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European Journal of Neuroscience European Journal of Neuroscience, Vol. 33, pp. 1018–1024, 2011 doi:10.1111/j.1460-9568.2011.07599.x Seven principles in the regulation of adult neurogenesis Gerd Kempermann CRTD – Center for Regenerative Therapies Dresden, and DZNE, German Center for Neurodegenerative Diseases, Dresden, Germany Keywords: dentate gyrus, hippocampus, learning, plasticity, stem cell Abstract Seven key elements describing the regulation of adult neurogenesis are proposed. (i) A distinction must be made between regulation and ‘control’ at the transcriptional level in order to appreciate the hierarchy of regulatory factors. (ii) The regulatory hierarchy comprises conceptual levels from behaviour to genes. Consequently, ‘regulation’ of neurogenesis can be confounded by confusing rather than integrating factors, levels and concepts. The immense spectrum of neurogenic regulators reflects the sensitivity of adult neurogenesis to many different types of stimuli, and provides a means of abstraction. (iii) Age per se does not seem to play a constant role in the modulation of this process, as the dramatic ‘age-related’ changes in adult neurogenesis only take place early in life. (iv) The regulatory hierarchy at any given time-point is corresponded by the directionality and sequential interdependence of different regulatory factors in the course of development. Regulation goes from non-specific to specific, and the following steps build on regulation at the previous ones. (v) This complexity is reflected at the genetic level in that adult neurogenesis is highly heritable and highly polygenic with single factors explaining little of the variance. (vi) As regulation is additive, there is an element of selfreinforcement in the regulation of adult neurogenesis, allowing the formation of regulatory reserves for situations of functional demand. (vii) The complexity of regulation makes adult neurogenesis sensitive to pathological disturbance at various levels, suggesting that different molecular events might result in similar and shared behavioural or functional phenotypes originating in the dentate gyrus. Introduction Adult hippocampal neurogenesis attracts so much attention and interest because it has become increasingly clear that the new neurons exert critical functions in the hippocampus and help in explaining particular aspects of learning and memory (Becker & Wojtowicz, 2007; Kempermann, 2008; Appleby & Wiskott, 2009; Garthe et al., 2009; Aimone et al., 2010). Most of the roughly over 3000 publications to date found in PubMed, however, are concerned with the regulation of adult neurogenesis. One underlying assumption is that knowing about how adult neurogenesis is regulated would also provide insight into its relevance and support the idea of its functional significance (Johnson et al., 2009; Mu et al., 2010; Pathania et al., 2010). Indeed, historically, the observation that adult neurogenesis is regulated by behavioural activity was taken as the first key argument that neurogenesis is more than an atavism but directly tied to (ethologically relevant) behaviour (Gage et al., 1998). ‘Regulation’, nevertheless, is a rather elusive term, and so far there have been few attempts to systematically address what is known about the regulation of adult neurogenesis. Given the vast number of papers, one key goal for the field should be to develop integrating views on the mechanisms by which adult neurogenesis is regulated and the reciprocal relationship between regulation and function. The sheer Correspondence: Dr G. Kempermann, as above. E-mail: [email protected] Received 22 September 2010, revised 30 November 2010, accepted 14 December 2010 number of factors that seem to ‘regulate’ adult neurogenesis suggests that, if the regulation is not random, some overarching principles must exist. The present brief review highlights seven principles of how adult hippocampal neurogenesis is regulated, and attempts a conceptual view rather than reviewing, again, individual factors. In the end, a potentially unifying concept remains to be identified, but the seven principles listed here, which are by no means exclusive, underscore important aspects that need to be appreciated if the unifying theory is attempted. Principle #1: Adult neurogenesis is regulated, whereas embryonic neurogenesis is controlled The distinction between ‘regulation’ and ‘control’ might sound like a semantic issue only, and in fact the terms are often used synonymously. But if regulation is seen as a deviation from a baseline, which is maintained by an intrinsic control, the difference becomes relevant. If considering individual factors with regards to their influence on adult neurogenesis, mechanisms that maintain the baseline level of neurogenesis fall into substantially different classes than those far more numerous factors that regulate neurogenesis beyond that baseline. The latter category is essentially absent in the embryonic brain, where neurogenesis is to a much larger degree determined by genetic programs. Activity-dependent regulation is found during foetal brain development, but is obviously less influential than after birth, ª 2011 The Author. European Journal of Neuroscience ª 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd Regulation of adult neurogenesis 1019 Principle #2: Regulation