeCarolis and Eisch, 2010). Second, psychiatric medications for clinical depression (e.g. antidepressants) and activities that were suggested to be antidepressive (e.g. physical exercise) were shown to be pro-neurogenic in both stressed and healthy animals (Banasr and Duman, 2007; Malberg et al., 2000). The antidepressant treatment demonstrated a delay of approximately two weeks, which is comparable to the lag time between the start of antidepressant treatment and observation of treatment efficacy. Third, from a traditional viewpoint, the hippocampus is a major component of the limbic system and involved in mood regulation. Thus the newborn neurons have been hypothesized as contributing to the role of the hippocampus in regulation emotions (Meltzer et al., 2005). Additionally, clinical studies have observed decreased hippocampal volumes in clinically depressed patients, which may be caused by a decrease in neurogenesis (Fotuhi et al., 2012). Because of these findings, an alteration in neurogenesis was suggested as the key pathophysiological event underlying clinical depression. The association between new neurons and depressive disorder attracted attention from different groups by providing an alternative biological explanation of psychiatric disorders. Later the term ‘‘neurogenesis hypothesis of depression’’ was used to represent the assumed causal relationship between altered neurogenesis and depression (Drew and Hen, 2007). Owing to the decreased production of neurons in the hippocampus, symptoms of depression related to memory and mood disturbances were found. It was shown in pre-clinical studies of antidepressants that enhanced neurogenesis could reverse the symptoms of depression (Samuels and Hen, 2011). The speculation that altered neurogenesis is involved in depression has initiated

Fig. 2. The neurogenesis hypothesis of psychiatric disorders. When an individual is subjected to risk factors associated with psychiatric illness, e.g. stress, neurogenesis is suppressed and psychiatric symptoms, such as mood and memory disturbance, develop. With proper treatment of the psychiatric illness, neurogenesis can be restored and the symptom will be alleviated.


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causative studies that investigate the role of new neurons in the disorder. To establish the causal relationship between neurogenesis and depression, techniques that suppress or ablate neurogenesis were employed. Early studies showed that instead of direct induction of depression-like behaviors, suppression of neurogenesis abolished the therapeutic effect of antidepressants. A study conducted by Santarelli et al. (2003) suppressed neurogenesis by X-irradiation, which decreased cell proliferation in the brain up to 85% while sparing cell division in other body parts. After irradiation, the animals were treated with antidepressants. Control animals, with normal neurogenesis, that were treated with antidepressants showed a decreased level of anxiety as exhibited by a decreased latency to enter an anxiogenic arena in the novelty suppression test. On the contrary, the irradiated animals that were treated with antidepressants did not show decreased anxiety in the behavioral test. Thus, it was concluded that ablation of neurogenesis prevents the anxiolytic effect of antidepressant treatment. These findings showed that neurogenesis is necessary for antidepressants to work therapeutically to reduce anxiety. Transgenic animals with specific genes knocked-out serve as another means of studying the importance of new neuron formation in antidepressant treatment (Li et al., 2008). One of the target genes in these studies is BDNF, a neurotrophin necessary for neuronal proliferation, survival, and differentiation (Taliaz et al., 2010). Mice with the receptor for BDNF (tyrosine kinase receptor, TrkB) turned off had impaired neurogenesis, which was not improved by antidepressant treatment, and exhibited induced depression- and anxiety-like behavior. Interestingly, when TrkB expression was ablated in differentiated neurons but not NPCs, the animals were responsive to antidepressant treatment, which was indicated by an increase in neurogenesis and decreased depression-like behavior. Similar findings were reported by other investigators who showed that blocking hippocampal neurogenesis prevented the therapeutic effect of psychotropic/antidepressant treatment (Airan et al., 2007; Jiang et al., 2005). Recent reports showed that new neurons are required to maintain a normal hypothalamic-pituitary-adrenal (HPA) axis, which is the main system for responding to stress (Snyder et al., 2011; Surget et al., 2011). In animals with suppressed neurogenesis, behavioral deficits such as anhedonia and behavioral despair were found, and this was associated with an impaired HPA system; the affected animals showed slower recovery of glucocorticoid levels after a stressful situation. Although antidepressants could reverse the behavioral deficit and restore HPA function, their effects were neurogenesis-dependent. Thus without intact neurogenesis, the therapeutic effect of antidepressants would be abolished. Apart from newborn neurons, increasing lines of evidence suggested that glial cells in non-neurogenic regions may contribute to the pathogenesis of psychiatric disorders. Glial cells can replenish their own populations in the adult brain (Czeh et al., 2008; Bonfanti and Nacher, 2012; Cayre et al., 2009), and they are involved in different important regulatory functions like synaptogenesis, mediating angiogenesis and neurogenesis, and interacting with neurons via cell to cell interaction (Cotter et al., 2001). Proliferation of glial cells in the medial prefrontal cortex decreased with chronic stress (Czeh et al., 2008) and the anterior cingulate cortex glial cell density was related to major depressive disorder (Cotter et al., 2001). Furthermore, ablation of astrocytes in adult animals with L-alpha-aminoadipic acid was shown to induce depression-like behaviors and anhedonia, which was similar to the consequence of chronic unpredictable stress (Banasr and Duman, 2008). A recently published study using tissue from post-mortem human brains provided evidence that antidepressant treatment may promote neurogenesis and angiogenesis (Boldrini et al., 2012).

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The hippocampi of patients with depression that received antidepressant treatment had higher numbers of NPCs and capillaries than did that of control subjects and patients with depression who did were not treated with antidepressants. A larger volume of DG was also found in treated patients than in the other two groups. Nevertheless, although different lines of evidence support the relationship between clinical depression and neurogenesis, not all of the studies show consistent results. For instance, an early clinical study used post-mortem human brain samples to investigate whether neurogenesis is suppressed in patients with depression (Reif et al., 2006). Surprisingly, no difference was found between the density of proliferative cells in the hippocampi of depressed patients versus those of normal controls. However, the lack of medication history of the subjects confounds the interpretation of the results of the experiment, as antidepressant treatment is likely to increase neurogenesis and mask the suppressed neurogenesis caused by depression. The inconsistent results obtained in these two studies imply that additional variables may complicate the use of human samples such as the feasibility of a proper control group and limited sample size. In addition, the relatively lower rate of neurogenesis in the human hippocampus also raises the question of whether neurogenesis is important enough to produce behavioral effects in humans. Furthermore, animal studies have shown that suppression of neurogenesis alone did not result in behavioral despair (Airan et al., 2007; David et al., 2009), which implies that deficit in neurogenesis is unlikely to be the sole factor causing depression. Suppressed neurogenesis was detected in all animal models of depression, although whether it occurs in patients with depression requires further confirmation. Indeed, although neurogenesis per se is unlikely to be the sole cause of depression, the therapeutic effect of antidepressants is neurogenesis-dependent. The altered neurogenesis in the hippocampus may contribute to symptoms related to emotional regulation and impaired memory (Pickard, 2011), which are common symptoms found in clinical depression. Similar to other psychiatric illnesses, clinical depression has a complex pathophysiology that involves not only neurogenesis (Tang et al., 2011), but different interrelated factors such as synaptogenesis, neuroinflammation, and dendritic plasticity. Different animal studies may support the involvement of these events in depression, but their exact roles and the related mechanisms remain unclear (Chen et al., 2010). Although it is understood that the use of human tissue and subjects would greatly facilitate such investigations, the difficulties and lack of suitable technology to investigate these events in human subjects further hinders advancement in the field (Samuels and Hen, 2011). Nevertheless, together with neurogenesis, investigation of the abovementioned phenomena will provide a more comprehensive view of the biology of depression in the future. 3.2. Neurogenesis and anxiety disorders Anxiety disorders are the most common psychiatric disorders, with a lifetime prevalence of over 25% (Kessler et al., 2005). Usually a chronic condition, anxiety disorders not only cause pervasive personal distress but also severely disrupt the patient’s quality of life daily living activities and productivity (DuPont et al., 1996). Anxiety disorder can be viewed as maladaptation to a specific stimulus. Although healthy individuals are able to assess whether a specific stimulus would cause a threat to their own lives, patients with this disorder exhibit exaggerated and heightened reactivity to even neutral stimuli (Kheirbek et al., 2012). Because the maladaptive response may be acquired through learning, neurogenesis in the hippocampus has been suggested as one of the neural substrates involved in the pathophysiology.


