The Role of Adult Neurogenesis in Psychiatric and Cognitive Disorders

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Available online at www.sciencedirect.com 121 122 123 124 125 126 www.elsevier.com/locate/brainres 127 128 129 Review 130 131 132 The role of adult neurogenesis in psychiatric 133 134 Q2 and cognitive disorders 135 136 Deana M Applen, Rene Solano Fonseca, Erzsebet Kokovay 137 Q1 138 University of Texas Health Science Center at San Antonio, Department of Cellular and Structural Biology, 7703, Floyd 139 Curl Drive, San Antonio, TX 78229, United States 140 141 142 article info abstract 143 144 Article history: Neurogenesis in mammals occurs throughout life in two brain regions: the ventricular– Q3 145 Accepted 13 January 2016 subventricular zone (V–SVZ) and the subgranular zone (SGZ) of the hippocampal dentate 146 gyrus. Development and regulation of the V–SVZ and SGZ is unique to each brain region, 147 Keywords: but with several similar characteristics. Alterations to the production of new neurons in 148 Adult Neurogenesis neurogenic regions have been linked to psychiatric and neurodegenerative disorders. 149 Ventricular–Subventricular Zone Decline in neurogenesis in the SGZ correlates with affective and psychiatric disorders, and 150 Subgranular Zone can be reversed by antidepressant and antipsychotic drugs. Likewise, neurogenesis in the – 151 Neurotransmitters V SVZ can also be enhanced by antidepressant drugs. The regulation of neurogenesis by 152 Psychiatric Disorders neurotransmitters, particularly monoamines, in both regions suggests that aberrant 153 neurotransmitter signaling observed in psychiatric disease may play a role in the 154 pathology of these mental health disorders. Similarly, the cognitive deﬁcits that accom- 155 pany neurodegenerative disease may also be exacerbated by decreased neurogenesis. This 156 review explores the regulation and function of neural stem cells in rodents and humans, 157 and the involvement of factors that contribute to psychiatric and cognitive deﬁcits. 158 This article is part of a Special Issue entitled SI:StemsCellsinPsychiatry. 159 & 2016 Published by Elsevier B.V. 160 161 162 163 181 164 Contents 182 165 183 166 1. Introduction...... 2 184 167 2. Neural stem cell developmental origins and lineage ...... 2 185 168 3. Factors regulating neurogenesis ...... 3 186 169 4. Neurotransmitter regulation of neurogenesis ...... 4 187 170 4.1. Neurotransmitter regulation of stem cells in the SGZ ...... 4 188 171 4.2. Neurotransmitter regulation of stem cells in the V–SVZ...... 4 189 172 4.3. Antidepressant drug actions in neurogenic regions ...... 5 190 173 5. Neurogenesis in humans...... 6 191 174 192 175 n 193 176 Corresponding author. Tel.: þ210 567 0725. 194 177 E-mail address: [email protected] (D. Apple). 195 178 http://dx.doi.org/10.1016/j.brainres.2016.01.023 196 179 & 0006-8993/ 2016 Published by Elsevier B.V. 197 180

Please cite this article as: Apple, D.M, et al., The role of adult neurogenesis in psychiatric and cognitive disorders. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.023 BRES : 44678

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198 6. Adult human neurogenesis and psychiatric disorders ...... 7 258 199 7. Conclusions and future perspectives...... 7 259 200 Author information ...... 7 260 201 Acknowledgments ...... 7 261 202 References ...... 7 262 203 263 204 264 205 1. Introduction rise to type C transit amplifying cells which in turn give rise 265 – 206 to type A neuroblasts. Neuroblasts then exit the V SVZ and 266 207 Neurogenesis is the process of producing new neurons from undergo extensive migration through the rostral migratory 267 208 neural stem cells (NSCs). In most brain regions, this process is stream to arrive at the olfactory bulb, where they mature into 268 209 restricted to a limited period during development, and ends GABAeric interneurons, many of which also express dopa- 269 210 shortly after birth (Gotz and Huttner, 2005; Ming and Song, mine (Alvarez-Buylla et al., 2001; Doetsch and Alvarez-Buylla, 270 211 2011; Taverna et al., 2014). However, neurogenesis is observed 1996; Doetsch et al., 1997; Ming and Song, 2011). The spatial 271 212 well into the postnatal period and throughout adulthood organization of these newborn neurons in the olfactory bulb 272 – 213 primarily in two discrete brain regions: the subgranular zone is dependent upon the location of their origin in the V SVZ, 273 – 214 (SGZ) of the dentate gyrus and the ventricular–subventricular and NSCs originating from different V SVZ microdomains 274 215 zone (V–SVZ), which lines the lateral wall of the lateral produce interneuron populations with distinct molecular 275 216 ventricles. The process of neurogenesis has been linked markers in the olfactory bulb (Merkle et al., 2014). NSCs also 276 217 behaviorally and biochemically to psychiatric disorders such give rise to oligodendrocytes and astrocytes (Doetsch et al., 277 218 as major depression, schizophrenia, and cognitive dysfunc- 2002; Lois and Alvarez-Buylla, 1993; McKay, 1997; Merkle 278 219 tion. The neurogenic cells of the hippocampus are commonly et al., 2004) however the lineage for these cells is less clear. 