of adult neurogenesis can be described at several conceptual levels, but is ultimately related to behaviour and function on one side and control on the other The argument from Principle #1 can be taken one step further. Adult neurogenesis is about plasticity, and plasticity is the reciprocal interaction between structure and function. There is no plasticity without the appropriate interaction with the outer world that provides the appropriate trigger. Brain activity and behaviour have no or little influence on the backbone process of adult neurogenesis, they rather influence quantity and quality at different stages of development by interacting with the underlying neurogenic programs. The implication of this insight is that – ultimately – all actual regulation of adult neurogenesis (as opposed to control) will be the consequence of and thus be dependent on behavioural activity or external stimuli. The individual pieces of information about regulation that we gather must always be seen within this extended context. They are positioned in a high-dimensional vector space defined by transcriptional control and behaviour. Seizures Caloric restriction Environmental enrichment Gingko LTP GH Il6 Stress Learning Exercise Opioids Ischemia Trauma The cloud of individual regulators Inflammation Nicotine Alcohol Endocannabinoids Astrocytes Neurons Acetylcholine BDNF Microglia T cells Norepinephrine GABA Serotonin Glutamate NT3 VEGF FGF2 IGF1 Notch Wnt Shh Extracellular matrix Akt1 ge netics E genetics pi Transcriptional Control Ep i when the individual begins interacting with the outer world. Many molecular mechanisms that govern embryonic brain development are also relevant for adult neurogenesis. For example, the sequence of transcription factors known from cortical development: Pax6 – Neurog2 – Tbr2 – Neurod1 – Tbr1, is also found in the neurogenic niches of the adult brain (Hodge et al., 2008; Brill et al., 2009). Signalling in the Wnt, Shh, Bmp and Notch systems similarly plays the expected important role. Disturbance in the backbone of control causes severe defects and abortive neurogenesis. Without these ‘usual suspects’ of neuronal development, no (adult) neurogenesis occurs (Lim et al., 2000; Lie et al., 2005; Breunig et al., 2008; Lugert et al., 2010), but for exactly that reason they often tell us little about the particularities of adult neurogenesis as opposed to neurogenesis in general. Many known ‘regulators’ of adult neurogenesis, in contrast, are of less relevance for embryonic brain development. Interference with them reduces neurogenesis or alters its quality, but usually does not abolish it altogether. Examples are the acetylcholinergic input to the dentate gyrus from the medial forebrain (Cooper-Kuhn et al., 2004; Mohapel et al., 2005; Cohen et al., 2008) or the serotonergic system (Brezun & Daszuta, 1999; Santarelli et al., 2003; Banasr et al., 2004; Klempin et al., 2010), hormones (Cameron & Gould, 1994; Shingo et al., 2001; Lichtenwalner et al., 2006), or endogenous psychotropic systems, like the endocannabinoids (Wolf et al., 2010) or the endorphins (Eisch et al., 2000). Knockout of the enzyme tryptophanehydroxylase 2, for example, eliminates all serotonin in the brain, but the animals have a remarkably mild developmental phenotype and can reach adulthood (Alenina et al., 2009), although serotonin plays important roles in many regulatory events. This is not to say that interfering with such factors would generally not have any phenotype in embryonic brain development (they indeed have), but the more remote the mediators are from the transcriptional level and the more their own regulation depends on brain activity and behaviour, the less dominant is the result for the overall process. The boundary between more or less extrinsic regulators and the transcription factors and other parts of the genetic machinery that execute their programmed action is obviously blurred because any extrinsic factor must ultimately act on an intrinsic system via intermediate messenger systems, and epigenetic mechanisms affect transcription of the genome as do transcription factors. But the distinction helps to see the complexity of neurogenic regulation and control, which is much more than immediately meets the eye of the observer in an altered ‘number of BrdU-positive cells’. When we study embryonic neurogenesis we are mostly interested in how the complex brain structure that we see in the adult has developed. Exploring adult neurogenesis, in contrast, means studying development under the conditions of the adult brain, in which development has otherwise largely ceased and in which neurogenesis has turned into an adaptive mechanism. This implies in other words that ‘control’ rather stands for original development, but regulation for plasticity on the basis of that development. One cannot understand adult neurogenesis without embryonic neurogenesis; but even knowing all about embryonic neurogenesis one will miss the particular complexity in the regulation of adult neurogenesis (Fig. 1). The distinctions, and thus the point of making them, have their limitations. Maintaining a homeostatic balance in a cell requires both control and regulation. But for understanding the particularities of adult neurogenesis it remains important to note that it is more than the control of neuronal development under the conditions of