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Pre-clinical animal studies have provided valuable information regarding the relationship between neurogenesis and anxiety disorders. After the discovery of the neurogenesis-promoting property of selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants useful in treating mood and anxiety disorders in animals (Malberg et al., 2000), anxiety-like behavior was suggested to be associated with neurogenesis. Based on this finding, other research groups have explored whether neurogenesis is essential for the anxiolytic action of these pharmaceuticals and thus has a role in anxiety-like behaviors. A pioneering study illustrated that the beneficial effects of SSRIs are dependent upon the development of new neurons (Santarelli et al., 2003). Under normal conditions, chronic treatment with fluoxetine, a SSRI, was shown to be anxiolytic in a noveltysuppressing test and that behavioral benefit was associated with increased neurogenesis. Interestingly, when X-irradiation was used to abolish neurogenesis in the DG, the anxiolytic action of fluoxetine could no longer be found. A similar finding was reported for another drug, HU210, a synthetic cannabinoid (Jiang et al., 2005) for which the anxiolytic effect is dependent on intact neurogenesis. Furthermore, pregabalin, an anticonvulsant used for treating generalized anxiety disorder and neuropathic pain, has also been shown to promote neurogenesis together with the prevention of stress-induced depression-like behaviors (Valente et al., 2012). However, not all anxiolytic treatments depend on intact neurogenesis. For example, the therapeutic effects of voluntary running and an enriched environment (Meshi et al., 2006) persisted even when neurogenesis was blocked. Compared to pharmaceutical agents, these treatments exert pervasive effects on different systems. This implies that the anxiolytic action of these approaches may depend on different physiological conditions rather than solely on neurogenesis. However, it is worthwhile to note that the use of different behavioral tests of anxiety in different studies that may cause discrepancies in the findings. Certain behavioral tests including the forced swimming test and open field test are neurogenesis-independent while the coat state test and novelty suppressed feeding test are neurogenesis-dependent (David et al., 2010). The variation of tests used in different research groups renders it difficult to compare the results across different studies, and the involvement of neurogenesis in the anxiety behavior and anxiolytic action of medications may be masked. The use of different paradigms to induce stress in animals is another confounding factor when interpreting the results. Application of the stress hormone corticosterone in a noveltysuppressed feeding paradigm, social defeat paradigm, and an unpredictable chronic mild stress paradigm are common methods used to induce anxiety in animal studies (Berton et al., 2006; Santarelli et al., 2003; Dulawa et al., 2004). Although all of these approaches are aimed at increasing psychological and physiological arousal, the variation in different methods may induce anxiety to different extents, which may affect the degree to which neurogenesis is suppressed. Moreover, a common risk factor for major depressive disorder and anxiety-related disorders being stress, may thus not clearly differentiate the difference between the two behavioral phenotypes in animal studies (Petrik et al., 2012). Furthermore, because depression-like and anxiety-like behaviors may influence each other, it is impossible to distinguish whether a specific animal model of stress is reflecting depression, anxiety, or some combination thereof. All of these intriguing factors increase the difficulty of establishing a clear causal relationship between anxiety disorder and neurogenesis. The amygdala is known for its role in regulating emotional responses to stress, and one study has shown that new cell proliferation in the amygdala is involved in stress and anxiety

behavior in animals (Lieberwirth et al., 2012a). Female prairie voles are monogamous and social animals with strong bonding to specific partners. When they were socially isolated, which is a distressing experience, the level of cell proliferation in the amygdala and ventromedial hypothalamus decreased (Lieberwirth et al., 2012a,b). That reduction was associated with behavioral changes as indicated by a higher anxiety level as compared to nonisolated animals. The level of cell proliferation in the amygdala is influenced by social and stressful experiences while the roles of the new cells are still unclear. To date there is still a lack of clinical studies that have investigated neurogenesis in patients with anxiety disorders including generalized anxiety disorders, phobia, and panic disorders. Although the amount of evidence is limited, among the different subtypes of anxiety disorders, post-traumatic stress disorder (PTSD) has been shown to be associated with a deficit in neurogenesis. PTSD is a disorder that occurs after a trauma and is characterized by repeatedly experiencing the memory, thoughts, and physiological hyperarousal related to the original trauma (Kheirbek et al., 2012). A common example of PTSD occurs in veterans who return from war and later develop symptoms of PTSD. An imaging study has shown deficits in the hippocampalrelated declarative verbal memory and hippocampal size in patients with PTSD. Chronic treatment with an SSRI was found to benefit the verbal memory and increase the size of the hippocampus (Vermetten et al., 2003). Although the size of the hippocampus is not a direct measure of neurogenesis, this study documents structural alterations in PTSD that were reversible by medication. Similar findings were reported in other studies such as one that administered anti-epileptic drugs to patients with PTSD (Bremner, 2006). The disruption of BDNF signaling in patients with PTSD further supports the role of neurogenesis in the disease (Kaplan et al., 2010). Studies conducted in animal models of PTSD in which inescapable shock has been used to induce a hyperarousal response have shown that hippocampal neurogenesis is suppressed under such conditions, and furthermore, that the hyperarousal behavior was associated with suppressed neurogenesis (Kikuchi et al., 2008). Similar to what has been seen in other animal models of depression and anxiety, chronic treatment with antidepressants was able to prevent the suppression of neurogenesis and thus block the PTSD-like response. In sum, from the information provided by both clinical and pre-clinical studies, it is likely that PTSD is associated with decreased neurogenesis, although further studies will need to be conducted to strengthen this hypothesis. The causal relationship between altered neurogenesis and anxiety disorder is still obscure, but Kheirbek et al. (2012) suggested a possible explanatory mechanism: a decrease in neurogenesis may cause anxiety disorders via a mechanism termed ‘‘pattern separation.’’ Pattern separation represents the ability of a healthy individual to differentiate perceptually similar stimuli, events, or cues. It has been proposed that people suffering from anxiety disorders may associate specific cues (e.g., anxiogenic cues) with a traumatic or anxiogenic experience. Exaggerated arousal and anxiety are then induced later when they are presented with novel, safe cues that resemble the previously conditioned ones, even when the context indicates safety. It has been suggested that this overgeneralization of memory for the anxiogenic cues is the mechanism underlying an anxiety disorder. This hypothesis has been supported by recent studies. For example, mice with ablated neurogenesis showed impaired pattern separation in a radial arm maze test (Aimone et al., 2011; Sahay et al., 2011). In contrast, increasing neurogenesis by engaging in voluntary running or through the inhibition of apoptosis in young neurons helped the mice to perform better


