Activity-Dependent Extrinsic Regulation of Adult Olfactory Bulb and Hippocampal Neurogenesis Dengke K

INTERNATIONAL SYMPOSIUM ON OLFACTION AND TASTE

Activity-dependent Extrinsic Regulation of Adult Olfactory Bulb and Hippocampal Neurogenesis Dengke K. Ma,a,b Woon Ryoung Kim,b,c Guo-li Ming,a,b,c and Hongjun Songa,b,c aThe Solomon Snyder Department of Neuroscience, bInstitute for Cell Engineering, and cDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

The adult mammalian brain continuously generates new neurons in the olfactory bulb and hippocampus throughout life. Adult neurogenesis, a highly dynamic process, has been shown to be exquisitely modulated by neuronal circuit activity at different stages, from proliferation of adult neural progenitors, to differentiation, maturation, integration, and survival of newborn neurons in the adult brain. Strategic activity-dependent addition of new neurons into the existing neuronal circuitry represents a prominent form of structural plasticity and may contribute to speciﬁc brain functions, such as learning, memory, and mood modulation. Here we review extrinsic mechanisms through which adult neurogenesis is regulated by environmental cues, physiological learning-related stimuli, and neuronal activities.

Key words: plasticity; adult stem cells; neurotransmitter; neurogenesis; neural activity

Introduction dition of populations of new neurons with functional synaptic inputs and outputs. Distinct fea- Since the pioneering studies by Altman et al. tures of these two types of plasticity may endow in the early 1960s, adult neurogenesis has now the brain with parallel yet complementary ca- been unambiguously established in discrete pacities for information processing. Common brain regions in most mammals.1–7 New exci- in all neural plasticity and similar to synap- tatory granule neurons and inhibitory granule tic changes, adult neurogenesis is under the and periglomerular interneurons are continu- exquisite control of neural activity. Studies in ously added to existing circuits in the dentate the last few years have delineated the sequen- gyrus and olfactory bulb, respectively (Fig. 1A). tial steps of endogenous adult neurogenesis in Such continuous adult neurogenesis represents these two brain regions, from proliferation and a surprising and intriguing type of plasticity fate specification of adult neural progenitors conserved in adult mammalian brains.5–8 In to differentiation, maturation, axon and den- contrast to the main form of neural plastic- dritic targeting, formation of functional synap- ity, through synaptic-level modification, adult tic inputs and outputs, and selective survival of neurogenesis confers plasticity through the ad- newborn neurons.9,10 Accumulating evidence has implicated adult neurogenesis in specific brain functions, such as olfactory learning, spa-

Address for correspondence: Hongjun Song, Ph.D., Institute for tial memory formation, and mediation of be- 11–15 Cell Engineering, Departments of Neurology and Neuroscience, Johns havioral effects of antidepressants. Accord- Hopkins University School of Medicine, 733 N. Broadway, BRB731, Baltimore, MD 21205. Voice: 443-287-7499; fax: 410-614-9568. ingly, many environmental cues, physiological [email protected] learning-related stimuli, and neuronal activities

International Symposium on Olfaction and Taste: Ann. N.Y. Acad. Sci. 1170: 664–673 (2009). doi: 10.1111/j.1749-6632.2009.04373.x c 2009 New York Academy of Sciences. 664 Ma et al.: Activity-dependent Adult Neurogenesis 665