279 – 220 linked to psychiatric disorders, and neurogenesis is thought NSCs are tightly regulated by the niche which in the V SVZ is 280 221 to be required for a therapeutic response to antidepressant bordered on one side by ciliated ependymal cells lining the 281 222 treatment. However, neural stem cells in the V–SVZ have also lateral ventricle and on the striatal side by a vast vascular 282 223 displayed changes in function and number in psychiatric plexus. Type B NSCs span these two compartments sending 283 224 disease, age, and with increased stress levels, which are often an apical process through the ependymal layer into the 284 225 a precipitating factor in the onset of psychiatric disorders. lateral ventricle and a basal process contacting blood vessels 285 226 NSCs have been shown to respond to treatment with anti- which allows NSCs to receive molecular signals from cere- 286 fl 227 depressant and atypical antipsychotic drugs, which can brospinal uid (Kokovay et al., 2012; Sawamoto et al., 2006), 287 228 rescue diminished neurogenesis. The functional implications ependymal cells (Lim et al., 2000) and the vasculature 288 229 of decreased neurogenesis in psychiatric disease, as well as (Delgado et al., 2014; Kokovay et al., 2010; Shen et al., 2008; 289 230 the therapeutic implications of rescuing neurogenesis with Tavazoie et al., 2008). In addition to type B NSCs, microglia, 290 231 interventions, remain unclear. The emerging links between niche astrocytes, type C, and type A cells are closely 291 – 232 neurogenesis and mental health disorders support the idea assembled in the V SVZ niche between the vasculature and 292 233 that neurogenic therapies may one day enhance less effective ependymal layer. 293 234 treatments for patients suffering from major depression, In the hippocampus, type 1 NSCs are mostly quiescent, 294 235 schizophrenia, cognitive decline, and neurodegeneration. with their cell bodies in the SGZ and processes extending 295 236 Here, we provide an overview of neurogenesis in the SGZ through the granular cell layer, and a tangential process 296 237 and V–SVZ, and explore the current literature on the relation- extending through the border of the hilus and the granular 297 238 ship between psychiatric disorders, therapeutics, and adult cell layer similar to radial glia (Seri et al., 2004). Two sex 298 þ 239 neurogenesis. determining region Y-box 2 (Sox-2) populations of progeni- 299 240 tor cells are present in the hippocampus: a quiescent radial 300 241 glia-like subpopulation expressing GFAP, nestin, and brain- 301 242 2. Neural stem cell developmental origins and lipid binding protein (BLBP), and a non-radial glia-like sub- 302 243 lineage population that is more proliferative and lacks the markers 303 244 associated with radial glia (Suh et al., 2007). Once activated, 304 245 Much of our understanding of adult NSC biology has come NSCs divide asymmetrically, giving rise to a type 2 daughter 305 246 from studies in rodents, which have shown that NSCs in the cell. type 2 cells are amplifying neural progenitor cells that 306 247 SGZ and the V–SVZ share many similarities but are two lack the GFAP expression of the type 1 mother cell, but retain 307 248 distinct populations of cells that differ significantly in their expression of Nestin (Encinas et al., 2006; Filippov et al., 2003; 308 249 development, organization, and function. NSCs from both the Kempermann et al., 2004). These progenitor cells proliferate 309 250 V–SVZ and SGZ are astrocyte-like cells with morphological in close association with astrocytes and the vasculature in 310 251 similarity to mature glia, express molecular markers common the SGZ (Ashton et al., 2012; Palmer et al., 2000). Type 2 cells 311 252 to astrocytes, including glial fibrillary acidic protein (GFAP) continue to divide on average 2.3 times before maturing into 312 253 and are mostly quiescent (Alvarez-Buylla et al., 2001; Laywell doublecortin-positive type 3 neuroblasts (Encinas et al., 2011). 313 254 et al., 2000; Merkle et al., 2004; Noctor et al., 2002). In the V– Neuroblasts mature into granule cells after migrating a short 314 255 SVZ, these NSCs are referred to as type B cells that, upon distance into the granular layer of the dentate gyrus. In the 315 256 activation, upregulate epidermal growth factor receptor granule cell layer, neuroblasts fully mature into glutamater- 316 257 (EGFR) and the progenitor marker Nestin and divide to give gic granule neurons and receive glutamatergic and GABAergic 317

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318 innervation from the entorhinal cortex while sending outputs NSC function. Movement of CSF directs migration of neuro- 378 319 to the CA3 pyramidal cell layer through the mossy fiber blasts (Sawamoto et al., 2006). Ependymal cell secretion of 379 320 pathway (Ming and Song, 2011; van Praag et al., 2002; Zhao noggin inhibits bone morphogenic protein (BMP) signaling in 380 321 et al., 2006). type B cells, preventing glial differentiation and allowing 381 322 Lineage tracing studies have revealed that V–SVZ NSCs are production of type C cells (Lim et al., 2000), although others 382 323 derived during development from striatal radial glia. The have found that noggin blocks neurogenesis while promoting 383 324 labeled radial glia in murine neonates were observed to give oligodendrogliogenesis (Colak et al., 2008). It should be noted 384 325 rise to neurons, oligodendrocytes, and astrocytes in the V– that these discrepant results may be due to differences in 385 326 SVZ. Lineage tracing also identified radial glia to be the origin methodology, as Lim and co-workers utilized an in