the adult brain. Adult neurogenesis Fig. 1. The cloud of regulation is large and not homogenous. It is helpful to conceptually distinguish between the numerous and heterogenous factors that regulate adult neurogenesis and those rather few indispensable ones that actually control it at the transcriptional level. Ways have to be identified to conceptually put regulatory events into hierarchies and systematic relationships (see also Fig. 2). Mentioned regulators are examples only – no specific relationships are implied in the figure. BDNF, brain-derived neurotrophic factor; FGF2, fibroblast growth factor 2; GABA, c-aminobutyric acid; GH, growth hormone; IGF1, insulin-like growth factor 1; IL6, interleukin 6; LTP, long-term potentiation; NT3, neurotrophin 3; VEGF, vascular endothelial growth factor. ª 2011 The Author. European Journal of Neuroscience ª 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 33, 1018–1024 1020 G. Kempermann An increasing number of studies is taking this principle into account by including one of the experimental paradigms of behavioural activity with known influence on adult neurogenesis, for example environmental enrichment and voluntary wheel running, into their study of how a particular candidate gene might affect adult neurogenesis (Feng et al., 2001; Cao et al., 2004; Corsini et al., 2009; Gobeske et al., 2009; Lugert et al., 2010). Ultimately, research on adult neurogenesis is hardly ever about the baseline, which is more or less just the transposition of the embryonic principles to the conditions of the adult brain, but about how well adult neurogenesis can perform its specific role in functionally relevant plasticity. The term regulation is so elusive, because it encompasses mechanisms from behavioural to molecular, which stand in a hierarchical relationship and form large and complex networks of interdependencies (Fig. 2). Whether one sees the genes at the top or bottom of that hierarchy matters little. Individual mechanisms of regulation might fill one or a few papers, but will always raise questions about their integration into the bigger picture. Obviously, regulation does not only occur by means of gene transcription. There are numerous posttranscriptional and post-translational regulatory events, which, however, ultimately must be programmed at the genetic level, too. The list of potential regulators of adult neurogenesis at all levels is long and continues to grow. What does it tell us, if so many different factors regulate neurogenesis and ultimately seem to have so similar consequences? It seems that adult neurogenesis is extremely sensitive to external stimuli. But this in turn might exactly be the point – the highly converging regulation, ultimately linked to behaviour, is a means of fine-tuning the plastic response provided by the new neurons. The immense width of regulatory mechanisms is a means of ‘listening to the world’. Adult neurogenesis can respond to numerous “Behavior” Nutrients Social context Energy Toxins “History/Biography” “Activity” Metabolism Motivation Perception Growth factors Spatial Learning Organism Emotions Learning Hormones Environment “Exercise” Brain Inhibition Excitation LTP Neurotrophic factors Excitation Oscillations Neurotransmitters Hippocampus Dentate gyrus Paracrine signaling Gap junctions Niche Extracellular Intracellular Matrix Posttranslational signaling Cytoplasm Modification RNAi Release pathways Glycosilation Nucleus Transcription epigenetics Phosphorylation different conditions, when these are translated into some sort of molecular signature. This only makes sense if a meaningful integration over all these various inputs can take place. Regulation of adult neurogenesis would thus be a kind of abstraction, being able to appropriately fine-tune the production of new neurons to many different situations, and the surprisingly large number of potential regulators would reflect this openness at the molecular level. Regulation in this context closes the circle of plastic responses to the world (Fig. 3). Principle #3: Adult neurogenesis is not regulated by age From the fact that many new neurons are produced in young animals and very few at old age, we have concluded that adult neurogenesis decreases with age and that age itself would be a potent, if not the most potent, negative regulator of adult neurogenesis (Kuhn et al., 1996; Kempermann et al., 1998; Ben Abdallah et al., 2010). It even seems that the ‘age-dependent decline’ has become a conceptual cornerstone of adult neurogenesis research. Generally, age would be a regulatory factor like no other, thus deserving particular highlighting. Passing of time affects all regulatory and controlling events. However, at least in rodents and humans, adult neurogenesis only decreases dramatically during a time, when – strictly speaking – it should not even be called truly ‘adult’ – childhood and adolescence (Ben Abdallah et al., 2010; Knoth et al., 2010; Fig. 4). In mice, dentate gyrus neurogenesis peaks at about postnatal day 8, and in terms of the processual characteristics transforms to ‘adult neurogenesis’ at about postnatal day 15. A mouse is ‘adult’ by many definitions not earlier than at least a week later. At 3 months, when the mouse is ‘adult’ by most standards, neurogenesis is already very low compared with postnatal levels, but hippocampal neurogenesis remains at a very low