Functional significance of adult neurogenesis Gerd Kempermann 1, Laurenz Wiskott 2 and Fred H Gage,3

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1 Functional significance of adult neurogenesis Gerd Kempermann 1, Laurenz Wiskott 2 and Fred H Gage,3 Function is the key criterion for determining whether adult neurogenesis be it endogenous, induced, or after transplantation is successful and has truly generated new nerve cells. Function, however, is an elusive and problematic term. A satisfying statement of function will require evaluation on the three conceptual levels of cells, networks, and systems and potentially even beyond, on the level of psychology. Neuronal development is a lengthy process, a fact that must be considered when judging causes and consequences in experiments that address function and function-dependent regulation of adult neurogenesis. Nevertheless, the information that has been obtained and published so far provides ample evidence that neurons generated in the adult can function and even suggests how they might contribute to cognitive processes. Addresses 1 Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Volkswagenstiftung Research Group at the Department of Experimental Neurology, Charité University Medicine Berlin, Berlin, Germany 2 Institute of Theoretical Biology (ITB), Humboldt University Berlin, Germany 3 The Salk Institute for Genetics, Laboratory of Genetics, La Jolla, California, USA gage@salk.edu or gerd.kempermann@mdc-berlin.de This review comes from a themed issue on Cognitive neuroscience Edited by John Gabrieli and Elisabeth A Murray /$ see front matter ß 2004 Elsevier Ltd. All rights reserved. DOI /j.conb Abbreviations SGZ subgranular zone Introduction The common perception is that new neurons in the adult brain would be beneficial. However, during evolution, the amount of adult neurogenesis decreased with increasing brain complexity. Whereas lower vertebrates, such as lizards, can regenerate entire brain parts, neurogenesis in adult mammals is restricted to a few regions. So there must be a trade-off between the benefits accrued from new neurons and the problems they cause for the network structure into which they need to integrate. Apparently, in the two neurogenic regions of the adult mammalian brain hippocampus and olfactory system the benefits outweigh the problems. Thus, the function of the new neurons becomes a central issue. Although it may seem self-evident that a neuron is not a true neuron unless it functions as one, a major challenge remains to develop concepts of what function actually means in this context, and then to figure out how to measure it. Function in adult neurogenesis can be considered on first, cellular, second, network, and third, system levels (Figure 1). In addition, to explain brain function in the more general sense of cognition we may eventually need an even broader definition, one that incorporates psychology and surpasses these three levels. For the purpose of the present review, we restrict ourselves to these three levels, which have been addressed in animal experiments. Signs of functionality in newborn neurons In essence, neuronal function is communication. However, because in many experimental contexts individual cells will be the only available targets for functional studies, in vivo and in vitro, it is helpful to consider function in isolated cells. Adult neurogenesis is a complex multi-step process that originates from precursor cells (i.e. stem cells and lineagedetermined progenitor cells) in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. In both systems, the stem cells appear to be cells with astrocytic properties [1,2]. In the hippocampus, these cells, designated type-1 cells (or B cells [1,2]) show the electrophysiological features of astrocytes: passive membrane properties and potassium currents [3,4]. By contrast, type-2 cells are highly proliferative progenitor cells in the same region. They have the electrophysiological properties that were originally described for glial precursor cells. Nevertheless, they appear to be in the neuronal lineage, because early neuronal markers and sodium currents basic electrophysiological hallmarks of neurons can be found in some type-2 cells. Activity-dependent regulation of neurogenesis as seen, for example, following exposure to environmental complexity also affects these type-2 progenitor cells [5]. Thus, the first indications of neuronal function appear at the level of precursor cells! The stability of new neurons might seem to be an important prerequisite for function, although from a purely theoretical point of view, adult neurogenesis could be transient and still be functional. In fact, new neurons survive for a long time in both the hippocampus and the olfactory system [6,7]. The decision for terminal neuronal differentiation is made early in development: once immature neurons are about one week into the postmitotic stage, they are likely to persist [7].