vitro 386 327 of type B and type C cells in the adult, thus establishing model for noggin antagonism of BMPs while Colak et al 387 328 striatal radial glia as the neonatal origin of V–SVZ NSCs directly tested exogenous noggin in vivo. We have shown 388 329 (Merkle et al., 2004). In contrast, the origin of NSCs in the that the close association between type B cells and ependy- 389 330 SGZ is a population of Hedgehog-responsive cells from mal cells requires the adhesion molecule vascular cell adhe- 390 331 embryonic day 15.5–17.5 in the ventral hippocampus which sion molecule 1 (VCAM1), which is expressed on the apical 391 332 migrate to the ventral and dorsal DG and are established in process of type B cells anchoring NSCs to the ependymal 392 333 this region by postnatal day 15 (Li et al., 2013). Descendants layer and allowing signaling between cerebrospinal fluid 393 334 derived from these hedgehog-responsive cells maintain their (CSF) and type B cell processes. Blockade of VCAM1 results 394 335 NSC characteristics and contribute to neurogenesis in the in aberrant proliferation and eventual depletion of the stem 395 336 adult. Embryonic neurogenesis and development are func- cell pool (Kokovay et al., 2012). Other important environmen- 396 337 tionally distinct from adult hippocampal neurogenesis. Adult tal cues come from growth factors such as epidermal growth 397 338 hippocampal neurogenesis is thought to be activity-depen- factor (EGF), and other EGF Receptor (EGFR) ligands (i.e. TGF 398 339 dent, and is established during adolescence in the rodent (Seroogy et al., 1993; Tropepe et al., 1997)) and fibroblast 399 340 brain prior to sexual maturity (Nicola et al., 2015). The timing growth factor (FGF) in the CSF, which stimulate proliferation 400 341 of onset for adult neurogenesis markers in the rodent of type C cells in vivo and stimulates neurosphere production 401 342 hippocampus correlates with the time when activity- and in vitro (Doetsch et al., 2002; Kuhn et al., 1997; Reynolds et al., 402 343 experience- dependent neurogenesis becomes critical for 1992). Type C cells become proliferative and migratory in the 403 344 learning, memory, and affective- related development. presence of EGF. Furthermore, EGF confers multipotency in 404 345 type C cells, which can give rise to neurons, astrocytes and 405 346 oligodendrocytes in vitro (Doetsch et al., 2002; Reynolds et al., 406 347 3. Factors regulating neurogenesis 1992). However, EGF does not increase neurogenesis in the 407 348 olfactory bulb in vivo (Kuhn et al., 1997). FGF induces 408 349 NSCs are highly responsive to environmental molecular cues, proliferation in the V–SVZ and increases the number of 409 350 which help in the establishment of the niche in embryos/ neuroblasts and levels of neurogenesis in the olfactory bulb 410 351 neonates while maintaining the neurogenic functions of the (Kuhn et al., 1997). Vascular endothelial growth factor (VEGF) 411 352 niche in the adult. The vasculature is a major regulator of has also been shown to promote proliferation in the V–SVZ, 412 353 NSC proliferation, migration, and differentiation. Elegant illustrating the necessity of vascular signals in neurogenesis 413 354 studies using an in vitro model established that secreted (Jin et al., 2002). 414 355 factors from the vasculature increase NSC self-renewal and The function of NSCs in the SGZ is heavily influenced by 415 356 neuron production (Shen et al., 2004). Furthermore, 3- environmental molecular cues. As in the V–SVZ, the vascu- 416 357 dimensional mapping of the V–SVZ niche showed that pro- lature in the SGZ has strong effects on the proliferation of 417 358 liferating type B and type C cells are preferentially associated NSCs. Bursts of endothelial cell division are commonly 418 359 with the vasculature (Shen et al., 2008; Tavazoie et al., 2008). observed along with clusters of increased neurogenesis 419 360 How this association is maintained is not clear, however, (Palmer et al., 2000). The receptor for VEGF colocalizes with 420 361 disruption of integrin-α6 results in aberrant proliferation these clusters of increased cell division. Indeed, infusion of 421 362 (Shen et al., 2008), suggesting that laminin–integrin interac- VEGF increases the number of doublecortinþ neuroblasts, 422 363 tion is required. We previously demonstrated that vascular which express VEGF Receptor 2 (Jin et al., 2002). Furthermore, 423 364 secretion of the chemokine stromal derived factor-1 (SDF-1) is treating postnatal day 16 cortical stem cell cultures with 424 365 required for neurosphere-expanded NSCs to home to the VEGF increases neurogenesis. Although EGF and FGF do not 425 366 vasculature. This experiment utilized transplantation of increase proliferation in the SGZ as observed in the V–SVZ, 426 367 adult-derived V–SVZ NSCs transduced with shRNA against EGF does favors the generation of astrocytes and reduces the 427 368 the SDF-1 chemokine receptor CXCR4 into naïve adult V–SVZ number of neuroblasts in the SGZ (Kuhn et al., 1997). Adrenal 428 369 (Kokovay et al., 2010). The results of this study suggest SDF-1 hormones have also been shown to have strong effects on 429 370 may play a role as a chemoattractant to endogenous stem neurogenesis in the SGZ. Adrenalectomized rats show an 430 371 cells as well. Endothelial cells have also been shown to increase in the number of GFAPþ labeled astrocytes and 431 372 secrete neurotrophin-3 (NT-3), which upon uptake by NSCs, enolase labeled neurons in the SGZ. However, replacement 432 373 induces the phosphorylation of endothelial nitric oxide of corticosterone in these rats suppresses proliferation (Gould 433 374 synthase (eNOS) and thus increases nitric oxide (NO) produc- et al., 1992). These results indicate that glucocorticoids, such 434 375 tion within B cells. NO reduces the cycling of B cells, therefore as corticosterone, negatively regulate neurogenesis and 435 376 regulating NSC proliferation and quiescence (Delgado et al., gliogenesis in the SGZ. The mechanism through which 436 377 2014). CSF and ependymal cells have also been implicated in glucocorticoids regulate neurogenesis in the SGZ may involve 437