Figure 1. Regulation of adult neurogenesis by various types of neural activity. (A) Schematic representation of a sagittal view of the adult mouse brain. New neurons are generated continuously throughout life in the SVZ–olfactory bulb (OB) system and the dentate gyrus (DG) of the hippocampus. (B) Activity-dependent neurogenesis in the adult OB. Transient am- plifying cells give rise to neuroblasts, migrating toward the OB through the rostral migratory stream (RMS). Within the OB, these neuroblasts differentiate into two types of interneurons as the granule cell and periglomerular cell (PGC). Integration into the preexisting circuits by newly entered neurons and their survival are predominantly influenced by odor experiences, such as enriched odor exposure or odor discriminate learning. (C) Activity-dependent neurogenesis in the dentate gyrus. Neural progenitors in the SGZ proliferate and differentiate into neuroblasts that migrate a short distance into the inner granular cell layer, processes that are modulated by various types of neural activity. The survival and integration of new neurons is also regulated in an activity-dependent manner. (In color in Annals online.) 666 Annals of the New York Academy of Sciences dynamically influence different stages of adult after normal stimulation was restored. Thymi- neurogenesis.16–18 The underlying molecular dine analog labeling revealed that the recov- and cellular mechanisms through which diverse ery was accompanied by the addition of a types of activity selectively regulate different large population of new neurons. Other sim- stages of adult neurogenesis are only beginning ilar experiments have shown that the increased to be unraveled. number of neurons after deprivation is due to rescued survival from the “default” apoptosis program.23–25 Thus, neuronal survival in the Activity-dependent Regulation of olfactory bulb can be profoundly influenced by Adult Olfactory Bulb Neurogenesis afferent activities. Several recent studies have directly exam- New neurons generated in the adult olfac- ined whether physiological exposure to an tory bulb originate from progenitors in the sub- odor-enriched environment or learning tasks ventricular zone (SVZ) of the lateral ventricle affect neurogenesis in the adult olfactory of the forebrain.19 The physical distance be- bulb.26 Using bromodeoxyuridine (BrdU) to tween the place of their birth and place of final birth date progenitors from SVZ and their destination naturally creates two distinct com- progeny, Rochefort et al.27 found that long- partments for potential extrinsic regulation. In term exposure to an odor-enriched environ- the SVZ, adult progenitor cells are located ment dramatically increased the number of in a developmental “vestige” where embry- surviving new neurons at 3 weeks after BrdU onic counterparts generate the majority of neu- injection. The number of BrdU-labeled pro- rons, and not surprisingly their maintenance, genitors was not altered 4 h after a single BrdU proliferation, and fate specification are subject injection, suggesting a lack of effects on cell to numerous developmental signaling controls proliferation. Interestingly, this effect appears in a largely activity-independent manner.19,20 to temporally transient, because the number Highly specialized niche structures, such as a of newborn neurons returned to control levels “glial tunnel,”21 may also function to segregate 30 days after experiencing the odor-enriched the earlier stages of neurogenesis from influ- environment.27 Furthermore, odor discrimina- ences of circuit neuronal activity. After neu- tion learning for an extended period, not just roblasts migrate through the rostral migratory exposure to a single odor, is also able to signifi- stream and reach the bulb, where olfactory cantly increase the survival of newborn neurons information processing takes place, the newly in the olfactory bulb.28 The effects are region generated neurons switch to radial migration to specific, because enriched odor exposure does their final positions and start to receive synap- not influence hippocampal neurogenesis. Al- tic inputs and are subject to activity-dependent though it remains under debate,29,30 olfactory survival and final integration into the preexist- bulb neurogenesis might be associated with spe- ing circuitry. cific olfactory functions, such as olfactory dis- Olfactory bulbs process odorant information crimination and olfactory memory. For exam- from the nose to the brain; thus, the main type ple, olfactory enrichment induces not only an of activity results from sensory stimuli of odor- increase in the number of surviving newborn ant exposure. Using a technique of reversible neurons but also enhancement of short-term ol- olfactory deprivation, Cummings et al. showed factory memory.6,26,27 Conversely,mutant mice that unilateral olfactory deprivation during the deficient in a neural cell adhesion molecule first postnatal month in rodents led to a dra- with reduced olfactory neurogenesis exhibit re- matic reduction in the size of the olfactory bulb duced olfactory sensitivity and olfactory mem- on the experimental side.22 Surprisingly, the ory.11 Studies have also indicated a correlation