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Environmental enrichment and neurogenesis: from mice to humans
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ScienceDirect Environmental enrichment and neurogenesis: from mice to humans Gregory D Clemenson1, Wei Deng2 and Fred H Gage2 The brain is a dynamic structure that constantly undergoes cellular and molecular changes in response to the environment. Ultimately, these experience-dependent changes modify and shape behavior. One example of this neuroplasticity is the robust and continuous generation of new neurons that occurs in the dentate gyrus (DG) of the hippocampus. These new neurons are thought to play a fundamental role in hippocampus-dependent behavior and are modulated by experience and changes in the environment. In this review, we will focus on the cognitive and molecular relationship between environmental enrichment and adult neurogenesis. In addition, we discuss some of the similarities between the human and animal literature in regards to neurogenesis, hippocampusdependent behavior, and environmental enrichment. Addresses 1 Center for the Neurobiology of Learning and Memory and Department of Neurobiology and Behavior, University of California, Irvine, United States 2 The Salk Institute for Biological Sciences, United States Corresponding author: Gage, Fred H ([email protected])
Current Opinion in Behavioral Sciences 2015, 4:56–62 This review comes from a themed issue on Cognitive enhancement Edited by Barbara Sahakian and Arthur Kramer
http://dx.doi.org/10.1016/j.cobeha.2015.02.005 2352-1546/# 2015 Published by Elsevier Ltd.
Environmental enrichment and the influence on neurogenesis The term enriched environment (EE) is often used to describe an environmental manipulation administered to rodents. EE is often characterized as a large environment with toys, tunnels, bedding and running wheels and designed to provide social, physical and sensory stimulation. Often times, the environments are periodically rearranged and new toys and objects are introduced to keep the environment novel. It is well established that EE modulates hippocampal neurogenesis and behavior, resulting in an increase in newborn neurons and enhanced hippocampus-dependent cognition [1]. One of the first reports demonstrated these pro-neurogenic effects of EE by simply allowing mice to live in an EE for 40 days. There was a significant increase in the number of Current Opinion in Behavioral Sciences 2015, 4:56–62
hippocampal granule cells and these mice showed a marked improvement in learning the Morris water maze (MWM) compared to mice in standard housing [2].
EE factors that interact with neurogenesis It is important to remember that there is no standardization of EE with regard to procedure and methodology. Studies vary drastically in terms of environment size, stimulation used (various tunnels and toys), with or without running wheels, as well as BrdU injection paradigms and timing of EE exposures. Despite these differences, we address several key factors that influence neurogenesis. Exercise is often studied independently of EE and for the purposes of this review, we will attempt to highlight influences specifically of EE without a running wheel and refer to these as ‘EE-only’. Due to the complexity of EE, there are many components, including social, sensory, spatial and physical stimulation that may contribute to the observed effects. The physical stimulation of EE provided by access to running wheels has been singled out as a robust regulator of neurogenesis. Exposure to a running wheel led to not only increased hippocampal neurogenesis but also improved spatial learning in the MWM and enhanced DG long-term potentiation (LTP) in mice [3,4–6]. A wealth of information exists on the positive effects of exercise and running [7,8]. In addition to numerous effects of exercise, independent of neurogenesis, wheel running has been shown to significantly influence hippocampus dependent cognition, synaptic plasticity, spine density, neurotransmitter release, and even angiogenesis in the hippocampus of the brain. While physical exercise has been shown repeatedly to play a crucial role in EE, the impact of the complexity and exploration of the EE cage itself on neurogenesis and cognition should not be underestimated. Despite variable results when using EE-only without a running wheel [5,6], a number of studies have shown that EE-only is capable of inducing neurogenesis [3,9,10,11,12,13,14]. Acute exposure (24 hours) to either EE-only or running wheel suggested that these two manipulations may influence different proliferative populations of granule cells [10]. One hour prior to the 24-hour exposure, animals received one injection of BrdU. Immediately following the initial start of the EE-only and exercise (running wheel) manipulation, there was no difference in BrdU+ cells between any of the groups. Upon completion of the 24-hour exposure, however, both EE-only and exercise www.sciencedirect.com
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groups showed a significant increase in absolute BrdU+ cells and BrdU+/Nestin-GFP+/Prox1+ (type-2b) cells when compared to controls. Interestingly, exercise animals showed a specific increase in the number of BrdU+/ Nestin-GFP+/Prox1 (type-2a) cells and EE-only animals showed a specific increase in the number of BrdU+/nesting-GFP /Prox1+ (type-3) cells. Despite the short exposure to EE-only and exercise, these results suggest a differential influence on hippocampal neurogenesis. Exercise increases proliferation in early type-2a progenitor cells whereas EE-only may exert a more specific influence on postmitotic type-3 cells. In addition to neurogenesis, animals exposed to EE-only show increased expression of the neurotrophic factor, nerve growth factor (NGF), and enhanced synaptogenesis [13,15]. Cognitively, animals exposed to EE-only showed improvements in spatial memory (object displacement task), working memory (T-maze), recognition memory (novel object recognition), and contextual fear memory [13,14]. These studies illustrate the molecular and behavioral changes associated with EE-only in mice. Many of these enhancements observed with EE-only may be attributed to the exploration of these intricate environments. Mice living in a large, multi-tiered enriched environment (no running wheel) for 3 months were tagged with radio-frequency identification transponders and their movements were monitored for the duration of their time in the EE [12]. Using ‘roaming entropy’ as a measure of explorative behavior, mice with higher roaming entropy correlated with more neurogenesis. Interestingly, although the mice are expected to have higher levels of physical exercise in a larger EE, the total locomotion of individual mice did not correlate with neurogenesis. This study highlighted the range of exploratory behavior in mice and, in light of its results, it is important to keep in mind that there are individual differences in the animals, and their individual experiences within the EE may vary drastically. Although we discuss slight individual differences between exercise and EE-only, it is important to remember that EE and exercise work together and the majority of EE studies use environments with running wheels inside. When exposed to EE, physical activity can increase simply because more space is provided to the animal, regardless of whether a running wheel is present or not. To demonstrate the effects of EE and exercise together, one study showed that both manipulations together could enhance neurogenesis beyond both EE alone and exercise alone [11]. By pre-exercising animals for 10 days and exposing these animals to EE afterwards for 30 days, they saw a 30% increase in new neurons compared to all other groups. Supporting the notion that physical activity has a greater effect on cell proliferation and EE influences survival [2,3,9,16], the authors suggest that exercise www.sciencedirect.com