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438 N-methyl-D-aspartate receptors (NMDAR) and the excitatory Inhibitory signaling from GABA has been shown to be a 498 439 effects of glutamate (Gould et al., 1997). Shh signaling has critical regulator of neurogenesis in the dentate gyrus (Song 499 440 important functions in maintaining the SGZ niche after et al., 2012). Type 2 amplifying progenitor cells are activated 500 441 development. The loss of sonic hedgehog (Shh) or smooth- by GABA, which promotes activity-dependent differentiation 501 ﬁ 442 ened (Smo) results in severe de ciencies in the hippocampus, of NSCs, likely through a GABAA-dependent mechanism 502 443 but without affecting the early SGZ invasion of hedgehog (Tozuka et al., 2005). This GABA-mediated depolarization of 503 444 responsive cells from the ventral hippocampus. In turn, Shh progenitors in the subgranular zone has been linked to the 504 445 signaling helps to retain more descendants of the hedgehog incorporation of AMPA receptors into immature granule cells, 505 446 responsive cells in the adult, thereby contributing to the a process necessary for learning and memory formation 506 447 maintenance of the postnatal SGZ (Li et al., 2013). (Chancey et al., 2013). Type 1 cells were found to be sensitive 507

448 to signaling via the GABAB receptor, where chronic GABABR 508 449 blockade increased neurogenesis in the subgranular zone 509 450 4. Neurotransmitter regulation (Felice et al., 2012). Migration of progenitors in the dentate 510 451 of neurogenesis gyrus is also GABA-dependent. Transgenic animals lacking 511 452 the GABA α4 receptor subunit had a significantly shorter 512 fl 453 NSCs are highly in uenced by monoaminergic neurotrans- migration distance into the granular cell layer, while animals 513 454 mitters. Two neurotransmitter in particular are common lacking the α2 subunit displayed an increase in the number of 514 455 targets for psychiatric pharmacological therapies: dopamine neuroblasts that migrated into the granular cell layer (Duveau 515 456 (DA) and serotonin (5-HT). These monoamines have been et al., 2011). The role of GABA in the dentate gyrus is heavily 516 fl 457 shown to in uence proliferation and neurogenesis within the dependent upon receptor type and subunit expression, con- 517 458 adult brain and these classical neuromodulators can have a ferring the capacity for differential modulation of hippocam- 518 459 profound effect on neurogenesis as levels of monoaminergic pal NSCs by GABA. It is well established that stress and 519 460 neurotransmitters change in the brain under conditions of anxiety can modulate GABA receptor expression, and these 520 461 psychiatric disease, age, or neurodegeneration. also alter neurogenesis (Earnheart et al., 2007). The specific 521 462 mechanisms by which different GABA receptor and subunit 522 463 4.1. Neurotransmitter regulation of stem cells in the SGZ arrangements alter SGZ neurogenesis are complicated and a 523 464 complete picture of GABA involvement in this process is 524 465 SGZ NSCs are highly dependent upon serotonergic innerva- currently unavailable. However, GABA signaling plays an 525 466 tion by projections from the raphe nuclei (Mongeau et al., obvious role in modulating readouts of neurogenesis, and 526 467 1997). Lesioned 5-HT projections from the raphe to the given the pharmacological tools immediately available for 527 468 dentate gyrus decreases proliferation of progenitor cells augmenting GABA function, a greater understanding of the 528 469 (Brezun and Daszuta, 1999). Adult neurogenesis has been specifics of GABA signaling will likely advance our ability to 529 470 shown to be enhanced in mice lacking the 5-HT transporter, a directly influence SGZ neurogenesis in the adult brain. See 530 471 genetic manipulation that leads to increased extracellular Table 1 for a summary of the most prominent neurotrans- 531 472 levels of 5-HT in the brain (Schmitt et al., 2007). The 5-HT1A mitter actions in the regulation of SGZ neurogenesis. 532 473 receptor is thought to mediate a bulk of the neurogenic 533 474 activity in the dentate gyrus. Depletion of 5-HT and simulta- 4.2. Neurotransmitter regulation of stem cells in the 534 475 neous activation of 5-HT1A receptors by 8-OH-DPAT results in V–SVZ 535 476 increased proliferation in the SGZ (Huang and Herbert, 2005). 536 477 Further, activation of 5-HT1A receptors alone has been The adult V–SVZ also receives serotonergic input from the 537 478 reported to increase proliferation (Santarelli et al., 2003) and raphe nuclei (Brezun and Daszuta, 1999). Lesion studies in 538 479 blockade of 5-HT1A receptors in the dentate gyrus reduces which the serotonergic raphe nuclei inputs to the V–SVZ are 539 480 proliferation of progenitors (Radley and Jacobs, 2002). In ablated reveal a decrease in neurogenesis (Banasr et al., 2004; 540 481 schizophrenia, 5-HT1A activation has been shown to improve Brezun and Daszuta, 1999). The serotonin (5-HT) receptor 541 482 cognitive symptoms and promote neurogenesis (Schreiber family contains a myriad of 5-HT receptors. Functionally, the 542