level for the remaining time of life. The one existing estimate for humans, even though only based on the number of doublecortinexpressing cells as surrogate measure, shows a very similar pattern (Knoth et al., 2010). The characteristic early decline is often taken as evidence that adult neurogenesis is ‘regulated’ by age, but for the most part of life no such ‘regulation’ exists. The data rather suggest that in rodents and primates beyond childhood or young adulthood levels of adult neurogenesis are generally quite invariant to age. The early steep loss in precursor cell proliferation and, hence, the potential for neurogenesis can be counteracted by, for example, physical activity (Kronenberg et al., 2006). Activity early in life could thus translate to a greater potential for plasticity in old age by maintaining the baseline at a higher level or at least postponing the decline. Experiencing old age as a chance for novel learning experiences might depend on preventive measures at a much younger age. If that window of early opportunities has been missed, the curve of possible changes in neurogenesis remains rather flat for the remaining time of life. This would be different if age was a regulator of neurogenesis with a linear effect across the lifespan. Splicing Modulates/alters Fig. 2. Regulation is hierarchical. Regulation occurs at numerous levels, from behaviour in a social context down to the genes. Although ultimately all regulation must somehow relate to genetic code, there are numerous posttranscriptional and post-translational regulatory events that contribute to the net effect. Many ‘regulators’ affect several hierarchical levels (e.g. neurotransmitters). The hierarchies thus structure the ‘cloud’ of Fig. 1, but they are deceiving because the structure of the ‘regulatory space’ is far more complex than simply layered. Still, even if details are difficult to grasp, regulation is hierarchical and must be conceptualized as such in order to allow deeper conclusions about ‘regulation’ and ‘control’. LTP, long-term potentiation. Experience of the environment; learning Stimulates/ finetunes Behavior in the environment Improves/ changes Stimulates Adult neurogenesis Optimizes Adapted hippocampal function Fig. 3. Plasticity means a feedback loop between structure and function, mediated by regulation. ª 2011 The Author. European Journal of Neuroscience ª 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 33, 1018–1024 250 000 Human 1000 900 800 700 600 500 400 300 200 100 0 200 000 150 000 Mouse 6 weeks 9 months 12 months 24 months 100 000 50 000 0 10 20 30 40 50 60 70 80 90 100 Years Fig. 4. Adult neurogenesis is not regulated by age. For most of the lifespan adult neurogenesis is at a rather constant, very low level. Very high levels of ‘adult’ neurogenesis are found at times, when the individual is not yet truly adult. The numbers in the figure reflect doublecortin (DCX)-expressing cells per section area of the human hippocampus, obtained from 54 post mortem samples and replotted here from Knoth et al. (2010). Doublecortin expression is only a rough proxy of ‘neurogenesis’, but can be addressed in humans. Inset – a similar picture can be drawn for rodents (McDonald & Wojtowicz, 2005; Kronenberg et al., 2006; Ben Abdallah et al., 2010). In many cases, the slope of the decline is even steeper than shown in this example. The rodent data are reprinted from Kronenberg et al., ‘Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus’, Neurobiology of Aging, Vol. 27, pp. 1505–1513, Copyright 2006, with permission from Elsevier. Principle #4: Regulation of adult neurogenesis at multiple stages of development is additive and later stages are dependent on previous ones Historically, the term ‘neurogenesis’ stood essentially for the proliferation of those precursor cells during embryonic brain development, whose progeny would become neurons (e.g. Altman, 1969). This restricted use was not exclusive, but became implicit in many statements about the generation of new neurons in the adult brain. Several studies only measured precursor cell proliferation, and equalled this measurement with the generation of new neurons. For the reasons stated in Principles #1 and #2, however, this would only make sense if precursor cell proliferation would indeed be strictly indicative of the net result at the level of functionally integrated new neurons. But this is not the case (Kempermann et al., 1997, 2006). During infancy of the field of adult neurogenesis research in the 1990s, it still seemed unorthodox to consider ‘neurogenesis’ as a process and not as an event. But the generation of neurons cannot be reasonably subsumed under single stages of that process that do not faithfully represent the end result. The processual nature of adult neurogenesis has the consequence that net regulation depends on influences at many different stages of neuronal development. Three are covered in most reports on adult neurogenesis: precursor cell proliferation; survival of newborn cells; and phenotypic differentiation; but numerous others have been identified. These stages are not independent of each other. Development is essentially unidirectional, and later stages build upon preceding ones. Cells that have not been generated in the first place cannot undergo modifications in maturation, migration, dendritic arborization, integration, etc., but