can ‘prime’ the neurogenic niche for cognitive stimulation, such as EE. Another influential factor of EE is the timing of EE exposure. More specifically, the age of the newborn neuron during EE exposure may be critical to the morphological and behavioral changes observed in these animals. Newborn neurons in the DG undergo a prolonged maturation process characteristic of an early period of hyperexcitability [17–20]. Interestingly, the effects of EE are most prominent when newborn neurons are 2 weeks old [21]. Multiple groups of animals received BrdU injections to label a newborn population of neurons. Each group of animals received 1 week of EE exposure but over different 1-week periods of maturation. The first group received the 1-week EE exposure immediately after BrdU injection; the second group received the 1-week EE exposure 1 week after BrdU injection, and so on. Although there were observable increases in neurogenesis when EE was presented within the first 3 weeks of neuronal birth, there was no difference in neurogenesis levels when 4-week-old neurons were exposed to EE. In addition, BrdU-labeled newborn neurons that experienced the EE during their second week responded greatest, as determined by co-expression of the immediate early gene c-fos, when re-exposed to the same EE 6 weeks after birth. This activation by the newborn neurons upon re-exposure to the same EE but not a different environmental exposure, suggest that they functional integrate into the existing DG circuitry, encoding information specifically about the previously seen EE. Together, these results highlight the sensitivity of newborn neurons to timing of EE exposure. In addition to timing of EE exposure, the overall age of the animal has a dramatic effect on hippocampal neurogenesis and cognition. Aging in animals is known to have a strong negative impact on hippocampal neurogenesis and cognition [22]; however, EE can reverse many of these deficits. Exposing aged mice to EE over a period of 10 months resulted in an almost 5-fold increase in the number of surviving newborn neurons [16]. This increase was also associated with enhanced spatial acquisition of the MWM. In a more recent study, aged rats underwent a 10-week EE exposure [23]. Spatial learning on the MWM and spatial memory during a 60-s probe trial were significantly improved in aged rats exposed to EE. Exposing aged rats to EE also resulted in an increase in the total number of new neurons, despite having no effect on neuronal differentiation. The age of the animals, along with the other factors of EE experiments, have not been standardized in previous EE studies, often resulting in variability when interpreting the effects of EE on neurogenesis.
Molecular mechanism for EE The molecular mechanisms for EE-induced hippocampal neurogenesis were studied with genomic approaches. Gene expression alteration caused by EE were explored Current Opinion in Behavioral Sciences 2015, 4:56–62
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using microarrays and other genomic methods [24,25,26]. Genes involved in neuronal activity and synaptic plasticity were induced by both short-term and long-term EE treatment; the exact sets of genes altered had little overlap, probably due to the gradual adaptation of the neuronal function to EE. Moreover, the effects of EE on gene expression were not evenly distributed across different brain regions, with the hippocampus being more influenced by EE [27]. EE-induced changes in noncoding genes such as miRNA have also been studied [28]. Despite such progress, how these changes in gene expression are related to the enhanced neurogenesis remains to be further investigated. In contrast to these genome-wide studies, several candidate genes have been well characterized for their role in EE-induced and exercise-induced neurogenesis. We will discuss two molecules — BDNF and VEGF — in detail. Both EE exposure and voluntary exercise can induce the expression of BDNF [29–30,31,32], a neurotrophin that supports survival, differentiation and neurite growth in existing neurons. BDNF and its receptor, TrkB, play important roles in adult hippocampal neurogenesis. Direct infusion of BDNF into the hippocampus resulted in an increase in neurogenesis [33]. On the other hand, disruption of BDNF–TrkB signaling by selective knockout of TrkB in adult neural progenitor cells (NPCs) led to decreased survival of newborn neurons at the immatureto-mature neuronal transition [34]. In addition, TrkBnull newborn neurons were defective in dendritic growth and synapse formation, consistent with the role of BDNF– TrkB pathway in neuronal differentiation. In another study, Li and colleagues reported that TrkB had a cell autonomous role in NPC proliferation in the hippocampus [35]. Furthermore, compared to that seen in wildtype control mice, the enhanced neurogenesis by EE was not observed in heterozygous knockout mice for BDNF (BDNF +/ ) [31]. Similarly, the running-induced increase in NPC proliferation was compromised in mice with TrkB deleted in the NPCs [35]. These findings suggest that BDNF–TrkB signaling plays important roles in both NPC proliferation and newborn neuron survival during adult neurogenesis and is a key mediator for EE-induced enhancement of neurogenesis. Another molecule whose expression is induced by EE is VEGF [36,37], a growth factor associated with vasculogenesis and angiogenesis. The dividing NSCs were found clustered at the tips of capillaries [38], suggesting that factors related to vasculature may affect neurogenesis. The role of VEGF in mediating EE-induced neurogenesis has been studied extensively. First, exogenous VEGF can effectively increase neurogenesis, bypassing the EE [36]. In addition, infusion of VEGF antagonists or down-regulation of VEGF by RNA interference blocked the EE-induced neurogenesis [36,39]. Similarly, administration of soluble Flt1, an antagonist for VEGF, Current Opinion in Behavioral Sciences 2015, 4:56–62
prevented the running-induced NPC proliferation [40]. Thus, VEGF is an important factor for mediating enhanced neurogenesis by EE and voluntary exercise.