483 and Newman-Tancredi, 2014; Sumiyoshi et al., 2001). This 5- 5-HT1A, 5-HT1B, 5-HT2C and 5-HT5A receptors have been 543 – 484 HT1A mediated neurogenesis may be due, in part, to the demonstrated in the V–SVZ (Banasr et al., 2004; Soumier 544 485 activation of this receptor on SGZ astrocytes, which can et al., 2010; Tong et al., 2014). In these studies, agonism of 545 486 regulate neurotrophic factor secretion (Aberg et al., 2000; 546 487 Manev et al., 2001; Whitaker-Azmitia et al., 1993). Agonism Table 1 – Neurotransmitter regulation of neurogenesis in 547

488 of 5-HT2C receptors in the SGZ also produces an increase in the SGZ. 548

489 neurogenesis (Banasr et al., 2004). Other 5-HT receptor sub- ↑ 549 fi fl 5-HT neurogenesis 490 types have been identi ed in the SGZ, but their in uence on ↑ 550 5-HT1A neurogenesis and proliferation neurogenesis in this region is still under debate (Alenina and ↑ 491 5-HT2C neurogenesis 551 492 Klempin, 2015; Lucas et al., 2007). The specific effects of 5-HT Other 5-HT receptors Disputed effects 552 ↑ 493 receptor activation is not currently well characterized. Future GABAAR differentiation 553 ↓ 494 studies will likely focus on understanding which 5-HT recep- GABABR neurogenesis 554 α ↑ 495 tor subtypes influence type 1, type 2, and type 3 stem and GABA 4 migration into granular cell layer 555 GABA α2 ↓migration into granular cell layer 496 progenitor cells, and on determining if 5-HT receptor activa- 556 497 tion produces a direct or indirect effect on neurogenesis. 557

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– 558 the 5-HT1A and 5-HT2C receptors increase proliferation of Table 2 Neurotransmitter regulation of neurogenesis in 618 – – 559 neural stem cells in the V SVZ, while agonism of the 5-HT1B the V SVZ. 619 560 receptor resulted in a decline in proliferative activity (Banasr 620 5HT ↑neurogenesis 561 et al., 2004; Soumier et al., 2010). Supraependymal axons that ↑ 621 5-HT1A proliferation – ↑ 562 enervate the V SVZ originate from the median and dorsal 5-HT2C proliferation 622 ↓ 563 raphe. These axons line the apical surface of the V–SVZ and 5-HT1B proliferation 623 ↑ 564 make contact directly on type B cells and ependymal cells. DA proliferation 624 D1-like receptors ↓proliferation 565 Lesion studies in which the raphe nuclei inputs to the V–SVZ 625 D2-like receptors ↑proliferation 566 are ablated reveal a decrease in neurogenesis. Infusion of 5- 626

567 HT2C agonizts into the lateral ventricles induces proliferation 627 568 of type B cells, while the antagonist induces the opposite 628 569 study implies a critical role for dopamine in the V–SVZ as it 629 effect reducing proliferation. Although modulation of 5-HT2C 570 significantly affects type B cell proliferation, type C and A appears to be linked to expression of EGF, a major contributor to 630 – 571 cells remain unaffected (Tong et al., 2014). The effects of V SVZ proliferation (Craig et al., 1996; Reynolds et al., 1992). The 631 – 572 serotonergic innervation on ependymal cells remain to be sensitivity of the V SVZneuralstemcellpopulationtotreatment 632 573 studied, but 5-HT signaling might affect ependymal cell cilia, with levodopa indicates a potential role for this region in 633 574 as serotonin has been shown to increase cilia beating fre- psychiatric disease. See Table 2 for a summary of the most 634 – 575 quency on ependymal cells in the brainstem of rats (Nguyen prominent neurotransmitter actions in the regulation of V SVZ 635 576 et al., 2001). Serotonin is one of the primary neurotransmit- neurogenesis. 636 577 637 ters involved in mood regulation and mood disorders. It is 578 638 possible, therefore, that changes in serotonin regulation seen 4.3. Antidepressant drug actions in neurogenic regions 579 639 with mood disorders may also result in a decline in neuro- 580 640 genesis in the V–SVZ, although the functional and behavioral Given the influence of neurotransmitters on NSC function, 581 641 implications of this in adults are not yet clear. perhaps it is not surprising that antidepressant drugs can 582 642 The V–SVZ receives dopaminergic innervation from the preferentially enhance neurogenesis in both the hippocam- 583 643 substantia nigra (SNc) and ventral tegmental area (VTA) pus and V–SVZ. In hippocampus, selective serotonin reuptake 584 644 (Baker et al., 2004; Freundlieb et al., 2006; Hoglinger et al., inhibitors (SSRIs), atypical antidepressants, selective norepi- 585 645 2004). Axonal projections from the posterior SNc innervate nephrine reuptake inhibitors, monoamine oxidase inhibitors 586 646 the posterodorsal V–SVZ while the anterior SNc projects (MAOIs), and tricyclic antidepressants all have been shown to 587 647 axons to the anterior V–SVZ and the rostral migratory stream increase neurogenesis in chronically treated animals 588 648 (Hoglinger et al., 2014). The VTA preferentially projects axons (Malberg, 2004). For example, the commonly used SSRI fluox- 589 649 to the ventral V–SVZ (Hoglinger et al., 