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in distinguishing similar contexts. These animal studies indicate that the pool of new neurons may be important in pattern separation, and that suppression of neurogenesis may induce deficits in pattern recognition possibly leading to anxiety disorders. 3.3. Neurogenesis and schizophrenia It has been suggested that the addition of new granule cells into the hippocampus during adulthood is a recapitulation of the embryonic formation of the cortex, which is compatible with the hypothesis that schizophrenia may be caused by the dysregulation of neurodevelopmental events (Pickard, 2011). Thus a generalized form of the ‘‘neurogenesis hypothesis’’ may explain the biological cause of schizophrenia. The initial study that used human post-mortem brain samples from patients with schizophrenia demonstrated a suppression of neurogenesis, as revealed by immunostaining (Reif et al., 2006). Compared to a control group, the density of Ki-67-immunopositive cells (proliferative cells) in the brains of schizophrenics was 60% lower. However, Ki-67-immunoreactivity represents all types of proliferative cells in the brain, including endothelial, glial (astroglia and microglia), and NPCs. Therefore cell quantification may represent not only neurogenesis but also angiogenesis and gliogenesis. Thus the results may not be a direct indicator of neurogenesis. Furthermore, as Ki-67 is an indicator of cell division, other processes of neurogenesis including migration, survival, and integration were not examined in this study. Nevertheless, despite limitations in the methodology, this result unambiguously indicated that deficits in neurogenesis is a pathological feature of schizophrenia, and that the altered neurogenesis may be associated with the cognitive dysfunction seen in the disease. Prenatal exposure to infection is a commonly accepted etiology of schizophrenia (Piper et al., 2012) and there are a number of different laboratories that have adopted animal models of prenatal infection to explore the pathophysiology of schizophrenia. To mimic maternal viral infection or immunoactivation, lipopolysaccharide (LPS) and polyriboinosinic-polyribocytidilic acid (polyI:C) were administrated to pregnant rodents (Meyer and Feldon, 2010; Anderson and Maes, 2012). The infected offspring showed behavioral and cognitive deficits that are found in schizophrenic patients, including prepulse inhibition disruption, and decreased attention and working memory, all of which are associated with suppressed hippocampal neurogenesis (Meyer et al., 2010). Interestingly, treatment with the antipsychotic risperidone could reverse the behavioral deficit and increase neurogenesis (Toblin et al., 2012). These animal studies demonstrate that new neuron production may be altered in the hippocampi of schizophrenic patients and that prenatal infection and neuroinflammation during neurodevelopment may be the underlying cause of the phenomenon. The relationship between neurogenesis and schizophrenia is further strengthened by pharmacological studies that investigated the effect of schizophrenia-inducing agents or treatments on neurogenesis. Phencyclidine, a hallucinogenic drug that causes schizophrenia-like symptoms in animal models (Liu et al., 2006), was shown to decrease neurogenesis. In contrast, atypical antipsychotics such as clozapine and olanzapine increased the proliferation of new cells in different structures in the brain including the prefrontal cortex, dorsal striatum, and hippocampus (Halim et al., 2004; Kodama et al., 2004; Wang et al., 2004a). Interestingly, the prototypic antipsychotic, haloperidol, was found to increase neurogenesis in gerbils (Dawirs et al., 1998) but not in rats (Wakade et al., 2002). This disparity may be the result of using different animal species and/or treatment schedules (acute or chronic). Nevertheless, these studies suggest that neurogenesis is

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subjected to regulation by antipsychotics, and their action on neurogenesis may explain part of the treatment mechanism. In the past two decades, genetic analysis has identified different genes associated with a susceptibility to developing schizophrenia. A candidate gene that has attracted much attention from the scientific community is the disrupted in schizophrenia 1 (DISC1) (Hennah et al., 2006). DISC1 was first identified in a Scottish family whose members presented with a wide range of severe psychiatric illnesses, including schizophrenia and schizoaffective disorder. A strong linkage between DISC1 and schizophrenia was later revealed (Schmitt et al., 2004; Wakade et al., 2002). DISC1 affected different measures, including working memory, cognitive performance, gray matter volume of prefrontal cortex, malformation of the hippocampus, and reduction of P300 amplitude in eventrelated potential. DISC1 possesses important neurodevelopmental functions such as cell proliferation, differentiation, neuronal migration, neurite outgrowth, and synaptic plasticity (Enomoto et al., 2009; Ming and Song, 2011). Working memory of transgenic mice with Disc1 (mouse ortholog of human DISC1) was found to be defective (Koike et al., 2006). Histological studies showed that abnormal cell morphology, rapid neurite growth, ectopic neuron location (Duan et al., 2007), atrophic dendrites and cell body (Lee et al., 2011), and changes in CA3 circuitry (Kvajo et al., 2011) could be found with Disc1 knock-out or mutation. These findings indicate the importance of DISC1 in different stages of neurogenesis, especially in the integration of newborn neurons into the mature circuit. The regulation of neurogenesis by DISC1 involves the neurotransmitters glutamate and GABA. The NMDA receptor, an ionotropic receptor of glutamate, is known for its necessity in the proper migration and integration of new neurons (Namba et al., 2011). When the NMDA receptor was blocked by memantine, DISC1 expression was suppressed. Simultaneously, the newborn neurons in the DG showed aberrant migration and positioning, which is characterized by the overextension of the migration in the hippocampus. The cellular abnormality could be prevented by exogenous expression of DISC1. DISC1 exerts its functions on neurogenesis through the regulation of GABA signaling pathway (Kim et al., 2012), which, ultimately, activates the AKT (protein kinase B) pathway. Depolarization induced by GABA signals control of the dendritic growth of new neurons, while the duration between depolarization and hyperpolarization determines how DISC1 regulates dendritic growth. When the duration is shortened, DISC1 loses its control over dendritic growth. Conversely, extension of the duration allowed DISC1 to regulate dendritic growth. If the expression of DISC1 is suppressed, its binding partner KIAA1212 will activate the AKT pathway and consequently the aberrant positioning of the neurons. Inhibiting the mammalian target of rapamycin (mTOR) could prevent the improper migration, as mTOR is a downstream effector of the AKT pathway (Kim et al., 2009). In short, glutamate, GABA, binding partners of DISC1, and the AKT pathway have been shown to allow DISC1 to exert its regulation on neurogenesis. As the functions disrupted by DISC1 dysregulation and mutation are revealed, intensive study of its effect on neurogenesis is underway. Another susceptibility gene of schizophrenia is neuronal PAS domain-containing protein 3 (NPAS3) (Kamnasaran et al., 2003). NPAS3 was first found to be associated with schizophrenia in a mother and daughter who both suffered from the disease (Kamnasaran et al., 2003). Disruption of the intron of the NPAS3 gene led to the production of proteins without the binding domain, which in turn deleted the DNA binding and dimerization ability of NPAS3. The important binding domain of NPAS3 is the basic helix– loop–helix structure, which allows the protein to have a regulatory role on the expression of a range of proteins responsible for circadian rhythm, detoxification and cell proliferation. Transgenic