EE and neurogenesis, a causal link Beneficial cognitive effects of EE exposure are well documented, but whether these behavioral effects are a direct result of EE-induced neurogenesis is still unclear. Here we present the few studies that have addressed the specific influence of EE-induced neurogenesis on hippocampus behavior. To address this question, a number of techniques have been used to target neurogenesis in the DG and a variety of behavioral measures. Eliminating neurogenesis systemically with the antimitotic agent methylazomethanol acetate (MAM) has produced mixed results. In some cases, MAM treatment of rats during EE impaired performance in object recognition memory and a trace fear conditioning paradigm, but not contextual fear conditioning or spatial navigation learning in the MWM [41,42]. Similarly, although focal irradiation almost completely ablated hippocampal neurogenesis in the DG of EE-exposed mice, it did not hinder the irradiated EE mice in their enhanced ability to learn the MWM [43], suggesting that the behavioral effects of EE are independent of neurogenesis. Although these studies focus on hippocampus-dependent behaviors, the relationship between EE and neurogenesis may be more pronounced with behaviors associated with the DG such as pattern separation [20,44–48]. Behaviorally, pattern separation is thought to be a critical component of episodic memory, allowing the encoding of similar experiences as distinct events, without interference [49,50]. A number of studies have been performed to demonstrate the involvement of the DG in pattern separation. Lesion of the DG (but not CA1) in rats specifically interfered with spatial pattern separation when choosing between two similar spatial locations [44]. Specifically knocking out NMDA receptors in the DG impaired the animals’ ability to distinguish between two similar contexts, but not traditional contextual fear conditioning [45]. Knocking out DG neurogenesis through irradiation and a lentiviral method impaired animals ability to pattern separation in a radial arm maze and an object-in-place touch screen task [47]. In vivo recordings of rats show that although both DG and CA3 can perform pattern separation functions, the DG is especially sensitive to small changes in the environment [46]. Only a handful of studies have observed the influence of EE and neurogenesis on pattern separation, however, increasing neurogenesis through EE is capable of enhancing pattern separation in mice. Mice were presented with a touch-screen task where they were taught to distinguish between spatially similar objects. In both young and aged mice, exercise, one of the key components of EE, enhanced their ability to recognize spatially www.sciencedirect.com
Environmental enrichment and neurogenesis Clemenson, Deng and Gage 59
similar objects, indicating an enhancement in pattern separation [51]. In addition, discriminating between two closely related contextual fear conditioning environments with extremely short exposures was known to be extremely difficult for rodents [52]. Without sufficient time to explore the context, animals were unable to associate shock and context. Interestingly, despite an increase in neurogenesis and successful discrimination between two different contexts, running animals were unable to perform this task whereas animals exposed to EE-only discriminated between two similar contexts (Figure 1). Exposure to an EE not only allowed mice to successfully discriminate in this difficult task, but ablating neurogenesis through focal irradiation also inhibited their performance, suggesting that newborn neurons induced through EE may contribute to environmentspecific behavior [14]. While these presented studies attempt to unravel the link between EE-induced neurogenesis and behavior, more work is needed to confirm and further understand the role of these newborn neurons.
a number of similarities that exist between rodents and humans in the literature (see Table 1). First, there is strong evidence to suggest that hippocampal neurogenesis occurs in humans. Postmortem tissue from terminal skin cancer patients who were treated with BrdU before death, displayed labeled BrdU cells in the DG of the hippocampus [53]. NPCs have even been discovered in the human hippocampus using proton nuclear magnetic resonance spectroscopy and a metabolic biomarker, as well as a novel carbon-dating technique [54,55]. Second, angiogenesis is closely linked to hippocampal neurogenesis [38] and exercise-induced neurogenesis is correlated with increases in cerebral blood volume (CBV) in mice [56]. Human participants that completed a 3-month aerobic exercise program displayed increases in DG CBV over the 3-month period, correlating with maximum volume of oxygen consumption (VO2max), a measure of aerobic fitness [56].
EE in humans Understanding the relationship between EE and neurogenesis in animals is already difficult, so an attempt to address EE in humans is highly ambitious. With regards to environmental enrichment, the most straightforward disparity is that standard laboratory rodents live in a small cage and the general human population already lives in what most would consider an ‘enriched environment.’ In addition to the obvious differences between humans and rodents, the tools available for us to learn about the mechanisms and underlying cellular processes of the human brain are limited compared to those we can use with the laboratory rodent. For example, fMRI allows us to compare brain regions active during behavior, but it is difficult to interpret the data because it is an indirect quantitative measure of blood flow changes in the brain, which is thought to correlate with neuronal activity. Despite these technical challenges, however, there are
Third, humans exhibit pattern separation-like behaviors similar to mice. In a behavioral task designed to test pattern separation, participants were presented with pictures of everyday objects and, during a testing phase, had to determine if previously viewed objects were ‘old’, ‘similar,’ or ‘new.’ fMRI revealed activation of the DG/CA3 region only when participants recognized ‘similar’ objects and not ‘old’ or ‘new’ [57]. In addition, this pattern separation ability declines in healthy human aging [58] similar to mice [51]. Finally, and perhaps most relevant to EE, the exploration and navigation of real and virtual environments correlate with increases in hippocampal volume, hippocampal activity, and even the firing of place-like and grid-like cells. Hippocampal gray matter was found to be significantly larger in licensed London taxi drivers when compared to
Figure 1
Enrichment
Neurogenesis
Contextual Discrimination
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Schematic outlining the effects of enrichment on neurogenesis and contextual discrimination. www.sciencedirect.com
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Table 1 Similarities between animal and human studies presented in this review, in regards to environmental enrichment and neurogenesis.