2014). These dopami- etine is effective at producing an increase in hippocampal 590 650 nergic projections contact type C progenitor cells that express 591 neurogenesis if treatment is continuous for at least 14 days 651 cognate D1-like and D2-like dopamine receptors (Coronas 592 (Malberg, 2004). Interestingly, electroconvulsive shock ther- 652 et al., 2004; Hoglinger et al., 2004; Winner et al., 2009). These 593 apy (ECT), often used as a last line of treatment against 653 G protein-coupled receptors are classically divided into two 594 depressive disorders resistant to pharmacological treatment, 654 groups based on their activity: D1-like (D1 and D5 receptors), 595 is also a potent inducer of neural stem cell proliferation 655 596 which activate adenylyl cyclase, and D2-like (D2, D3, and D4), (Madsen et al., 2000). 656 597 which inhibit adenylyl cyclase. In the developing brain, It has been established that neurogenesis in the hippo- 657 598 activation of the D1 receptor on proliferating cells decreases campus is, in fact, necessary for the production of behavioral 658 599 proliferation of progenitors by retarding the progression from effects of antidepressant drugs, and that ablation of neuro- 659 600 G1 to S phase of the cell cycle. However, activation of D2-like genesis also prevents behavioral improvements in animals 660 601 receptors enhanced proliferation of progenitors by promoting being treated with antidepressants (Santarelli et al., 2003). 661 602 the transition from G1 to S phase (Ohtani et al., 2003). It is Reports on the necessity of neurogenesis in effective treat- 662 603 likely that a similar response remains in the adult neural ment of mood disorders are not surprising given the changes 663 – 604 stem cell population of the V SVZ. that take place in the hippocampus of patients with depres- 664 – 605 In the adult brain, loss of dopaminergic signaling in the V SVZ sion or other affective disorders. Cognitive deficits, mood 665 606 has detrimental effects on neural stem cell proliferative capacity. dysregulation, and declines in hippocampal volume have all 666 607 Lesion of dopaminergic inputs using 6-hydroxydopamine (6- been correlated with mental disorders that display decreased 667 608 OHDA) or 1-methyl-4-pheynyl-1,2,3,6-tetrahydropyridine (MPTP) neurogenesis, such as major depression, post-traumatic 668 609 produced a loss of tyrosine hydroxylase (TH)-positive dopami- stress disorder, schizophrenia, and Alzheimer’s disease 669 610 nergic projections to the V–SVZ, and a decline in neural stem cell (Bremner et al., 1995; Bremner, 2001; DeCarolis and Eisch, 670 611 proliferation (Baker et al., 2004; Freundlieb et al., 2006; Hoglinger 2010). Interestingly, in Huntington’s disease, in which 671 612 et al., 2004; Winner et al., 2009). O’Keeffe and coworkers (O'Keeffe patients exhibit early signs of cognitive distress, neurogen- 672 613 et al., 2009) reveal a concomitant decline in EGF production in the esis appears to decline preferentially in the striatum of 673 614 V–SVZ following dopaminergic lesion, and have demonstrated a humans (Ernst et al., 2014). Given the underlying structural 674 615 reversal of this deficit through levodopa administration. This and cognitive deficits in these mental disorders, targeting 675 616 676 617 677

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678 neurogenesis directly as a therapeutic intervention may lead Investigations in human V–SVZ and olfactory bulb 738 679 to improved patient outcomes in future mental health treat- revealed a cytoarchitecturally distinct V–SVZ niche organiza- 739 680 ment paradigms. tion and neuroblast migration compared to rodents 740 681 The effects of antidepressant treatments are somewhat (Bergmann et al., 2012; Ernst et al., 2014; Sanai et al., 2011). 741 682 different in the V–SVZ, where it has been reported that In humans, the V–SVZ displays a dense ribbon of astrocytes 742 683 chronic fluoxetine alone decreases neurogenesis (Ohira and after a subependymal gap (Sanai et al., 2004). These astro- 743 684 Miyakawa, 2011). However, if the antidepressant treatment is cytes show multipotency in vitro and can generate neurons, 744 685 given in conjunction with corticosterone or chronic stress, astrocytes and oligodendrocytes (Sanai et al., 2011). Although 745 686 which both decrease neurogenesis and are major contribu- these putative neural stem cells display strong germinal 746 687 tors to the development of mood disorders, then antidepres- capacity in vitro, their migratory route differs between 747 688 sant drugs actually reverse this decline in neurogenesis rodents and humans. Early work by Sanai and colleagues 748 689 (Hitoshi et al., 2007; Lau et al., 2007). Further, antidepressant revealed that neurogenesis in the olfactory bulb is virtually 749 690 treatment following stroke, which increases neurogenesis, absent in human adult tissue (Sanai et al., 2004). More recent 750 691 can enhance proliferation of neural stem cells and improve work has revealed that olfactory neurogenesis does occur in 751 692 their migration toward sites of brain damage, but does not humans, but only in infants up to 18 months of age. The level 752 693 enhance survival, differentiation, or behavioral outcomes in of olfactory neurogenesis declines dramatically by 24 months 753 694 either hippocampus or V–SVZ (Sun et al., 2015). of age and is virtually absent in adult tissue (Sanai et al., 754 695 2011). In support of these studies, recent studies estimated 755 696 cell turnover predicted to be only 1% of human olfactory bulb 756 697 5. Neurogenesis in humans cells across a 100 year lifespan using 14C dating (Bergmann 757 698 et al., 2012). 