bulb size had mostly recovered within 40 days between the age-dependent decline of olfactory Ma et al.: Activity-dependent Adult Neurogenesis 667 bulb neurogenesis and fine odorant discrimina- the olfactory bulb. The dentate gyrus receives tion ability.31 These functional correlations sug- inputs from numerous regions of the brain.35 gest that the activities from odorant-related en- Particularly, the SGZ is known to be enriched vironmental stimuli may not only increase the in exuberant neuronal communications be- number of surviving neurons but also enhance tween mature granule neurons and local in- their integration into the circuitry to participate terneurons.36 The spatial proximity to high in information processing. Using immediate- neuronal network circuit activity may place early gene activation to monitor the integra- adult hippocampal neurogenesis under more tion of new neurons, Magavi et al. showed that elaborate, activity-dependent control than in odor familiarization specifically increases the the SVZ. response of adult-born neurons but depresses The hippocampus is a brain region crucial the response of the overall population of gran- for acquisition of new episodic memory and the ule neurons.32 dentate gyrus plays a role in “pattern separa- In addition to odorants and olfactory learn- tion,”37 distinguishing similarly encoded con- ing, other physiological conditions have also textual information. This functional require- been shown to modulate olfactory bulb neu- ment may engender the dentate gyrus to be rogenesis in rodents. Compared to subordinate superiorly sensitive to the surrounding environ- male mice, pheromones from dominant males ment and ongoing cortical activity. Consistent stimulate neuronal production in the olfactory with this notion, the dentate hilus region is one bulb of female mice by increasing cell prolif- of the major loci responsible for temporal lobe eration in the SVZ (Fig. 1B).33 In a similar epilepsy.38 As part of the limbic system, another vein, pregnancy of female mice promotes both established role of the dentate gyrus is its mod- SVZ proliferation and the production of new ulation of emotions, such as stress and depres- interneurons in the olfactory bulb through pro- sion.39 As reviewed below, major types of activ- lactin (Fig. 1B).34 Although the SVZ progeni- ity in the dentate gyrus, including those induced tors express receptors for these gender-specific of an enriched environment, voluntary exer- cues, it remains unclear to what extend neu- cises, and cognitive and emotional processes, ronal activity is directly involved in mediating modulate different aspects of adult hippocam- the actions of these cues and the long-term pal neurogenesis. outcome. Exposure to an enriched environment is known to produce structural and functional alterations in the brain; its specific effects on Activity-dependent Regulation adult hippocampal neurogenesis were exam- of Adult Neurogenesis ined by Kempermman et al.40 Compared with in the Hippocampus littermates housed in standard cages, significantly more new neurons were found in the Neurogenesis in the adult hippocampus oc- dentate gyrus of mice exposed to an enriched curs in the granule cell layer of the dentate environment. Surprisingly, van Praag et al. fur- gyrus. New neurons are born in the subgran- ther showed that voluntary exercise alone, with- ular zone (SGZ) and then migrate a short dis- out other components of an enriched environ- tance before maturing into excitatory dentate ment, was sufficient to enhance neurogenesis.41 granule cells in the inner granule cell layer This effect could be observed as early as day 1 (Fig. 1C). The entire neurogenesis process, in- after the start of exercise, but the most pro- cluding progenitor proliferation, fate specifica- found effect was detected after 3 days of exer- tion, migration, and neuronal differentiation, cise, manifested by the enhanced proliferation is spatially restricted compared to the exten- of early neural progenitors. Continued exercise sive spreading of neurogenesis from the SVZ to elicits a predominantly enhanced survival of 668 Annals of the New York Academy of Sciences newborn neurons and results in a net increased genitor proliferation, survival, and dendritic de- number of integrated neurons in the adult velopment of newborn neurons.44,45 brain. Cognitive activity, mainly from hippocampus-dependent learning, also modulates Cellular and Molecular Mechanisms adult hippocampal neurogenesis. Training on associative learning tasks that require the hip- The activity-dependent regulation of adult pocampus, such as trace eye blink conditioning neurogenesis in both the olfactory bulb and and Morris water maze learning, significantly the dentate gyrus of the hippocampus has now increases the number of newly generated neu- been widely observed and extensively stud- rons in the adult dentate gyrus, whereas tasks ied. The specific molecular and cellular mech- that do not require the hippocampus do not anisms through which activity regulates dif- change the numbers of new neurons.42 Analysis ferent stages of adult neurogenesis, however, using BrdU-based birth dating further suggests are only beginning to be