Neurogenesis – evidence for the presence of neurogenesis Kempermann et al. [2·] VanPraag et al. [1,3·]
Eriksson et al. [53·] Manganas et al. [54] Spalding et al. [55]
Palmer et al. [38] Pereira et al. [56·]
Pereira et al. [56·]
Clelland et al. [47] Creer et al. [51·] Clemenson et al. [14·]
Bakker et al. [57·] Stark et al. [58]
Freund et al. [12·]
Maguire et al. [59,61] Woollett and Maguire [60·]
Harvey et al. [62] Schmidt-Hieber and Hausser [63]
Ekstrom et al. [64·] Jacobs et al. [65·]
Angiogenesis – presence and increase of vasculature with neurogenesis
Pattern separation – behavior dependent on the dentate gyrus
Spatial navigation / exploration – hippocampal involvement in the spatial navigation and exploration of environments Place cells – presence in the hippocampus during the navigation of a virtual environment
control subjects [59]. As un-licensed taxi drivers trained to become licensed taxi cab drivers, there was a selective increase in hippocampal gray matter [60]. The increase in hippocampal volume by London taxi drivers was correlated with a spatial navigation expertise and memory of the city of London. Similar to real world environments, the hippocampus also activates during the exploration and navigation of virtual environments in humans and animals alike [61–63]. Both place-like and grid-like cells have even been observed in humans during a virtual-navigation task, using single-neuron recordings from electrodes surgically implanted in patients undergoing treatment for epilepsy [64,65]. In the same way that exploration of a novel environment is correlated with neurogenesis in mice [12], the spatial exploration and navigation of real and virtual environments correlate with structural and functional changes in the hippocampus of humans.
hippocampus-dependent behaviors like spatial navigation activate the hippocampus and that continuous exposure to large complex city environments can increase hippocampal volume (similar to long EE exposures in mice). In the same way that rodents use place and grid cells to explore their environment, evidence exists to suggest the presence of these same cell types in the human hippocampus. In addition, although we cannot visualize neurogenesis in humans, DG-specific processes like pattern separation are not only observable in humans but they also activate similar regions of the brain and are influenced by the same environmental factors. Knowing that these similarities exist in basic hippocampus-dependent processes may one day lead us to a way to enrich our own lives and enhance performance on hippocampal behaviors.
Conflict of interest Despite the plethora of differences between humans and the standard laboratory rodent, it is amazing to see that Current Opinion in Behavioral Sciences 2015, 4:56–62
The authors declare that they have no competing financial interests. www.sciencedirect.com
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neurotrophic factor gene induced by an enriched environment. Hippocampus 2011, 21:127-132. 33. Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S: Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol 2005, 192:348-356. 34. Bergami M, Rimondini R, Santi S, Blum R, Gotz M, Canossa M: Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxietylike behavior. Proc Natl Acad Sci U S A 2008, 105:15570-15575. 35. Li Y, Luikart BW, Birnbaum S, Chen J, Kwon CH et al.: TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 2008, 59:399-412. 36. Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM et al.: VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 2004, 36:827-835. This study highlights VEGF as a regulator of neurogenesis and environmental enrichment may work through VEGF. 37. Van der Borght K, Kobor-Nyakas DE, Klauke K, Eggen BJ, Nyakas C et al.: Physical exercise leads to rapid adaptations in hippocampal vasculature: temporal dynamics and relationship to cell proliferation and neurogenesis. Hippocampus 2009, 19:928-936. 38. Palmer TD, Willhoite AR, Gage FH: Vascular niche for adult hippocampal neurogenesis. J Compar Neurol 2000, 425:479-494. 39. Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA: Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A 2002, 99:11946-11950. 40. Fabel K, Fabel K, Tam B, Kaufer D, Baiker A et al.: VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci 2003, 18:2803-2812. 41. Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E: Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 2002, 12:578-584. 42. Bruel-Jungerman E, Laroche S, Rampon C: New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur J Neurosci 2005, 21:513-521. 43. Meshi D, Drew MR, Saxe M, Ansorge MS, David D, Santarelli L, Malapani C, Moore H, Hen R: Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nat Neurosci 2006, 9:729-731. 44. Gilbert PE, Kesner RP, Lee I: Dissociating hippocampal subregions: double dissociation between dentate gyrus and CA1. Hippocampus 2001, 11:626-636. 45. McHugh TJ, Jones MW, Quinn JJ, Balthasar N, Coppari R, Elmquist JK, Lowell BB, Fanselow MS, Wilson MA, Tonegawa S: Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 2007, 317:94-99. 46. Leutgeb JK, Leutgeb S, Moser MB, Moser EI: Pattern separation in the dentate gyrus and CA3 of the hippocampus. Science 2007, 315:961-966. 47. Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ: A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 2009, 325:210-213. 48. Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, Hen R: Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 2011, 472:466-470. 49. Sayah A, Wilson DA, Hen R: Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 2011, 70:582-588.