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animals with NPAS3 disruption displayed a schizophrenia-like phenotype, such as impaired memory and disruption in sensorimotor gating and social recognition (Erbel-Sieler et al., 2004). Because of their behavior and the fact that they have the same genetic deficit as humans, NPAS3 transgenic animals serve as animal models of schizophrenia. These animals, simultaneously, showed suppressed neurogenesis in the hippocampus (Pieper et al., 2010). When the NPAS3 knock-out mice were treated with the anti-apoptotic compound aminopropyl carabazole, the survival of new neurons was improved and the malformation of the DG was reversed. This result suggests that NPAS3 mutation may result in the premature death of neurons. In other words, NPAS3 may act as a survival checkpoint to determine whether the newborn neurons are properly integrated into the existing circuit (Pickard, 2011). Further exploration on the effect of NPAS3 on neurogenesis may shed light on a novel schizophrenia treatment that has neuroprotective properties. Neuregulin 1 (NRG1) is another schizophrenia-associated susceptibility gene (Harrison and Law, 2006). The gene product is important for proper development of the nervous system, as it is involved in synaptogenesis, activity-dependent plasticity of synapse, expression of excitatory neurotransmitters, and processes of neurogenesis (Law et al., 2004). If the signaling pathway of NRG1 is disturbed, hypofunction of the NMDA receptor would occur, which is hypothesized to be a major mechanism underlying schizophrenia (Hahn et al., 2006). Due to the trophic effect of the NRG family, it is not surprising that NRG1 and NRG2 have been shown to be pro-neurogenic in both the SVZ and hippocampus (Ghashghaei et al., 2006; Mahar et al., 2011). Considering the biological roles of NRG1 and the association between the gene and schizophrenia, NRG1 may contribute to the symptoms of the disease by altering neurogenesis. Similar to other psychiatric illnesses, schizophrenia is highly likely to be multifactorial and polygenic. Various genes such as DISC1, NPAS3, and NRG1 may contribute to the pathology of schizophrenia. These genes play an essential role in the survival and proliferation of NPCs and provide support that neurogenesis is disturbed in schizophrenia. Together with the findings about the pro-neurogenic effects of antipsychotics and suppressed neurogenesis in animal models of schizophrenia, it is likely that the ‘‘neurogenesis hypothesis’’ could be extended to include schizophrenia. The altered neurogenesis in diverse brain regions may, with further evidence, explain the symptomatology of the illness like disrupted cognition, memory, and social interaction (Kempermann et al., 2008).

Fig. 3. The molecular mechanisms underlying regulation of stroke-induced neurogenesis.

(Androutsellis-Theotokis et al., 2006). The same study also revealed that the Notch pathway interacts with the Shh pathway in regulating NSCs (Balordi and Fishell, 2007; Angot et al., 2008). 4.2. Shh signaling The Shh signaling pathway is involved in the proliferation and maintenance of NPCs in the intact brain. It is also associated with EPO in mediating adult neurogenesis. EPO is known to regulate neurogenesis in both the adult normal and ischemic brains through its receptor EPOR in the adult SVZ. Infusion of EPO significantly increased ischemia-induced neurogenesis, whereas blockage of the Shh pathway with cyclopamine or siRNA significantly suppressed EPO-increased neurogenesis (Liu et al., 2007). 4.3. Wnt signaling Wnt signaling promotes proliferation and neuronal differentiation in adult hippocampal progenitor cells in the DG (Lie et al., 2005). Expression of Wnt and BMP family genes in SVZ NPCs of adult rodents were altered after stroke. However, how these genes regulate the proliferation and differentiation of NPCs after stroke remains to be determined (Morris et al., 2007). 4.4. Neurotrophic factor and growth factors Neurotrophic and growth factors are crucial regulators in ischemia-induced neurogenesis in the adult brain.

4. Regulation of stroke-induced neurogenesis A variety of factors that regulate neurogenesis in the normal adult brain also exert their actions in ischemic stroke-induced neurogenesis. Here, we review current data on morphogens, growth factors, neurotransmitters, and transcriptional factors that are involved in the regulation of adult neurogenesis after stroke (Fig. 3). 4.1. Notch signaling Notch signaling is involved in neurogenesis in the neurogenic regions of the intact adult brain. Recent research has documented that expression of Notch and Hes1 in SVZ NPCs significantly increased after stroke (Zhang et al., 2008). Inhibition of the Notch signaling pathway with siRNA or g-secretase inhibitor blocked stroke-induced neurogenesis (Zhang et al., 2008). Moreover, an in vivo study demonstrated that administration of Notch ligand delta-like 4 (Dll4) together with FGF-2 after stroke significantly increased the rate of proliferation of SVZ neural progenitor cells

4.4.1. BDNF BDNF, one of the most extensively studied neurotrophic factors, is necessary for NSC proliferation and differentiation in the adult brain. Two research groups have revealed that the expression of BDNF and its receptor increased after ischemic stroke (Kokaia et al., 1998; Arai et al., 1996). Intrastriatal infusion of BDNF before ischemia in adult rats increased the survival of neurons in the dorsolateral side of the striatum and resulted in improved functional recovery (Andsberg et al., 2002). Furthermore, infusion of human mesenchymal stem cells expressing the BDNF gene after ischemic stroke greatly reduced the infarct volume. Consistent with these observations, knockout of BDNF in mice resulted in larger infarct volumes after MCAO as the inhibition of endogenous BDNF after ischemic injury may decrease the survival of neurons (Endres et al., 2000; Larsson et al., 2002). 4.4.2. FGF-2 FGF-2 is a well-known growth factor that plays a role in neurogenesis in the adult brain. Studies have reported that FGF-2