those cells that have been produced can become subject to a large number of potential regulatory stimuli. Consequently, the individual impact of regulation and the latest stages of development will be quantitatively small but highly specific. Regulation at the beginning at early stages, most notably precursor cell proliferation, will be less specific. With each potentially regulatable step the framework for the regulation of the following stages shifts and the conditions change. Presumably, fewer factors affect the latest, most specific stages than the non-specific early ones (Fig. 5). The directionality and sequential dependence of regulatory events in the course of neurogenesis substantially complicate models and theories of how adult neurogenesis is regulated, but lie at the heart of the entire process. Voluntary wheel running prominently induces precursor cell proliferation, which in very acute settings does not lead to an increase in net neurogenesis (Steiner et al., 2008). Continued exercise lets the pro-proliferative response wear off, but now a second effect sets in – neurogenesis at later stages continues to rise, even when proliferation has already returned to baseline (Kronenberg et al., 2003; Snyder et al., 2009). A pro-survival stimulus (e.g. by exposure to an enriched environment) settled upon the running-induced proliferation increases this secondary effect of running on later stages of neuronal development (Fabel et al., 2009). The effects become additive. This implies that, although proliferation is not a good predictor of net neurogenesis, a greater potential for neurogenesis due to increased precursor cell proliferation enhances the response to a stimulus that affects primarily later stages. Principle #5: Adult neurogenesis is a quantitative, polygenic trait The consequence of Principle #4 is that there is no master switch and no ‘neurogenesis’ gene, whose manipulation would suffice to regulate (and control) adult neurogenesis. In genome-wide mapping studies, individual gene loci explain very little variance, although the overall heritability is fairly high (at least in the genetic reference populations chosen; Kempermann et al., 2006; Poon et al., 2010). Single gene studies, which obviously remain necessary to study potential contributions of individual factors, tend to obscure this fact and might lead to paradoxical results. Several studies have, for example, shown that interfering with different individual candidate signalling pathways could abrogate the exercise-induced increase in Number of possible regulators Number of DCX-positive cells per area dentate gyrus [mm2] Regulation of adult neurogenesis 1021 Maintenance Proliferation/ expansion Differentiation/ fate choice Migration Maturation Cell cycle exit Survival Integration Neuritogenesis Fig. 5. Preceding regulatory events limit the range of possible following steps. In the course of neuronal development, the influence of regulatory events at later stages is limited by the range of options left by decisions at previous stages. Overall, the width of regulation decreases. Regulation at later stages builds upon the foundation laid at earlier stages. ª 2011 The Author. European Journal of Neuroscience ª 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 33, 1018–1024 1022 G. Kempermann precursor cell proliferation and neurogenesis [vascular endothelial growth factor (VEGF; Fabel et al., 2003), insulin-like growth factor (IGF)1 (Trejo et al., 2001), Akt1 (Bruel-Jungerman et al., 2009), bone morphogenic proteins (BMPs) (Gobeske et al., 2009), cannabinoid receptor 1 (Wolf et al., 2010), etc.]. At face value, some of these results seem mutually exclusive – if VEGF is blocked, IGF1 should be sufficient to do the job. This particular paradox has not been formally resolved. The solution might lie in the combination of the poor resolution of our experiments with respect to measuring adult neurogenesis and the complexity of the regulation. In the above example, Akt1 would lie downstream of both VEGF and IGF1, linking both pathways but without any guarantee that either factor might not also affect additional, independent pathways (BruelJungerman et al., 2009). Intracellular regulatory pathways form complicated networks of direct and indirect interactions, which – as outlined above – change with time. Their convergence on the control mechanisms of adult neurogenesis might themselves be subject to modulation in some sort of ‘meta-regulation’. In principle, the laws of these interaction networks should be understandable and a higherorder description of ‘regulation’ be possible. The natural balance in these systems or networks can be disturbed at different levels, provoking compensatory changes at others. The same applies to the sequence of events in the course of adult neurogenesis. This leads to testable hypotheses: how does, for example, precursor cell proliferation respond, when survival is affected? At a more mechanistic level, such analyses will become considerably more complicated due to the hierarchical and combinatorial influence of diverse regulators. For example, how do the effects of regulatory key factors like brain-derived neurotrophic factor on precursor cells and their progeny change when there is more serotonin around or when the Wnt pathway is dampened? No single regulator is independent. One can obviously push this argument