14C dating, along with other histological evidence, 758 699 The discovery of neurogenesis in the human adult and the shows that instead of giving rise to new neurons in the 759 700 regenerative capacity of neural stem cells has spurred inter- olfactory bulb, neuroblasts from the V–SVZ migrate to the 760 701 est in designing novel therapies for conditions such as stroke, striatum in humans (Ernst et al., 2014). This difference in NSC 761 702 traumatic brain injury, and neurodegenerative diseases. migration between rodents and humans suggests the pre- 762 703 However, many studies on NSCs employ rodent models and sence of a functionally divergent mechanism for V–SVZ 763 704 little is known about adult neurogenesis in humans. Neuro- neurogenesis across species. The striatum is commonly 764 705 genesis in the adult human SGZ was first demonstrated in associated with motor function, but recently it has been 765 706 the late 1990s by Eriksson and coworkers (Eriksson et al., identified as necessary for cognitive flexibility, as evolution- 766 707 1998). In this study, terminally ill cancer patients were ary expansion of this region correlates with an increase in 767 708 injected with the nucleotide analog bromodeoxyuridine cognitive function and ability in modern humans (Ernst and 768 709 (BrdU) for diagnostic purposes during their cancer treatment. Frisen, 2015). Carbon dating of two different neuronal popu- 769 710 Immunohistochemical analysis of postmortem brain samples lations in the striatum of humans identified postnatal turn- 770 711 revealed BrdU incorporation within the DNA of dividing cells over of interneurons but not of medium spiny neurons, 771 712 of the hippocampus, which appear morphologically indistin- suggesting progenitors from human V–SVZs contribute to 772 713 guishable from adult-born hippocampal neurons observed in the population of interneurons in the striatum. However, 773 714 rodent models. Ethical concerns prohibit further studies such recent work has demonstrated that subpopulations of astro- 774 715 as this one in terminally ill human subjects, but the strong cytes in the striatal tissue can give rise to new neurons in this 775 716 evidence of adult hippocampal neurogenesis gained from this region, suggesting that the striatum may have an inherent 776 717 patient population was an invaluable contribution to the capacity to regenerate neurons independent of the neighbor- 777 718 scientific community. ing neurogenic cells in the V–SVZ (Magnusson et al., 2014). 778 719 A later study provided additional direct evidence of adult Regardless of the NSC source, discovery of striatum-specific 779 720 hippocampal neurogenesis in humans. Nuclear bomb testing neuronal turnover is of particular interest in the study of 780 721 during the Cold War produced elevated levels of 14C in the neurodegenerative diseases with prominent striatal involve- 781 722 atmosphere, which are mirrored in the 14C incorporation into ment, such as Huntington’s disease. Some studies suggest 782 723 the human body (Harkness, 1972). Levels of 14C have been cell death in the striatum (as in the case of Huntington’s 783 724 declining since testing in the 1950s, but are still detectable disease) induces proliferation and thickening of the human 784 725 and correlate with levels in human tissue. Spalding and V–SVZ, instigating migration to the striatum through the 785 726 colleagues found that postmortem brain samples probed for caudate nucleus (Curtis et al., 2007). Interestingly, carbon 786 727 14C levels in the hippocampus revealed that adult neurogen- dating indicates a decrease in new neurons in the striatum of 787 728 esis does occur, at least into the fifth decade of life, in this Huntington’s disease patients when compared to age- 788 729 brain region (Spalding et al., 2013). Further, neurogenesis is matched healthy subjects (Ernst et al., 2014), suggesting that 789 730 restricted to a subpopulation of cells in the hippocampus that this increase in proliferation does not compensate for 790 731 is subjected to turnover throughout life. Specifically, the neuronal loss. 791 732 dentate gyrus of the hippocampus is the location of high cell In humans, neurogenic regions receive similar innervation 792 733 turnover, according to 14C measurements taken in aged by monoaminergic projections as observed in rodents, how- 793 734 tissue. However, there is still a net loss in neurons in the ever there are no reports on how NSCs in the SGZ and SVZ 794 735 dentate gyrus throughout life, indicating that continued respond to neurotransmitter signaling in the human brain. It 795 736 neurogenesis throughout adulthood delays, but does not is well established that SGZ neurogenesis increases in 796 737 arrest, neuronal volume loss with age. response to antidepressant treatment in animal models 797