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expression in the brain increased significantly after ischemic stroke (Naylor et al., 2005). Overexpression of FGF-2 by a retrovirus significantly increased the proliferation of progenitor cells after ischemic stroke in both FGF-2 deficient mice and wild-type mice (Yoshimura et al., 2001). Conversely, FGF-2 knockout mice showed a reduction of ischemia-induced progenitor proliferation when compared with wild type mice. Moreover, administration of bone marrow stromal cells engineered to produce FGF2 (Ikeda et al., 2005) has been shown to decrease infarct size. Taken together, these findings suggest that FGF2 has a hand in NPC proliferation and neuroprotection after ischemic stroke. Several potential mechanisms underlying the neurogenic effect of FGF-2 in the ischemic injured brain have been presented. These include upregulation of BDNF, induction of GDNF, and downregulation of the NMDA receptor (Mattson et al., 1993; Lenhard et al., 2002; Kiprianova et al., 2004). 4.4.3. EGF EGF, a known mitogen involved in the proliferation of adult NPCs, has an effect similar to FGF-2 in regulating neurogenesis after stroke. Importantly, the expression of EGF-receptor on type C cells or TAPs was found to be increased after ischemic stroke (Ninomiya et al., 2006). Ischemia also causes an upregulation of Heparin binding EGF (HB-EGF) (Tanaka et al., 2004), which is known to act through the EGF receptor to promote neurogenesis. Previous studies have demonstrated that exogenous EGF administration in ischemic animals rescued 20% of the interneurons that would have died after ischemia, suggesting the neurogenic role of EGF in the adult brain after ischemic injury (Teramoto et al., 2003). Furthermore, infusion of EGF together with FGF-2 into the brain of adult rats was found to promote DG and SVZ NPC proliferation after focal ischemic stroke (Nakatomi et al., 2002; Tureyen et al., 2005). Administration of HB-EGF enhanced postischemic neurogenesis and contributed to the improvement of functional recovery (Jin et al., 2004b). Overexpression of HB-EGF by viral delivery also led to a significant improvement in neurological function after ischemic stroke, which was attributed to increased neurogenesis by HB-EGF(Sugiura et al., 2005). 4.4.4. IGF-1 IGF-1, primarily produced in the liver, plays a major role in brain development. Several studies have demonstrated that focal ischemia significantly induced an increase in IGF-1 expression, its receptor and binding proteins (Yan et al., 2006). Blockage of IGF-1 by intracerebroventricular administration of IGF-1 antibodies resulted in a significant inhibition of neural progenitor proliferation induced by ischemic stroke, suggesting that IGF-1 regulates neurogenesis after ischemia (Yan et al., 2006). Conversely, administering IGF-I after ischemic stroke promoted neurogenesis (Dempsey et al., 2003; Zhang et al., 2004) and reduced neuronal loss (Brywe et al., 2005). In vitro studies demonstrated that IGF-I stimulated the proliferation of cultured NPCs via phosphorylation of the PI-3-kinase/Akt signaling pathway (Kalluri et al., 2007). Furthermore, IGF-1 also enhanced glycogen synthase kinase phosphorylation, suggesting its involvement in NPC survival (Kalluri et al., 2007). 4.4.5. VEGF Vascular endothelial growth factor (VEGF) is the major angiogenetic growth factor, which can induce angiogenesis and vasculogenesis through interaction with the VEGF receptor on endothelial cells. Our previous study revealed that VEGF promotes the proliferation of NPCs both in vitro and in vivo in the adult rat brain (Jin et al., 2002). Wang et al. (2007) showed that VEGF overexpression in transgenic mice greatly promoted ischemiainduced neurogenesis. Furthermore, intravenous administration of

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VEGF after stroke promoted angiogenesis in the ischemic penumbra and improved neurological performance. In addition, we previously showed that VEGF ICV administration to rats after focal ischemic stroke reduced infarct volume and resulted in enhanced neurological recovery suggesting that VEGF induces neurogenesis and neuroprotection after ischemic stroke (Sun et al., 2003) 4.5. Neurotransmitters Neurotransmitters released from nerve terminals have been demonstrated to promote neurogenesis in adult intact brains. Studies have also shown the involvement of the glutamate signaling pathway in post-ischemic neurogenesis. Abnormal glutamatergic neurotransmission, in particular disrupted glutamatergic receptor expression, has been reported to play a significant role in neuronal death after ischemic stroke. Several studies have revealed that activation of the NMDA receptor, an ionotropic glutamate receptor, blocks proliferation of NPCs while inhibition of NMDA receptors via antagonists promotes NPC proliferation (Cameron et al., 1995; Nacher et al., 2003). A subsequent study conducted by Kluska et al. (2005) also reported that administration of an NMDA antagonist during brain ischemic stroke induced by photothrombosis resulted in enhanced neurogenesis in the hippocampus of rats. However, Bernabeu and Sharp (2000) reported that administration of NMDA and AMPA receptor antagonists prevented stroke-induced neurogenesis in the SGZ when given at the time of transient global ischemia. These conflicting results may be attributed to species-specific differences and the type of ischemic stroke. The mechanism by which glutamatergic signaling pathway mediate stroke-induced neurogenesis is unclear. Several other neurotransmitters such as GABA and dopamine have also been reported to play significant roles in the intact adult brain. However, their roles in mediating ischemic stroke-induced neurogenesis still need further evaluation. 4.6. Transcriptional factors Post-ischemic neurogenesis is a complex process that involves multiple steps and can be influenced by many transcription factors. These factors do not act independently but interact with each other and take part in other signaling pathways to mediate neurogenesis. cAMP response element-binding (CREB) protein, a transcription factor that plays a significant role in regulating cellular growth and development, was reported to be involved in the regulation of survival, migration, and differentiation of neural progenitors in the intact adult brain (Herold et al., 2011). Kitagawa et al. reported that brain ischemic injury induced a massive release of glutamate into the extracellular space, which interacted with glutamate receptors and activated the glutamate signaling pathway. Activation of the glutamate pathway activated Ca2+/CaM kinase, the PI3K and Ras/ MAPK cascades, which promoted activation of CREB. Consequently, associated proteins were recruited to form a large transcription complex, which then regulated the associated gene expression. Target genes of CREB include many transcription factors, growth factors, neurotransmitters, cell cycle-related proteins, and cell survival-related molecules. Among these molecules, BDNF and Bcl2 have protective functions in neurons (Kitagawa, 2007). Pax6 is mainly expressed in migrating neuroblasts in the RMS to the OB in intact adult brain and is reported to mediate neural differentiation (Hack et al., 2004). Previous research demonstrated that the expression of Pax6 increased after cerebral ischemic injury (Tonchev et al., 2006). Thereafter, Pax6 activated several transcription factors such as Tbr1, Ngn2, Tbr2, and NeuroD (Osumi et al., 2008). The increase in transcription factors regulated the


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expression of their downstream molecules and resulted in altered post-ischemic neurogenesis.

speculate that deregulation in GABAergic transmission may impair adult neurogenesis in animal models of AD by affecting the survival and maturation of newborn neurons.