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50. Yassa MA, Stark CE: Pattern separation in the hippocampus. Trends Neurosci 2011, 34:515-525. A thorough review on pattern separation in both rodents and humans, from theoretical work to electrophysiology. 51. Creer DJ, Romberg C, Saksida LM, van Praag H, Bussey TJ: Running enhances spatial pattern separation in mice. Proc Natl Acad Sci U S A 2010, 107:2367-2372. A recent follow up study from the same lab showing that exercise can increase pattern separation. 52. Fanselow MS: Conditioned fear-induced opiate analgesia: a competing motivational state theory of stress analgesia. Ann NY Acad Sci 1986, 467:40-54. 53. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH: Neurogenesis in the adult human hippocampus. Nat Med 1998, 4:1313-1317. This study presented the first evidence that dividing cells are present in the dentate gyrus of humans. 54. Manganas LN, Zhang X, Li Y, Hazel RD, Smith SD, Wagshul ME: Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 2007, 318:980-985. 55. Spalding KL, Bergmann P, Alkass K, Bernard S, Salehpour M, Huttner HB, Bostrom E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, Frisen J: Dynamics of hippocampal neurogenesis in adult humans. Cell 2013, 153:1219-1227. 56. Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, Sloan R, Gage FH, Brown TR, Small SA: An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A 2007, 104:5638-5643. This study provided a novel side by side comparison of angiogenesis and cerebral blood volume in both mice and humans. 57. Bakker A, Kirwan CB, Miller M, Stark CE: Pattern separation in the human hippocampal CA3 and dentate gyrus. Science 2008, 319:1640-1642. This study presented human evidence that behavioral pattern separation correlated specifically with activity in the DG/CA3 of the brain. 58. Stark SM, Yassa MA, Lacy JW, Stark CE: A task to assess behavioral pattern separation (BPS) in humans: data from healthy aging and mild cognitive impairment. Neuropsychologia 2013, 51:2442-2449. 59. Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RS, Frith CD: Proc Natl Acad Sci U S A2000, 97:4398-4403. 60. Woollett K, Maguire EA: Acquiring ‘‘the Knowledge’’ of London’s layout drives structural brain changes. Curr Biol 2011, 21:2109-2114. This study was a follow up to the ‘London taxi driver’ study showing that as drivers trained to get their taxi license, the showed structural changes in their hippocampus. 61. Maguire EA, Burgess N, Donnett JG, Frackowiak RS, Frith CD, O’Keefe J: Knowing where and getting there: a human navigation network. Science 1998, 280:921-924. 62. Harvey CD, Collman F, Dombeck DA, Tank DW: Intracellular dynamics of hippocampal place cells during virtual navigation. Nature 2009, 461:941-946. 63. Schmidt-Hieber C, Hausser M: Cellular mechanisms of spatial navigation in the medial entorhinal cortex. Nat Neurosci 2013, 16:325-331. 64. Ekstrom AD, Kahana MJ, Caplan JB, Fields TA, Isham EA, Newman EL, Fried I: Cellular networks underlying human spatial navigation. Nature 2003, 425:184-188. This study presented the first evidence of place cells in the human hippocampus and other regions of the brain. 65. Jacobs J, Weidemann CT, Miller JF, Solway A, Burke JF, Wei XX, Suthana N, Sperling MR, Sharan AD, Fried I, Kahana MJ: Direct recordings of grid-like neuronal activity in human spatial navigation. Nat Neurosci 2013, 16:1188-1190. This study presented evidence of the existence of grid cells in the human hippocampus and other regions of the brain.
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ScienceDirect Environmental enrichment and neurogenesis: from mice to humans Gregory D Clemenson1, Wei Deng2 and Fred H Gage2 The brain is a dynamic structure that constantly undergoes cellular and molecular changes in response to the environment. Ultimately, these experience-dependent changes modify and shape behavior. One example of this neuroplasticity is the robust and continuous generation of new neurons that occurs in the dentate gyrus (DG) of the hippocampus. These new neurons are thought to play a fundamental role in hippocampus-dependent behavior and are modulated by experience and changes in the environment. In this review, we will focus on the cognitive and molecular relationship between environmental enrichment and adult neurogenesis. In addition, we discuss some of the similarities between the human and animal literature in regards to neurogenesis, hippocampusdependent behavior, and environmental enrichment. Addresses 1 Center for the Neurobiology of Learning and Memory and Department of Neurobiology and Behavior, University of California, Irvine, United States 2 The Salk Institute for Biological Sciences, United States Corresponding author: Gage, Fred H ([email protected])
Current Opinion in Behavioral Sciences 2015, 4:56–62 This review comes from a themed issue on Cognitive enhancement Edited by Barbara Sahakian and Arthur Kramer
http://dx.doi.org/10.1016/j.cobeha.2015.02.005 2352-1546/# 2015 Published by Elsevier Ltd.
Environmental enrichment and the influence on neurogenesis The term enriched environment (EE) is often used to describe an environmental manipulation administered to rodents. EE is often characterized as a large environment with toys, tunnels, bedding and running wheels and designed to provide social, physical and sensory stimulation. Often times, the environments are periodically rearranged and new toys and objects are introduced to keep the environment novel. It is well established that EE modulates hippocampal neurogenesis and behavior, resulting in an increase in newborn neurons and enhanced hippocampus-dependent cognition [1]. One of the first reports demonstrated these pro-neurogenic effects of EE by simply allowing mice to live in an EE for 40 days. There was a significant increase in the number of Current Opinion in Behavioral Sciences 2015, 4:56–62
hippocampal granule cells and these mice showed a marked improvement in learning the Morris water maze (MWM) compared to mice in standard housing [2].