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798 (Santarelli et al., 2003). Given the highly conserved nature of neural stem cell responsiveness to drugs used in treating 858 799 neurotransmitter signaling in higher mammals, it is reason- psychiatric disorders further supports this idea. Neurogenesis 859 800 able to presume that similar effects on NSC proliferation and in the SGZ has been shown to be necessary for effective 860 801 migration may eventually be observed in human neurogenic treatment of mood and psychiatric disorders, while the V– 861 802 regions. Neurotransmitters can also influence growth factors, SVZ is not typically linked to psychiatric dysfunction. How- 862 803 neurotrophic receptors, and other factors involved in neuro- ever, the recent evidence of V–SVZ neural stem cell control, in 863 804 genesis (Hagg, 2009). Future advances in our ability to study part by monoamines involved in mood, cognitive, and neu- 864 805 neurotransmission and neurogenesis in vivo may eventually rodegenerative disorders, indicates that neurogenesis in this 865 806 broaden our understanding of neurogenesis regulation by region may also play a role in maintenance of normal mood 866 807 neurotransmitters in the human brain. For now, animal and cognitive regulation. In humans, it is likely that the 867 808 models are providing the first answers to these questions ultimate fate of V–SVZ neural stem cells is integration into 868 809 on neurotransmitter regulation of NSCs. the striatal tissue rather than the olfactory bulb, as seen in 869 810 rodents. The involvement of the human V–SVZ and striatum 870 811 in adult neurogenesis has revised our understanding of 871 812 6. Adult human neurogenesis and psychiatric neurodegenerative diseases that have an early cognitive or 872 813 disorders mood component. Our knowledge of adult neurogenesis and 873 814 neural stem cell regulation has grown exponentially over the 874 815 The functional implications of adult human hippocampal last two decades, however we still lack a complete under- 875 816 neurogenesis remain unclear. It is thought that neurogenesis standing of the neurogenic process in the human brain. 876 817 in hippocampus is particularly important in memory forma- Further work on understanding human adult neurogenesis 877 818 tion and consolidation, and dysfunctional neurogenic pat- may reveal a critical role of the V–SVZ and striatum in mood, 878 819 terns are likely involved in mood and psychiatric disorders. cognition, and neurodegeneration. 879 820 For example, in a postmortem examination of hippocampal 880 821 tissue from schizophrenic patients, it was found that there is 881 822 a dramatic decrease in the number of proliferating cells in the Author information 882 823 SGZ (Allen et al., 2015). Stress and depression contribute to 883 fl 824 decreased neurogenesis, and antidepressant treatment has The authors have no con icts of interest or disclosures at 884 825 been shown to reverse this loss of hippocampal neurogenesis this time. 885 826 (Mahar et al., 2014). Future work will clarify the connections 886 827 between neurogenesis and psychiatric disorders, and may Acknowledgments 887 828 lead to the development of targeted neurogenesis therapies 888 829 for mental illnesses. 889 The Kokovay laboratory is supported by The University of 830 Adult neurogenesis in the human V–SVZ is increasingly 890 Texas Rising STARS Award and a William and Ella Owens 831 recognized as a potential player in the development of 891 Medical Research Foundation Grant. DMA is supported by a Q5 832 psychiatric and cognitive disorders. Recent attention has been 892 Training Fellowship, Institutional National Research Service 833 given to the role of the striatum in schizophrenia, where 893 Award, Translational Science Training Program (TL1 834 dopamine hyperactivity is thought to contribute to the pathol- 894 TR001119) and a Barshop Institute Biology of Aging Training 835 ogy of schizophrenia (Simpson et al., 2010). Several reports 895 Program (T32 AG021890). 836 have suggested that increased adult neurogenesis in the V– 896 837 SVZ may alleviate symptoms of schizophrenia by targeting references 897 838 dopamine signaling at NSCs (Inta et al., 2012). Given the 898 839 evidence indicating that progenitors from the V–SVZ migrate 899 840 to the striatum in humans, it is plausible to speculate that 900 Aberg, M.A., et al., 2000. Peripheral infusion of IGF-I selectively 841 – 901 alterations in V SVZ neurogenic activity may contribute to the induces neurogenesis in the adult rat hippocampus. J. 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Astrocytes regulate adult hippocampal 910 851 The discovery of the remarkable process of adult neurogen- neurogenesis through ephrin-B signaling. Nat. Neurosci. 15, 911 852 esis has revolutionized our understanding of the brain’s 1399–1406. 912 853 response to disease and damage. The changes that occur in Baker, S.A., Baker, K.A., Hagg, T., 2004. Dopaminergic nigrostriatal 913 projections regulate neural precursor proliferation in the adult 854 neurogenic cell populations in response to stress, psychiatric 914 mouse subventricular zone. Eur. J. Neurosci. 20, 575–579. 855 disorders, and in the early stages of neurodegenerative Banasr, M., et al., 2004. Serotonin-induced increases in adult cell 915 856 disease indicate that neural stem cells may hold therapeutic proliferation and neurogenesis are mediated through differ- 916 857 potential for treatment of these pathologies. Evidence of ent and common 5-HT receptor subtypes in the dentate gyrus 917

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Please cite this article as: Apple, D.M, et al., The role of adult neurogenesis in psychiatric and cognitive disorders. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.023