5. Regulation of AD-induced neurogenesis 6. Regulation of PD-induced neurogenesis The greatest genetic risk factor for the sporadic form of AD is the presence of the e4 allele in apolipoprotein E (ApoE4) (Bu, 2009), while mutations in the APP, PS1, and PS2 are involved in familial AD. Surprisingly, several molecules involved in the pathogenesis of AD are involved in the regulation of adult neurogenesis. sAPP, secreted by a-secretases during APP cleavage, was found to promote neurogenesis via inhibiting overactivation of CDK5 and tau hyperphosphorylation (Han et al., 2005). Furthermore, sAPP also regulated the proliferation of EGF-overexpression of neural progenitors in the SVZ, suggesting its positive effect on neurogenesis (Caille et al., 2004). ApoE4 was also reported to be associated with adult neurogenesis. Yang et al. (2011) found that inhibition of ApoE promoted DG NPC proliferation at an early stage, which resulted in depletion of Type 1 NSCs over time. Using ApoE knockout mice, Gang Li et al. demonstrated that a lack of ApoE reduced hippocampal neurogenesis but increased astrogenesis (Li et al., 2009). Results from research using transgenic mouse models of AD revealed that the mutant APP, PS1, and PS2 were associated with changes in adult neurogenesis observed in AD. In our previous study, using PDGF-APP Sw, Ind mice, we observed increased BrdU and immature neuronal markers DCX expressions in the SVZ and DG in transgenic mice, suggesting that mutating APP had a positive effect on neurogenesis and that this injury-induced neurogenesis may be a compensatory mechanism in Alzheimer’s disease (Jin et al., 2004c). Consistent with our observation, Lopez-Toledano and Shelanski (2007) revealed increased neuronal proliferation and differentiation in the DG of transgenic mice overexpressing human APP Sw, Ind. However, discrepancies exist regarding the neurogenic response in APP transgenic mice because several studies have reported decreased neurogenesis in the DG or in both the DG and the SVZ in these transgenic animals (Zhang et al., 2007; Wolf et al., 2006). Mutations of PS1 have been reported to have a negative effect on neurogenesis in the AD mouse model. In a previous study, Wang et al. found that PS1M146V knock-in mice displayed impaired hippocampus-dependent contextual learning and reduced adult neurogenesis in the DG (Wang et al., 2004c). Using hu-PS1P117L transgenic mice, Wen et al. reported that the PS1 FAD mutant P117L impaired the survival of BrdU-labeled NPCs and resulted in fewer new neurons being generated during the four-week post-labeling period (Wen et al., 2004). These reports indicate that PS1 regulates adult neurogenesis in the hippocampus and also identifies a new mechanism by which PS1 mutants impair this process. Another possible cause of altered neurogenesis in AD is deregulation in GABAergic transmission. Using hAPP-J20 transgenic mice, Sun et al. observed that the GABAA Cl current reversal potentials (EGABA) of adult-born GCs in hAPP-J20 mice was significantly more hyperpolarized, indicating a faster developmental transition in this animal model (Sun et al., 2009a). This correlated with impaired maturation and the functional responses of newborn neurons during the first three weeks. However, inhibition of GABAA receptors during the first seven days after birth suppressed GABAergic signaling thereby normalizing the neuronal development in hAPP mice. This indicates that abnormal GABAergic neurotransmission may lead to reduced neurogenesis in models of AD. In ApoE4 transgenic mice, Li et al. found that the number of GABAergic interneurons in the hippocampus decreased, which resulted in impaired maturation of newborn neurons. Interestingly, the authors potentiated GABAA receptor, and found that they were able to improve dendritic development and restore neurogenesis in this transgenic mouse model (Li et al., 2009). Therefore, we can

Unlike neurogenesis after ischemic stroke, DG & SVZ neurogenesis is decreased in both animal models of PD and patients with PD. Experimental depletion of dopamine in MPTP-intoxicated mice and macaques, or 6-OHDA-lesioned rats and mice, led to impaired proliferation of NSCs in the SVZ and SGZ, which in turn resulted in reduced migration and neuronal differentiation in the OB (Hoglinger et al., 2004; Baker et al., 2004). Moreover, the endogenous NSCs proliferating in the SVZ, the SGZ, and OB were also decreased in post-mortem brains of PD patients (Hoglinger et al., 2004). This impaired neurogenesis in PD may be a consequence of dopaminergic denervation. Mounting supporting evidence includes the following: (1) dopamine plays a regulatory role in endogenous neurogenesis in the SVZ and the hippocampus of the adult intact brain. (2) The dopamine receptors, including D1-like (D1L), D2-like (D2L), and D3 receptors (Beaulieu and Gainetdinov, 2011), are expressed in the SVZ. Of note, the D2L receptors are abundantly present in Type C cells or TAPs. Activation of D2L receptors by selective agonist directly increased SVZ NPC proliferation (Hoglinger et al., 2004), whereas intraventricular administration of a D3 receptor agonist 7-OH-DPAT significantly increased proliferation in the SVZ and the RMS of rats, which was abolished by co-administration of a selective dopamine D3 receptor antagonist (Van Kampen et al., 2004). (3) The location of dopaminergic projections from the midbrain to the neostriatum and nucleus accumbens overlaps with the SVZ. In brains from 6-OHDA-lesioned rats, destruction of the DA neurons in the SN and ventral tegmental area reduced the proliferation of NSCs in the SVZ, suggesting dopaminergic regulation of adult neurogenesis through the nigrostriatal pathway (Baker et al., 2004). Several research groups have reported the presence of dopaminergic neurogenesis in the normal adult SN or in animal models of PD. The SN of the rat was found to contain NPCs, which, when cultured with FGF-2 or FGF-8 in vitro or transplanted into the dentate hilus in vivo, produced cells that expressed immature (bIII-tubulin) or mature (NeuN) neuronal markers (Lie et al., 2002). Furthermore, immature neurons, which express PSA, were detected in the SN of patients with PD (Yoshimi et al., 2005). Using nestin-LacZ transgenic mice, Shan et al. observed enhanced proliferation and dopaminergic differentiation after MPTP administration. Activation of the D3 receptor by 7-OH-DPAT promoted cell proliferation and dopaminergic differentiation in the SN of an animal model of PD (Van Kampen and Eckman, 2006). However, several research groups failed to show nigral neurogenesis in normal or MPTP-treated mice and normal or 6-OHDA-treated rats (Arias-Carrion et al., 2007). The controversy of adult DA neurogenesis in the SN suggests that the relationship between neurogenesis and Parkinsonism may be complex, whereas differences in the animal models employed or the severity or duration of the disease may explain some of the disparities in research findings. 7. Regulation of HD-induced neurogenesis 7.1. Decreased neurotrophic factor and growth factor expression Mounting evidence indicates that reduced neurotrophic support in the HD brain may contribute to decreased neurogenesis in models of HD. BDNF, a key neurotrophic factor for brain development and adult neurogenesis, was reported to be down-regulated