EE factors that interact with neurogenesis It is important to remember that there is no standardization of EE with regard to procedure and methodology. Studies vary drastically in terms of environment size, stimulation used (various tunnels and toys), with or without running wheels, as well as BrdU injection paradigms and timing of EE exposures. Despite these differences, we address several key factors that influence neurogenesis. Exercise is often studied independently of EE and for the purposes of this review, we will attempt to highlight influences specifically of EE without a running wheel and refer to these as ‘EE-only’. Due to the complexity of EE, there are many components, including social, sensory, spatial and physical stimulation that may contribute to the observed effects. The physical stimulation of EE provided by access to running wheels has been singled out as a robust regulator of neurogenesis. Exposure to a running wheel led to not only increased hippocampal neurogenesis but also improved spatial learning in the MWM and enhanced DG long-term potentiation (LTP) in mice [3,4–6]. A wealth of information exists on the positive effects of exercise and running [7,8]. In addition to numerous effects of exercise, independent of neurogenesis, wheel running has been shown to significantly influence hippocampus dependent cognition, synaptic plasticity, spine density, neurotransmitter release, and even angiogenesis in the hippocampus of the brain. While physical exercise has been shown repeatedly to play a crucial role in EE, the impact of the complexity and exploration of the EE cage itself on neurogenesis and cognition should not be underestimated. Despite variable results when using EE-only without a running wheel [5,6], a number of studies have shown that EE-only is capable of inducing neurogenesis [3,9,10,11,12,13,14]. Acute exposure (24 hours) to either EE-only or running wheel suggested that these two manipulations may influence different proliferative populations of granule cells [10]. One hour prior to the 24-hour exposure, animals received one injection of BrdU. Immediately following the initial start of the EE-only and exercise (running wheel) manipulation, there was no difference in BrdU+ cells between any of the groups. Upon completion of the 24-hour exposure, however, both EE-only and exercise www.sciencedirect.com
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groups showed a significant increase in absolute BrdU+ cells and BrdU+/Nestin-GFP+/Prox1+ (type-2b) cells when compared to controls. Interestingly, exercise animals showed a specific increase in the number of BrdU+/ Nestin-GFP+/Prox1 (type-2a) cells and EE-only animals showed a specific increase in the number of BrdU+/nesting-GFP /Prox1+ (type-3) cells. Despite the short exposure to EE-only and exercise, these results suggest a differential influence on hippocampal neurogenesis. Exercise increases proliferation in early type-2a progenitor cells whereas EE-only may exert a more specific influence on postmitotic type-3 cells. In addition to neurogenesis, animals exposed to EE-only show increased expression of the neurotrophic factor, nerve growth factor (NGF), and enhanced synaptogenesis [13,15]. Cognitively, animals exposed to EE-only showed improvements in spatial memory (object displacement task), working memory (T-maze), recognition memory (novel object recognition), and contextual fear memory [13,14]. These studies illustrate the molecular and behavioral changes associated with EE-only in mice. Many of these enhancements observed with EE-only may be attributed to the exploration of these intricate environments. Mice living in a large, multi-tiered enriched environment (no running wheel) for 3 months were tagged with radio-frequency identification transponders and their movements were monitored for the duration of their time in the EE [12]. Using ‘roaming entropy’ as a measure of explorative behavior, mice with higher roaming entropy correlated with more neurogenesis. Interestingly, although the mice are expected to have higher levels of physical exercise in a larger EE, the total locomotion of individual mice did not correlate with neurogenesis. This study highlighted the range of exploratory behavior in mice and, in light of its results, it is important to keep in mind that there are individual differences in the animals, and their individual experiences within the EE may vary drastically. Although we discuss slight individual differences between exercise and EE-only, it is important to remember that EE and exercise work together and the majority of EE studies use environments with running wheels inside. When exposed to EE, physical activity can increase simply because more space is provided to the animal, regardless of whether a running wheel is present or not. To demonstrate the effects of EE and exercise together, one study showed that both manipulations together could enhance neurogenesis beyond both EE alone and exercise alone [11]. By pre-exercising animals for 10 days and exposing these animals to EE afterwards for 30 days, they saw a 30% increase in new neurons compared to all other groups. Supporting the notion that physical activity has a greater effect on cell proliferation and EE influences survival [2,3,9,16], the authors suggest that exercise www.sciencedirect.com
can ‘prime’ the neurogenic niche for cognitive stimulation, such as EE. Another influential factor of EE is the timing of EE exposure. More specifically, the age of the newborn neuron during EE exposure may be critical to the morphological and behavioral changes observed in these animals. Newborn neurons in the DG undergo a prolonged maturation process characteristic of an early period of hyperexcitability [17–20]. Interestingly, the effects of EE are most prominent when newborn neurons are 2 weeks old [21]. Multiple groups of animals received BrdU injections to label a newborn population of neurons. Each group of animals received 1 week of EE exposure but over different 1-week periods of maturation. The first group received the 1-week EE exposure immediately after BrdU injection; the second group received the 1-week EE exposure 1 week after BrdU injection, and so on. Although there were observable increases in neurogenesis when EE was presented within the first 3 weeks of neuronal birth, there was no difference in neurogenesis levels when 4-week-old neurons were exposed to EE. In addition, BrdU-labeled newborn neurons that experienced the EE during their second week responded greatest, as determined by co-expression of the immediate early gene c-fos, when re-exposed to the same EE 6 weeks after birth. This activation by the newborn neurons upon re-exposure to the same EE but not a different environmental exposure, suggest that they functional integrate into the existing DG circuitry, encoding information specifically about the previously seen EE. Together, these results highlight the sensitivity of newborn neurons to timing of EE exposure. In addition to timing of EE exposure, the overall age of the animal has a dramatic effect on hippocampal neurogenesis and cognition. Aging in animals is known to have a strong negative impact on hippocampal neurogenesis and cognition [22]; however, EE can reverse many of these deficits. Exposing aged mice to EE over a period of 10 months resulted in an almost 5-fold increase in the number of surviving newborn neurons [16]. This increase was also associated with enhanced spatial acquisition of the MWM. In a more recent study, aged rats underwent a 10-week EE exposure [23]. Spatial learning on the MWM and spatial memory during a 60-s probe trial were significantly improved in aged rats exposed to EE. Exposing aged rats to EE also resulted in an increase in the total number of new neurons, despite having no effect on neuronal differentiation. The age of the animals, along with the other factors of EE experiments, have not been standardized in previous EE studies, often resulting in variability when interpreting the effects of EE on neurogenesis.