to triviality. Systems biology, as the scientific answer to such complexity is called, has sometimes a questionable reputation because complexity per se is no answer to the question of regulation (Wolkenhauer & Ullah, 2007). Science is, after all, the art of complexity reduction. But the issue is, how far this reduction needs to be taken. Here the answer is that very reductionistic experiments will miss key components and might generate contradictory results. So, while the full complexity might be impossible to capture and understand, more integration is needed than can ultimately be provided by summing up individual single-gene studies. Principle #6: Regulation of adult neurogenesis is selfreinforcing The observation that regulation of adult neurogenesis can be additive suggests that if neurogenesis continues to be regulated over time further regulation will be facilitated. The entire activity-dependent regulatory mechanism obeys a use-it-or-lose-it rule. In other words, it is plastic itself. At this point, age comes back into the equation, but not as a negative regulator, rather as an opportunity. Older animals that have experienced a lot would have retained more responsive neurogenic machinery in the adult hippocampus but would actually require less regulation, because the network adaptation that can be achieved by adult neurogenesis is cumulative. The ‘neurogenic reserve’ provided by a maintained precursor cell pool in the aging hippocampus (Kempermann, 2008) must have a correspondent at the level of regulation – there must be a regulatory reserve as well. The concept of plasticity implies a feedback loop, which in this case includes adult neurogenesis and its regulation (Fig. 3; For an updated discussion of the neurogenic reserve hypothesis, see Kempermann et al., 2010). Principle #7: Regulation of adult neurogenesis can fail in complex ways If embryonic development fails, severe malformations with broad functional implications (or even death) are the consequences. If only ‘adult’ neurogenesis fails, this results in a deficit in cellular plasticity in one single neuronal network and will impair the function of the hippocampus. The dentate gyrus still retains its usual form, and in most cases its general network structure; it might be smaller, but given the immense natural variation in dentate gyrus size this will be difficult to assess in individuals. Other defects might be more qualitative in nature, not changing cell numbers and gross regulation at all, but resulting in problematic connectivity. If the current ideas about the functional relevance of adult-born neurons hold, the functional consequences of adult neurogenesis are specific and precisely defined. Consequently, a great number of misregulations might ultimately result in very similar functional phenotypes at the level of the dentate gyrus. This is thus, in other words, the pathological flip side of Principle #2. If the functional contribution of adult neurogenesis is indeed as fundamental as we assume and the broad spectrum of potential regulators reflects the sensitivity of the system, a great number of pathological events interfere with neurogenesis-based cognitive and affective function; regulatory sensitivity has its price. Concluding remarks – the eighth principle The number of principles – seven – was chosen deliberately. The list is not meant to be – and cannot be – exhaustive, but the choice of just seven principles was also not far-fetched and the scope of the mentioned ideas covers substantial ground. But one final principle that has been shining through this text and somehow cuts across the others needs to be mentioned again. In the end, all regulation of adult neurogenesis has to be seen in its relation to function. At diverse points of this article we have alluded to this fact. Regulation of adult neurogenesis occurs to achieve, maintain, modify or improve the function of: (i) the new neurons; (ii) the dentate gyrus; (iii) the hippocampus; (iv) the brain; and (v) the individual (and the list is not complete). There is a seamless transition from the function of the cell to the behaviour of the individual. Function is thus something like the overarching eighth (or thus – first) principle. But as little as regulation can be captured in one simple concept, function is something generic. Adult neurogenesis satisfies very specific functional needs. Adult neurogenesis is the solution that evolution found to solve a particular functional challenge, which we have not yet fully understood. We will not extend this question here, but one day in the not so far future a review article ‘Seven principles in the function of adult hippocampal neurogenesis’ should be possible. It is safe to predict that a principle referring to the complex and activity-dependent regulation of adult neurogenesis will be part of such an overview. Abbreviations IGF1, insulin-like growth factor 1; VEGF, vascular endothelial growth factor. References Aimone, J.B., Deng, W. & Gage, F.H. (2010) Adult neurogenesis: integrating theories and separating functions. Trends. Cogn. Sci., 14, 325–337. Alenina, N., Kikic, D., Todiras, M., Mosienko, V., Qadri, F., Plehm, R., Boye, P., Vilianovitch, L., Sohr, R., Tenner, K., Hortnagl, H. & Bader, M. (2009) Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc. Natl Acad. Sci. 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