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both in transgenic animal models of HD and in patients with HD (Ciammola et al., 2007; Zajac et al., 2010; Conforti et al., 2008). The decreased expression of BDNF in HD was found to be associated with the huntingtin protein. It has been reported that wild-type huntingtin protein stimulated transcription of the gene encoding BDNF via interaction with the cytoplasmic transcriptional factor complex repressor-element-1 transcription factor (REST)/neuronrestrictive silencer factor (NRSF) and inhibited the silencing activity of NRSE (Zuccato et al., 2003). However, in HD, the mutant huntingtin protein failed to target the transcriptional factor complex REST/NRSF thus causing the complex to accumulate abnormally in the nucleus, which resulted in suppressed transcription of NRSEcontrolled genes including the BDNF gene. Another study showed that normal huntingtin protein enhanced microtubule-based transport of BDNF via HAP1 and the p150Glued while mutant huntingtin perturbed the association of motor proteins with microtubules, which led to the reduced axonal transport of BDNF, thus resulting in a decreased expression of neurotrophic factor in the HD brain (Gauthier et al., 2004). Based on previous studies that showed that BDNF could promote adult neurogenesis both in normal and injured brains, we speculate that decreased expression of BDNF may contribute to compromised neurogenesis in HD. Other growth factors may also participate in mediating adult neurogenesis in the HD brain. In our previous study, we showed that FGF-2 stimulated neurogenesis in the SVZ and promoted neuroblast migration in HD transgenic R6/2 mice, suggesting that it may have a hand in the compromised neurogenic response in HD (Jin et al., 2005). Kandasamy et al. (2010) showed that the expression of TGF-b1 was increased in HD and this increased TGFb1 signaling was associated with alterations in neurogenesis in transgenic animal models of HD. 7.2. Neurotransmission deficits Dopamine, a catecholamine neurotransmitter, is involved in adult neurogenesis in the normal brain. Emerging evidence also has shown that the dopaminergic signaling pathway is implicated in the HD brain. Dunah et al. (2002) reported that mutant huntingtin could inhibit the expression of DA receptors by interacting with Sp1-mediated transcription. Furthermore, brain DA levels were decreased in the brains of R6/1 and R6/2 transgenic mice (Petersen et al., 2002; Hickey et al., 2002), while tyrosine hydroxylase levels were decreased both in patients with HD and a mouse model of HD (Yohrling et al., 2003). Since DA signaling has a positive effect in adult neurogenesis regulation, it is possible that the deficit of this neurotransmitter may contribute to the impaired neurogenesis observed in the HD brain. 7.3. Dysregulation of transcriptional factor Another possible mechanism underlying the impaired hippocampal neurogenesis in HD mice involves the dysregulation of the transcription factor, NeuroD. It is a basic helix–loop–helix transcription factor that plays a crucial role in neural development and regulation of adult neurogenesis. Marcora et al. (2003) showed that normal huntingtin interacted with NeuroD and stimulated the activity of NeuroD via HAP1 and mixed-lineage kinase 2 (MLK2). Moreover, NeuroD expression decreased in the hippocampus in the R6/2 mouse model of HD (Fedele et al., 2011). However, whether compromised NeuroD pathway is the direct cause of impaired neurogenesis in the HD brain remains to be further investigated. 7.4. Mitochondrial deficiencies It is widely accepted that mitochondrial deficiency is one of the mechanisms that may contribute to HD pathogenesis (Gil and

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Rego, 2008). Previous research demonstrated that a reduction of mitochondrial enzyme KGDHC is involved in the pathogenesis of HD in patients (Klivenyi et al., 2004). Using a mouse model deficient in KGDHC, Calingasan et al. showed that inhibition of mitochondrial enzyme KGDHC led to decreased numbers of neural progenitors and impaired proliferation in the DG, indicating that KGDHC plays a role in adult neurogenesis regulation (Calingasan et al., 2008). Taken together, it is possible that mitochondrial deficiencies in HD may contribute to reduced neurogenesis observed in the HD brain. 8. Regulation of neurogenesis in psychiatric illnesses The NSCs/NPCs in the DG and SVZ are under the regulation of a range of intrinsic and extrinsic factors. Neurotransmitters play different roles in the neurogenic process. Serotonin is one of the molecules associated with depression (Diaz et al., 2012). Activation of its corresponding receptor 5HT(2B) promotes neurogenesis, while its inactivation suppresses neurogenesis. Glutamate may be a positive regulator of neurogenesis through its ionotropic and metabotropic receptors (Schlett, 2006), but the regulation is complex and the expression of its receptors on the neural progenitor cells needs to be further confirmed (Nacher and McEwen, 2006). GABA was shown to depolarize immature neurons and promote their differentiation (Tozuka et al., 2005). The promotion/suppression effect on neurogenesis exerted by dopamine and acetycholine depended on the specific type of receptors expressed in the NPCs (Veena et al., 2011). Trophic factors are another category of molecules that would affect neurogenesis. BDNF is a well recognized positive regulator for NPC proliferation and survival. In depressive patients, the serum level of BDNF was decreased while treatment with antidepressants could reverse the suppression (Hunsberger et al., 2009). Other trophic factors including VEGF and IGF-1 also showed proneurogenic effects (Warner-Schmidt and Duman, 2006, 2007), and simultaneously decreased the effect of depression and anxiety-like behavior. The downstream pathways of the trophic factors converge on the cAMP-response element binding protein (CREB) signaling pathway. Antidepressants are used to alleviate clinical symptoms of depression. Tricyclic antidepressants (TCAs), SSRIs, monoamine oxidase inhibitors (MAOIs), and selective norepinephrine reuptake inhibitors (SNRIs) are common antidepressants that show clinical therapeutic effects after treatment for at least two weeks (Hunsberger et al., 2009). The prolonged treatment period was associated with cellular, probably neurogenic, changes in the brain (D’Sa and Duman, 2002). Antidepressant treatment has been shown to involve the MAPK/ERK and Wnt/GSK signaling pathways (Hunsberger et al., 2009). The downstream molecules of these two pathways are neurotrophic factors such as BDNF and CREB (Nibuya et al., 1995, 1996), which are pro-neurogenic, pro-survival, and neuroprotective. Interestingly, non-pharmacological treatment like exercise and electroconvulsive therapy (ECT) were shown to promote neurogenesis and upregulate MAPK/ERK pathways (Hunsberger et al., 2007; Hellsten et al., 2002). These results show a convergence of different treatment modules in the neurotrophic factor and neuroprotective pathway. Antipsychotics, which are medications for patients with schizophrenia, are traditionally classified as typical or atypical. Similar to antidepressants, the clinical effect (e.g. suppression of delusion) usually takes a few weeks to appear (Kapur et al., 2005; Agid et al., 2003). Antipsychotics, especially atypical ones, were shown to have neuroprotective and pro-neurogenic properties by activation of several intracellular signaling pathways like MAPK, Akt, Bcl-2, and neurotrophic factor pathways (Hunsberger et al., 2009). Treatment with clozapine and olanzapine promoted