explored. Particu- that the learning behavior specifically promotes larly, the extrinsic mechanisms of how diverse the survival of new neurons between 1 and types of activities are translated into actions on 3 weeks after they are generated in the adult sequential processes of adult neurogenesis re- brain.42 Interestingly, the survival of earlier, main unclear. Although various cell types in 3-day-old newborn neurons is actually inhib- the brain, such as microglia, endothelial cells, ited by the similar Morris water maze learning and T cells, have been shown to play inter- paradigm, suggesting a stage-dependent effect esting roles,46–48 mature neurons are likely the and a finely sculpted developmental selection major cellular players in extrinsic regulation of newborn neurons for strategic addition.43 of neurogenesis by mediating effects of neural The learning process involves precisely timed activity. Here we focus our discussion on two and highly patterned neuronal activity; exces- major types of molecular mediators for activity- sive or abnormal patterns of activity, such as dependent adult neurogenesis: neurotransmit- those occurring during temporal lobe epileptic ters and membrane-associated and diffusible seizures, dramatically impact neurogenesis, in- factors from neurons. cluding progenitor proliferation and dendritic GABA is the major neurotransmitter used development, synapse formation, and survival by mature interneurons in the brain and has of new neurons as documented in numerous emerged as a key regulator for adult neu- clinical and experimental settings.44 On the rogenesis.18 GABA, activating both synaptic other hand, negative emotional activity,includ- and extrasynaptic GABA-A receptors, causes ing stress and depression, has been shown to hyperpolarization of mature neurons while it be a potent inhibitor of adult hippocampal depolarizes neural progenitors and immature neurogenesis.39 The major effect of stress on neurons in the adult brain.10,49 Electrophysi- neurogenesis appears to be decreased cell pro- ological analysis revealed that neural progeni- liferation, while reduced cell survival of new- tors are initially activated by ambient GABA, born neurons has also been reported. The dis- followed by sequential GABAergic and gluta- crepancy may be due to the different stress matergic inputs.18 In the SVZ, GABA released paradigms used in the different studies.39 from migrating neuroblasts regulates prolifera- Stressful events are known to induce depres- tion, which is probably not directly connected sion; interestingly, a variety of antidepressant to circuit activity-dependent modification.50 treatments elevate hippocampal neurogenesis. In the SGZ, GABA is released from local in- The most effective antidepressant used in clin- terneurons and tonically activating progenitors ics, electroconvulsive treatment, promotes the and immature neurons. Importantly,both tonic entire adult neurogenic process, including pro- and phasic GABA activation is essential for the Ma et al.: Activity-dependent Adult Neurogenesis 669 maturation, dendritic development, and synap- activation of new neurons promotes competi- tic integration of newborn granule cells.51,52 tive survival of these new neurons during the 1– Given extensive recurrent connections between 3 weeks after their birth.59 In the second phase, granule cells and interneurons in the adult den- NR2B-dependent activation of NMDARs is re- tate gyrus,36 the ambient GABA levels might re- quired for the enhanced synaptic plasticity of flect general local circuit activity and translate glutamatergic inputs to new neurons during the neuronal stimuli into actions on neural pro- 4–6 weeks after their birth, potentially serving genitors, while phasic GABA activation may as a substrate for learning from new experi- serve as an input-specific modulator for imma- ence.60,61 Parallel to such a direct impact of ture new neurons. Interestingly, recent studies glutamate on newborn neurons, NMDAR ac- have shown that both tonic and phasic GABA tivation in mature neurons is known to lead activation of neural progenitors and immature to a gene expression program that produces newborn neurons in the dentate gyrus is mod- diffusible factors profoundly influencing adult ulated by chemokine stromal cell-derived fac- neurogenesis. tor 1 coreleased from local interneurons.53,54 Cells membrane-associated or diffusible fac- Current evidence suggests that regulation by tors serve as major mediators for short-range GABA from interneurons creates a favorable cell–cell communication. Given that adult neu- condition to orchestrate the integration of new ral progenitors and their progeny are exten- neurons into a mature neuronal environment sively regulated by a plethora of growth factors, in the SGZ. It would be interesting to examine neurotrophins, and developmental cues,20,62 whether activity-dependent maturation, inte- nearby mature neurons are suited to contribute, gration, and survival of new neurons also re- producing these diffusible niche factors or their cruits GABA-mediated regulation in the olfac- antagonists in response to neuronal activity. tory bulb. Brain-derived neurotrophin factor is one prime Glutamate is the major