Molecular mechanism for EE The molecular mechanisms for EE-induced hippocampal neurogenesis were studied with genomic approaches. Gene expression alteration caused by EE were explored Current Opinion in Behavioral Sciences 2015, 4:56–62
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using microarrays and other genomic methods [24,25,26]. Genes involved in neuronal activity and synaptic plasticity were induced by both short-term and long-term EE treatment; the exact sets of genes altered had little overlap, probably due to the gradual adaptation of the neuronal function to EE. Moreover, the effects of EE on gene expression were not evenly distributed across different brain regions, with the hippocampus being more influenced by EE [27]. EE-induced changes in noncoding genes such as miRNA have also been studied [28]. Despite such progress, how these changes in gene expression are related to the enhanced neurogenesis remains to be further investigated. In contrast to these genome-wide studies, several candidate genes have been well characterized for their role in EE-induced and exercise-induced neurogenesis. We will discuss two molecules — BDNF and VEGF — in detail. Both EE exposure and voluntary exercise can induce the expression of BDNF [29–30,31,32], a neurotrophin that supports survival, differentiation and neurite growth in existing neurons. BDNF and its receptor, TrkB, play important roles in adult hippocampal neurogenesis. Direct infusion of BDNF into the hippocampus resulted in an increase in neurogenesis [33]. On the other hand, disruption of BDNF–TrkB signaling by selective knockout of TrkB in adult neural progenitor cells (NPCs) led to decreased survival of newborn neurons at the immatureto-mature neuronal transition [34]. In addition, TrkBnull newborn neurons were defective in dendritic growth and synapse formation, consistent with the role of BDNF– TrkB pathway in neuronal differentiation. In another study, Li and colleagues reported that TrkB had a cell autonomous role in NPC proliferation in the hippocampus [35]. Furthermore, compared to that seen in wildtype control mice, the enhanced neurogenesis by EE was not observed in heterozygous knockout mice for BDNF (BDNF +/ ) [31]. Similarly, the running-induced increase in NPC proliferation was compromised in mice with TrkB deleted in the NPCs [35]. These findings suggest that BDNF–TrkB signaling plays important roles in both NPC proliferation and newborn neuron survival during adult neurogenesis and is a key mediator for EE-induced enhancement of neurogenesis. Another molecule whose expression is induced by EE is VEGF [36,37], a growth factor associated with vasculogenesis and angiogenesis. The dividing NSCs were found clustered at the tips of capillaries [38], suggesting that factors related to vasculature may affect neurogenesis. The role of VEGF in mediating EE-induced neurogenesis has been studied extensively. First, exogenous VEGF can effectively increase neurogenesis, bypassing the EE [36]. In addition, infusion of VEGF antagonists or down-regulation of VEGF by RNA interference blocked the EE-induced neurogenesis [36,39]. Similarly, administration of soluble Flt1, an antagonist for VEGF, Current Opinion in Behavioral Sciences 2015, 4:56–62
prevented the running-induced NPC proliferation [40]. Thus, VEGF is an important factor for mediating enhanced neurogenesis by EE and voluntary exercise.
EE and neurogenesis, a causal link Beneficial cognitive effects of EE exposure are well documented, but whether these behavioral effects are a direct result of EE-induced neurogenesis is still unclear. Here we present the few studies that have addressed the specific influence of EE-induced neurogenesis on hippocampus behavior. To address this question, a number of techniques have been used to target neurogenesis in the DG and a variety of behavioral measures. Eliminating neurogenesis systemically with the antimitotic agent methylazomethanol acetate (MAM) has produced mixed results. In some cases, MAM treatment of rats during EE impaired performance in object recognition memory and a trace fear conditioning paradigm, but not contextual fear conditioning or spatial navigation learning in the MWM [41,42]. Similarly, although focal irradiation almost completely ablated hippocampal neurogenesis in the DG of EE-exposed mice, it did not hinder the irradiated EE mice in their enhanced ability to learn the MWM [43], suggesting that the behavioral effects of EE are independent of neurogenesis. Although these studies focus on hippocampus-dependent behaviors, the relationship between EE and neurogenesis may be more pronounced with behaviors associated with the DG such as pattern separation [20,44–48]. Behaviorally, pattern separation is thought to be a critical component of episodic memory, allowing the encoding of similar experiences as distinct events, without interference [49,50]. A number of studies have been performed to demonstrate the involvement of the DG in pattern separation. Lesion of the DG (but not CA1) in rats specifically interfered with spatial pattern separation when choosing between two similar spatial locations [44]. Specifically knocking out NMDA receptors in the DG impaired the animals’ ability to distinguish between two similar contexts, but not traditional contextual fear conditioning [45]. Knocking out DG neurogenesis through irradiation and a lentiviral method impaired animals ability to pattern separation in a radial arm maze and an object-in-place touch screen task [47]. In vivo recordings of rats show that although both DG and CA3 can perform pattern separation functions, the DG is especially sensitive to small changes in the environment [46]. Only a handful of studies have observed the influence of EE and neurogenesis on pattern separation, however, increasing neurogenesis through EE is capable of enhancing pattern separation in mice. Mice were presented with a touch-screen task where they were taught to distinguish between spatially similar objects. In both young and aged mice, exercise, one of the key components of EE, enhanced their ability to recognize spatially www.sciencedirect.com
Environmental enrichment and neurogenesis Clemenson, Deng and Gage 59
similar objects, indicating an enhancement in pattern separation [51]. In addition, discriminating between two closely related contextual fear conditioning environments with extremely short exposures was known to be extremely difficult for rodents [52]. Without sufficient time to explore the context, animals were unable to associate shock and context. Interestingly, despite an increase in neurogenesis and successful discrimination between two different contexts, running animals were unable to perform this task whereas animals exposed to EE-only discriminated between two similar contexts (Figure 1). Exposure to an EE not only allowed mice to successfully discriminate in this difficult task, but ablating neurogenesis through focal irradiation also inhibited their performance, suggesting that newborn neurons induced through EE may contribute to environmentspecific behavior [14]. While these presented studies attempt to unravel the link between EE-induced neurogenesis and behavior, more work is needed to confirm and further understand the role of these newborn neurons.