2 Functional significance of adult neurogenesis Kempermann, Wiskott and Gage 187 Figure 1 Levels of functional analysis Individual System Network Cell Stem cell Synapses New neuron New neuron? Circuits? Watermaze Exit Exit? Current Opinion in Neurobiology Levels of functional analysis in adult neurogenesis. Function is an elusive term with a variety of theoretical and practical meanings on different conceptual levels. Adult neurogenesis has so far been addressed on the levels of cells, networks and systems. But from these levels functional significance of new neurons has also been inferred on a fourth level, the cognitive level. This is the level of the individual, with its psychological and social contexts. Such implications are important but difficult and sometimes problematic, as the conceptual levels overlap. Neurons use synapses to form networks and integration of networks leads to the establishment of complex circuitry in functional systems, such as the hippocampus or the olfactory system. Tests of function are very different on the different conceptual levels. Thus, function will mean very different things depending on the experimental situation. Functional analysis of single cells becomes particularly important when aiming to grow neurons of desired neurotransmitter types in culture. Song et al. [8] found that co-culturing adult-derived precursor cells with astrocytes induced their development into electrically active neurons that formed networks in vitro. Organotypic slice cultures and co-culture systems can add another level of complexity to in vitro studies and blur the border with the network level. Benninger et al. [9] showed that neurons derived from embryonic stem cells in vitro functionally integrated into early postnatal hippocampal slice cultures. The implanted cells gradually expressed a mature profile of receptors and voltage gated channels and became synaptically integrated. Functional integration of new neurons in vivo Functional integration on a network level in vivo requires that the new neurons extend dendrites and axons and form synapses. As early as 1988, Stanfield and Trice [10] demonstrated that new granule cells in the adult dentate gyrus extend axons along the mossy fiber tract. This structural integration was later confirmed by two other groups [11,12]. It is not clear how predictive structural integration is for actual function, but it is an obvious requirement. Wichterle et al. [13], for example, recapitulated motoneuron differentiation from embryonic stem cells in vitro and showed that after implantation the new cells formed adequate synapses on the target muscles.

3 188 Cognitive neuroscience After labeling newly generated hippocampal cells with a retrovirus expressing a reporter gene, van Praag et al. [14 ] showed that, over weeks, new cells developed electrophysiological characteristics very similar to older granule cells. Thus, adult-generated neurons became electrophysiologically functional in vivo and were integrated as granule cells. In the olfactory bulb, two types of neurons are generated during adulthood. Most develop into granule cells in the glomeruli, but a small percentage (5%) become interneurons in the periglomerular layers [6]. Carleton et al. [15 ] followed retrovirally labeled neuroblasts from the SVZ to the olfactory bulb. They identified five electrophysiologically distinguishable stages of neuronal maturation. Spontaneous synaptic activity was found late and spiking activity even later, after the cells had completed migration to their target. This delayed maturation might be protective to both the migrating cells and the networks into which they integrate. Very rapidly after entering the target region, the new cells express g-aminobutyric acid (GABA) and glutamate receptors and become responsive to stimuli from the olfactory nerve layer of the bulb [16 ]. Carlén et al. [17 ] infected entorhinal cortex neurons with a pseudorabies virus, which is propagated transsynaptically. They found reporter gene expression in new neurons of the dentate gyrus and in CA3, suggesting that the new granule cells became part of the synaptic network. In the olfactory bulb, olfactory stimuli evoked an upregulation of c-fos gene expression in newborn neurons, which also supports the theory of functional synaptic integration. Jessberger et al. [18 ] used activity-dependent gene regulation in the hippocampus to show that training a hippocampus-dependent learning task (Morris water maze) induced c-fos expression in newborn granule cells. Over a time scale of weeks, 80% of the new neurons matured into responsiveness to a general synaptic stimulus (systemic application of kainic acid), allowing a first glimpse at functional maturation across the entire population of new cells. In the gray zone between network and system levels lie studies that tamper with adult neurogenesis and examine the functional consequences. Such