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phosphorylation of MEK1/2 and Akt, which then led to cell proliferation and survival (Lu et al., 2004; Lu and Dwyer, 2005). Other cascades including Bcl-2, GSK-3, and CREB were also regulated by the antipsychotics (Hunsberger et al., 2009), which may reflect the clinical efficacy of the drugs. Another category of molecules that has recently been shown to regulate neurogenesis in psychiatric diseases is inflammatory molecules. A pro-inflammatory cytokine, macrophage migration inhibitory factor, promoted neurogenesis (Conboy et al., 2011). Transgenic animals with this factor knocked-out showed decreased neurogenesis and exaggerated depression-like behaviors. In contrast, interleukin 1b was elevated in patients with depression and was shown to decrease hippocampal neurogenesis (Zunszain et al., 2012). The list of factors that affect neurogenesis is increasing, and the wide range of factors that regulate neurogenesis indicates the complexity of the process. 9. Clinical implication of neurogenesis in psychiatric illnesses Currently, the diagnosis of psychiatric disorders depends mainly on clinically based observations, medical history, and interviews, as reliable biological markers of the illnesses are not yet available. The manifestation of symptoms such as mood alteration, memory disturbance, and changes in motivation suggests the involvement of the limbic system. Due to the plasticity in the hippocampus, a neurogenesis hypothesis suggests a possible direction for developing a biological diagnostic tool for psychiatric disorders. The estimated rate of neurogenesis in a human adult is approximately 5000 neurons per month (Czeh and Lucassen, 2007), which accounts for less than 0.05% of granule neurons in the DG. Because the population is small, it is unlikely that the suppressed neurogenesis causes the reduction of hippocampal volume in depression patients. Furthermore, blocking neurogenesis did not cause behavioral despair directly in animal models (Yau et al., 2011). Although neurogenesis per se is unlikely to be the sole cause of depression, the therapeutic effect of antidepressants is neurogenesis-dependent. This argument is supported by the observation that up-regulation of neurogenesis requires a prolonged treatment period of antidepressant, which is similar to the clinical time frame for the therapeutic effect (Malberg et al., 2000). The altered neurogenesis in hippocampus may contribute to symptoms related to emotional regulation and impaired memory (Pickard, 2011), which are common symptoms found in clinical depression. In short, there is no solid clinical or preclinical evidence showing that depression is caused by altered neurogenesis; rather, the newborn neurons may instead be related to the pharmacological treatment and symptoms related to mood and memory dysfunction. Although molecular mechanisms and cellular events have been investigated intensively, further development of treatment or diagnostic methods related to neurogenesis needs further examination, particularly in regard to clinical studies. The symptoms of anxiety disorders and preclinical studies suggested that neurogenesis is involved in the pathophysiology of anxiety disorders. Based on findings from animal studies, it is promising to further explore non-pharmacological treatments that promote neurogenesis for anxiety disorders. Stimulating, selfrewarding activities such as physical exercise, enriched environment, and social interaction may be potential treatment modules, as these have been therapeutic for stressed animals in regard to affective and cognitive functions. In fact, the use of activities to motivate patients has been a common practice in rehabilitation (Shinohara et al., 2012; Liu et al., 2012). The lack of side effects for these activity-based treatments provides an advantage over pharmacological treatments, but selection of the activity should be individualized, because a single treatment module may not be

rewarding for all patients. Inter-individual variability should be considered when applying the treatment to patients. It is foreseeable that future studies will explore whether suppressed neurogenesis could be used as a viable marker for psychiatric illnesses. Confirmation of such an association will suggest the monitoring of neurogenesis as a biological indicator of mental status. A signal processing method, magnetic resonance spectroscopy, was used to indirectly assess neurogenesis in the hippocampus, which provides a non-invasive approach for studying neurogenesis in patients (Manganas et al., 2007). An alternative, mildly invasive approach uses biopsied olfactory epithelium as an indicator of neurogenesis in CNS (Cascella et al., 2007). The olfactory receptor neurons in the epithelium, which are similar to the neural precursors in SVZ and hippocampus, proliferate throughout adulthood. It has been proposed that the proliferation rate of olfactory epithelium neurons reflects the neurogenesis rate in the brain, and deficits in olfaction have been found in schizophrenic patients (Cascella et al., 2007). Thus the biopsy of the olfactory epithelium opens another window for studying neurogenesis in living humans. 10. Conclusion Adult neurogenesis in physiological and pathological conditions has been investigated for decades. Currently the focus has shifted from proving neurogenesis in adult to understanding its intrinsic functions and regulatory mechanisms. Neurogenesis in some areas of the CNS and proliferating cells that migrate and differentiate into neurons in multiple regions of the CNS suggest that disordered CNS can be repaired through neurogenesis, at least to some degree. However, this is still challenging, as we know little about the functional properties of the insult-generated precursor cells and their resultant behavior due to neurogenesis. The mechanisms that trigger augmented cell proliferation and regulation of migration of progenitor cell progeny and their differentiation into specific neural types under pathological conditions are also poorly understood. Understanding the fundamental mechanisms regulating adult neurogenesis in physiological and pathological conditions will thus provide the basis for cell replacement therapy. Effective cell therapy will need to be founded on grasping the fundamental mechanisms that regulate adult neurogenesis under physiological and pathological conditions. There has been much progress in understanding the inducement of neurogenesis due to CNS disease. However, the frequency with which endogenous stem cells replace neurons after CNS disease without additional manipulation is minimal, and in order to render this process functionally relevant, we must develop strategies based on our insights into the mechanisms of both adult neurogenesis and development in conjunction with knowledge of the specific disease mechanism. To conquer these challenges, a broad, multidisciplinary approach is needed, and as we continue forward, we will no doubt encounter more obstacles and questions. Despite the seemingly overwhelming challenge, the prospects of functional repair and restoration of the diseased brain make our efforts extremely worthwhile. Acknowledgements The work of the authors (LB and SKF) has been supported by funding from the Jessie Ho Professorship in Neuroscience (The University of Hong Kong for Educational Development and Research Limited) and the Fundamental Research Funds for the Central Universities, No. 21609101. This work was also supported by Chinese National Natural Science Foundation grants 81371396 and 81171088 (to ZGQ) and by US Public Health Service Grants NS57186 and AG21980 (to KJ).


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Hydrogen sulfide therapy in brain diseases: from bench to bedside.

The Application of Human iPSCs in Neurological Diseases: From Bench to Bedside.

Essential tremor: from bedside to bench and back to bedside.

Linagliptin: from bench to bedside.

Erythropoietin: from bench to bedside.

[Endocrinology: from bench to bedside].

Advances in neuroimmunology: from bench to bedside.

Research advances in esophageal diseases: bench to bedside.

Nutrition in cachexia: from bench to bedside.

The role of the nitric oxide pathway in brain injury and its treatment--from bench to bedside.

Ovarian Aging, from Bench to Bedside.

Adipose Stem Cells: From Bench to Bedside.

Biology of Cholangiocytes: From Bench to Bedside.

Pancreatic cancer: from bench to bedside.

Enzalutamide: Development from bench to bedside.

[Pulmonary artery chemoembolization--from bench to bedside].

Cystic fibrosis from bench to bedside.

Imaging Neuroinflammation - from Bench to Bedside.

miR-34: from bench to bedside.

Developmental psychoneuroimmunology: from bench to bedside.

Moss-made pharmaceuticals: from bench to bedside.

Biomarker development, from bench to bedside.

Peritoneal dialysis: from bench to bedside.

Imaging technologies from bench to bedside.