a number of similarities that exist between rodents and humans in the literature (see Table 1). First, there is strong evidence to suggest that hippocampal neurogenesis occurs in humans. Postmortem tissue from terminal skin cancer patients who were treated with BrdU before death, displayed labeled BrdU cells in the DG of the hippocampus [53]. NPCs have even been discovered in the human hippocampus using proton nuclear magnetic resonance spectroscopy and a metabolic biomarker, as well as a novel carbon-dating technique [54,55]. Second, angiogenesis is closely linked to hippocampal neurogenesis [38] and exercise-induced neurogenesis is correlated with increases in cerebral blood volume (CBV) in mice [56]. Human participants that completed a 3-month aerobic exercise program displayed increases in DG CBV over the 3-month period, correlating with maximum volume of oxygen consumption (VO2max), a measure of aerobic fitness [56].
EE in humans Understanding the relationship between EE and neurogenesis in animals is already difficult, so an attempt to address EE in humans is highly ambitious. With regards to environmental enrichment, the most straightforward disparity is that standard laboratory rodents live in a small cage and the general human population already lives in what most would consider an ‘enriched environment.’ In addition to the obvious differences between humans and rodents, the tools available for us to learn about the mechanisms and underlying cellular processes of the human brain are limited compared to those we can use with the laboratory rodent. For example, fMRI allows us to compare brain regions active during behavior, but it is difficult to interpret the data because it is an indirect quantitative measure of blood flow changes in the brain, which is thought to correlate with neuronal activity. Despite these technical challenges, however, there are
Third, humans exhibit pattern separation-like behaviors similar to mice. In a behavioral task designed to test pattern separation, participants were presented with pictures of everyday objects and, during a testing phase, had to determine if previously viewed objects were ‘old’, ‘similar,’ or ‘new.’ fMRI revealed activation of the DG/CA3 region only when participants recognized ‘similar’ objects and not ‘old’ or ‘new’ [57]. In addition, this pattern separation ability declines in healthy human aging [58] similar to mice [51]. Finally, and perhaps most relevant to EE, the exploration and navigation of real and virtual environments correlate with increases in hippocampal volume, hippocampal activity, and even the firing of place-like and grid-like cells. Hippocampal gray matter was found to be significantly larger in licensed London taxi drivers when compared to
Figure 1
Enrichment
Neurogenesis
Contextual Discrimination
X
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Schematic outlining the effects of enrichment on neurogenesis and contextual discrimination. www.sciencedirect.com
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Table 1 Similarities between animal and human studies presented in this review, in regards to environmental enrichment and neurogenesis.
Neurogenesis – evidence for the presence of neurogenesis Kempermann et al. [2·] VanPraag et al. [1,3·]
Eriksson et al. [53·] Manganas et al. [54] Spalding et al. [55]
Palmer et al. [38] Pereira et al. [56·]
Pereira et al. [56·]
Clelland et al. [47] Creer et al. [51·] Clemenson et al. [14·]
Bakker et al. [57·] Stark et al. [58]
Freund et al. [12·]
Maguire et al. [59,61] Woollett and Maguire [60·]
Harvey et al. [62] Schmidt-Hieber and Hausser [63]
Ekstrom et al. [64·] Jacobs et al. [65·]
Angiogenesis – presence and increase of vasculature with neurogenesis
Pattern separation – behavior dependent on the dentate gyrus
Spatial navigation / exploration – hippocampal involvement in the spatial navigation and exploration of environments Place cells – presence in the hippocampus during the navigation of a virtual environment
control subjects [59]. As un-licensed taxi drivers trained to become licensed taxi cab drivers, there was a selective increase in hippocampal gray matter [60]. The increase in hippocampal volume by London taxi drivers was correlated with a spatial navigation expertise and memory of the city of London. Similar to real world environments, the hippocampus also activates during the exploration and navigation of virtual environments in humans and animals alike [61–63]. Both place-like and grid-like cells have even been observed in humans during a virtual-navigation task, using single-neuron recordings from electrodes surgically implanted in patients undergoing treatment for epilepsy [64,65]. In the same way that exploration of a novel environment is correlated with neurogenesis in mice [12], the spatial exploration and navigation of real and virtual environments correlate with structural and functional changes in the hippocampus of humans.
hippocampus-dependent behaviors like spatial navigation activate the hippocampus and that continuous exposure to large complex city environments can increase hippocampal volume (similar to long EE exposures in mice). In the same way that rodents use place and grid cells to explore their environment, evidence exists to suggest the presence of these same cell types in the human hippocampus. In addition, although we cannot visualize neurogenesis in humans, DG-specific processes like pattern separation are not only observable in humans but they also activate similar regions of the brain and are influenced by the same environmental factors. Knowing that these similarities exist in basic hippocampus-dependent processes may one day lead us to a way to enrich our own lives and enhance performance on hippocampal behaviors.
Conflict of interest Despite the plethora of differences between humans and the standard laboratory rodent, it is amazing to see that Current Opinion in Behavioral Sciences 2015, 4:56–62
The authors declare that they have no competing financial interests. www.sciencedirect.com
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