correlational evidence for a relationship between adult neurogenesis and function will increasingly come from knockout and transgenic studies. Impairment of DNA methylation, for example, leads to increased genomic instability in neural stem cells, decreased adult neurogenesis and reduced long-term potentiation (LTP) in the dentate gyrus [19]. Studies that blocked adult neurogenesis altogether went one step further. Inhibition was achieved either by the application of cytostatic drugs [20,21 ] or by local irradiation [22]. Both manipulations block cell proliferation, and thus eliminate the dividing precursor cells, from which adult neurogenesis originates. Functional relevance of adult-generated neurons In 2001, Shors et al. [20] eliminated dividing cells with a treatment of the cytostatic agent MAM (methylazomethanol acetate) and demonstrated that performance on a hippocampus-dependent learning task was disturbed, whereas a hippocampus-independent version of the same task was spared. Eye-blink conditioning was chosen as the test. Although the trace version of this task has a hippocampal component, it might not adequately represent the complexity of hippocampal function, including higher cognitive processes. In fact, the effects of MAM were not detectable or ambiguous on other hippocampal tests, including the Morris water maze [21 ]. New neurons might be particularly important for learning when trace intervals separate the associated stimulus, but the question is whether or not the more complex task would contain many disguised trace situations. Experience of environmental complexity [23] as well as more specific learning stimuli lead to an increased recruitment of new neurons from the pool of dividing progenitor cells [24]. However, the length of time it takes neurons to mature and become integrated on the network level argues against the idea that they could be of any acute use in the situation that might have triggered their generation. Thus, the time scale of the ablation experiments seems problematic: effects of disrupted neurogenesis should show up weeks after the defect, not immediately. The potential contributions of adult neurogenesis to cognition are most likely to be found in longterm adaptations rather than acute benefits. Santarelli et al. [22] addressed the hypothesis that a failure of adult hippocampal neurogenesis might (partially) underlie the pathogenesis of major depression. In general, this hypothesis has led to an important new orientation in the discussion of a potential function of adult neurogenesis: the context is even wider than learning [25 27]. Santarelli et al. directed irradiation to the hippocampus and demonstrated that the effects of antidepressants on performance on an anxiety task were dependent on the integrity of the SGZ [22]. Monje and co-workers [28], however, had shown severe irradiation effects on the stem cell niche in the SGZ. Thus, because irradiation damages both stem cells and microenvironment, including the local neuronal network, it is difficult to evaluate how much of the behavioral result was due to the blockade of neurogenesis alone. Modulating input from the limbic system (standing for the emotional context of information), for example, converges at the dentate gyrus and the integrity of this network will be altered by irradiation. The emotional modulation and tagging of information in the dentate gyrus could thus be affected. Because of this

4 Functional significance of adult neurogenesis Kempermann, Wiskott and Gage 189 modulatory input, however, the putative link between new neurons and emotional behavior is particularly interesting, because it widens the discussion beyond reductionistic learning paradigms. But the discussion of complex functional pathology, as in the case of major depression, requires an interpretation on both the network and the system levels. The available data from studies that involve damage to the SGZ show how difficult it is to directly link an experimental manipulation at the earliest developmental stages of adult neurogenesis to an outcome at the systems level. The black box in between is simply too large. Evaluation of the potential functional contributions of new neurons to the hippocampus is complicated by the fact that the function of the dentate gyrus itself is far from clear. In general, the hippocampus consolidates memory: it processes information for long-term storage in cortical areas. CA3 appears to serve as a temporary auto-associative memory in this context (see [29 31] for an overview of computational models of hippocampal function). The dentate gyrus might then encode information to make it usable by CA3. For instance, it might reduce the overlap, that is, the number of commonly active neurons, between different input patterns by generating a sparse representation. As sparse patterns have fewer active neurons in common and therefore less interference (or