neurotransmitter example. As a classic activity-dependent neu- used by excitatory principal neurons in the rotrophin,62 its expression is bidirectionally sen- brain and has long been implicated in regulat- sitive to activity in dentate granule neurons and ing adult hippocampus neurogenesis through can exert pleiotropic yet strong influences on N -methyl-D-aspartate receptors (NMDARs). adult hippocampal neurogenesis.63,64 In the ol- Direct injection of N -methyl-D-aspartate nega- factory bulb, the extracellular matrix glycopro- tively regulates cell proliferation in the adult rat tein tenascin-R regulates the initiation of the dentate gyrus,55,56 while induction of long-term detachment of neuroblasts from the migrating potentiation at the glutamatergic perforant chain as well as their radial migration.65 In- path to dentate granule cells promotes the terestingly, tenascin-R is expressed from adult proliferation of adult neural progenitors and olfactory bulb neurons in an activity-dependent survival of newborn neurons in an NMDAR- manner, as it is markedly reduced by odor dependent fashion.57,58 These results suggest deprivation. Similarly, other extrinsic factors, that glutamate has both cell autonomous effects including Wnts and their antagonists, fibrob- in immature neurons and non-cell autonomous last growth factors, vascular endothelial growth effects through modulation of existing neuronal factors, and neuropeptide VGF, may be regu- circuits. Although local mature neurons have lated by various neuronal stimuli in the den- predominantly heightened NMDAR signaling, tate gyrus and perhaps also in the olfactory ionotropic glutamate receptors are present in bulb to modulate activity-dependent neuroge- immature neurons and early progenitors. In- nesis.62 Ample evidence suggests that the ge- terestingly, direct NMDAR signaling has been netic program driving activity-dependent gene shown to regulate newborn neurons during two expression of diffusible factors in mature gran- critical periods.10 Inthefirstphase,NMDAR ule neurons requires NMDAR signaling, which 670 Annals of the New York Academy of Sciences is critically important for synaptic plasticity and neurogenesis and neuronal activity resulting information storage of neurons per se.66,67 This from various environmental cues, physiological may provide a mechanism by which encoded learning-related stimuli, and internal cognitive, information from patterned neuronal stimuli emotional activities. The remarkable scope and is specifically and precisely translated into lo- modes of activity-dependent regulation of adult cal neurogenic responses for strategic neuronal neurogenesis suggest that the adult brain has addition to the circuitry. evolved mechanisms to exquisitely tailor neuronal addition into its information processing capacity, to which in turn the new population Functional Implications of neurons contributes. Neuron-derived GABA, glutamate signal- The scope and modes of activity-dependent ing, and diffusible factors have emerged regulation of adult neurogenesis discussed as major molecular mediators for activity- above have interesting implications for func- dependent modification of adult neurogen- tional contributions of newborn neurons. Dur- esis. The molecular mechanisms underlying ing adult neurogenesis, nearly half of the pre- activity-dependent survival and integration re- cociously generated neurons are destined to main to be further studied. Many other neuro- die,5,28,59 and this specific stage of life-or-death transmitter systems are known to innervate the decision has predominantly been used to serve SVZ, olfactory bulb, and SGZ, and their spe- as the substrate of activity-dependent modi- cific roles in regulating different phases of adult fication in both the olfactory bulb and hip- neurogenesis are being characterized. Finally, pocampus. Importantly, the survival of individ- exploring the mutual relationship between ac- ual neurons is competitive, so that only new tivity and neurogenesis in the context of neural neurons activated by information-relevant ac- circuit dynamics to infer the exact functional tivity are selectively preserved and integrated role of adult neurogenesis remains a great and into the circuitry. One intriguing idea is that challenging yet rewarding goal. the newly integrated neurons (4–6 weeks) with enhanced plasticity may encode information that is specific to what that particular neuron Acknowledgments has encountered during its history of activity- This work was supported by grants from dependent regulation, such as competitive sur- the NIH, McKnight Scholar, NARSAD, Rett vival (1–3 weeks), thus representing a trace of Syndrome Research Foundation, the Muscular memory.59,60,68 The same GABA-, glutamate-, Dystrophy Association, and the Packard Cen- or diffusible factor-based mechanisms may ter for ALS Research at Johns Hopkins (to H.S.) have been used during the earlier period and from the NIH, Sloan, March of Dimes, (1–3 weeks) and later encoding of the memory and Adelson Medical Research Foundation trace (4–6 weeks) perpetuates the time-specific (to G.-L.M.). network activity or input-specific information.

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