cross-talk), this would improve reliability of pattern storage and retrieval in CA3 [32]. The dentate gyrus receives input from many other parts of the brain, and many neurotransmitter systems have terminals in the SGZ. This input from numerous brain regions is important because part of the consolidation process involves tagging the information that is to be stored with temporo-spatial coordinates as well as emotional coloring. The emotional context dictates the priority of memorizing the information; the temporo-spatial information is the basis of episodic memory. The hippocampus not only allows storage of information, but it also makes later association possible. Classical memory formation, that is, the transfer or integration of hippocampal memory contents into the cortex, mainly seems to occur in CA1 at least in the sense of its electrophysiological equivalent, LTP. Episodic memory (such as in the one-trial association learning task developed by Day et al. [33]) is dependent on glutamate action in CA1. The finding that adult neurogenesis occurs two synaptic relay stations before this step supports the idea that neurogenesis functionally contributes to a processing step independent of the actual storage into the cortex. Suggestively, the genetically determined baseline level of adult hippocampal neurogenesis correlates with parameters describing the acquisition of a hippocampal learning task, but not the probe trial performance often taken to reflect the retention or recall of the stored information [34 ]. The contribution of new neurons to the variance in learning is relatively low, ranging between 10 and 20% in this study. Thus, there is no strict linear relationship between hippocampal learning and non-specific inducibility of adult neurogenesis, as for example by physical activity [35]. Many factors, not just new neurons, contribute to hippocampal function. Two later studies in aged rats pointed in the same direction and confirmed that a correlation between water maze performance and the total number of new neurons [36] rather than progenitor cell proliferation alone exists [37]. Within the essentially tri-synaptic network of the hippocampus, adult neurogenesis occurs at a bottleneck position. Because mossy fibers, the axons of old and new granule cells, are scarce, the addition of even a small number of neurons can make a relatively large difference. Thirty thousand new neurons would be lost among the billions of neocortical neurons, but in the mossy fiber tract, they can account for a net increase of 10%. The new gatekeepers at the gateway to memory theory builds on this key position: it seems that the mossy fiber connection has to be as sparse as possible but as strong as necessary [38]. Adult hippocampal neurogenesis would provide a means of optimizing this system to allow processing a level of information complexity and novelty frequently encountered by the individual. Adult neurogenesis decreases with increasing age, but in relative terms a much stronger induction is possible in the aged than in the young hippocampus [39]. The benefits of an adaptation of the mossy fiber system are cumulative and an investment for the future. Younger animals encounter relatively more novel experiences, whereas older animals have seen it all and need less potential for adaptation. In the olfactory bulb, olfaction plays a major role in regulating adult neurogenesis [40,41 ], but physiological activators of adult hippocampal neurogenesis, voluntary physical activity and exposure to a complex environment do not affect neurogenesis in the adult olfactory bulb [42]. Initial theoretical concepts, including a first computational model, have been developed to explain how new neurons contribute to the function of the olfactory bulb [43,44]. Conclusions Functional neurogenesis is possible in the adult brain but, ironically, we are still far from truly understanding what neuronal function means. The function of neurons is extremely complex and is revealed on different conceptual levels (cellular, network and system as a minimum distinction), thus hindering simple interpretations. Manipulations of adult neurogenesis and of a potential functional outcome occur on different time scales, making it likely that the function of new neurons is part of long-term adaptation processes rather than acute benefits.

5 190 Cognitive neuroscience Nevertheless, we already know enough to recognize adult neurogenesis as a realistic contributor to cognitive function, be it under physiological or regenerative conditions. Acknowledgements We would like to thank ML Gage for editing the manuscript. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A: Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999, 97: Seri B, Garcia-Verdugo JM, McEwen BS, Alvarez-Buylla A: Astrocytes give rise to new neurons in the adult mammalian hippocampus. 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