Environmental Enrichment and Neuronal Plasticity
Abstract and Keywords
This chapter reviews the literature on environmental enrichment and specifically discusses its influence on the hippocampus of the brain. In animal models, the term “environmental enrichment” is used to describe a well-defined manipulation in which animals are exposed to a larger and more stimulating environment. This experience has been shown to have a powerful and positive impact on hippocampal cognition and neuroplasticity in animals. In humans, however, the translation of environmental enrichment is less clear. Despite the fact that humans live considerably more enriching lives compared to laboratory animals, studies have shown that training and expertise (such as exercise and spatial exploration) can lead to both functional and structural changes in the human brain. This chapter is a comprehensive review of environmental enrichment, drawing parallels between animal models and humans to present a more complete understanding of environmental enrichment.
The brain is a dynamic structure that is highly influenced by the surrounding environment. In response to a continuously changing environment, the brain experiences a host of modifications, from the addition of new neurons to the rewiring of existing networks. It is these experience-dependent modifications that ultimately modify and shape behavior. While the effects of environmental enrichment were originally described in multiple regions of the brain, including a number of cortical regions, one of the most robust examples of how the environment can directly influence neuroplasticity lies within the hippocampus of the brain. In this chapter, we will focus on the effects of environmental enrichment on hippocampal brain structure and function. We will outline the basic underlying mechanisms of environmental enrichment, dissect some of its individual components, and discuss its use as an intervention for aging and several neurodegenerative diseases. Finally, we will explore environmental enrichment from a human perspective, to attempt to gain a better understanding of how this effective manipulation might relate to us.
History of Environmental Enrichment
Environmental enrichment is a simple manipulation involving the use of an environment that is designed to promote physical, cognitive, sensory, and social stimulation. Often, enriched environments used in rodent studies consist of a large space with toys, tunnels, bedding, running wheels, and additional littermates to achieve the desired stimulation. While there is no consensus as to how these environments should be designed, exposing animals to a larger and more stimulating environment is beneficial to the brain and has a dramatic effect on both brain structure and function (van Praag et al., 2000).
Enrichment’s effects were first described by Donald Hebb, who made the simple observation that lab rats brought home as pets were cognitively smarter than their littermates who remained in the lab (Hebb, 1947). While anecdotal, it was the first report that the surrounding environment could have a profound influence on behavior. In the 1960s, environmental enrichment manipulation was characterized in more detail by Mark Rosenzweig and colleagues. Housing of animals in cages with toys, ladders, tunnels, and running wheels produced significant changes in the neurochemistry and anatomy of the cerebral cortex (Bennett et al., 1969; Diamond et al., 1966; Krech et al., 1960; Bennett, 1960; Rosenzweig et al., 1962). Animals exposed to these more complex environments had heavier and thicker cerebral cortices (Bennett et al., 1969), which was attributed to an increase in the number and length of the glia (Diamond et al., 1966). Following these initial studies, environmental manipulations were found to impact a number of different molecular and behavioral characteristics, including dendritic and synaptic complexity (Greenough & Volkmar, 1973; Greenough et al., 1978; Holloway, 1966), gliogenesis (Altman & Das, 1964; Diamond et al., 1966), neurogenesis (Kempermann et al., 1997; Walsh, Budtz-Olsen, et al., 1969; Walsh & Cummins, 1979), and learning (Kempermann et al., 1997). Although environmental complexity influenced many regions of the brain, it was clear from these studies that it had a particularly profound effect on the hippocampus of the brain (Kempermann et al., 1997).
Environmental Enrichment on Hippocampal Neuroplasticity and Behavior
The hippocampus, and more specifically the dentate gyrus, is one of two regions (the second region being the olfactory bulb) in the mammalian brain that continuously generates new neurons throughout life (Aimone et al., 2014; Gonçalves et al., 2016). Neural stem cells in the subgranular zone of the dentate gyrus give rise to neural progenitor cells (NPCs), which ultimately differentiate into either neurons or glia (Gage, 2000). Once these NPCs have committed to a neuronal fate, they undergo an extended maturation, characterized by distinct electrophysiological and morphological steps, before functionally integrating into the existing hippocampal circuitry (Ge et al., 2007; Schmidt-Hieber, Jonas, & Bischofberger, 2004; van Praag et al., 2002; Zhao, Teng, Summers, Ming, & Gage, 2006). This process of hippocampal neurogenesis is a robust example of neuroplasticity in the brain that is highly sensitive to the surrounding environment.
Animals that are exposed to an enriched environment have more newborn neurons in the dentate gyrus of the hippocampus compared to controls housed in standard cages (Kempermann et al., 1997). While individual components of enriched environments (e.g., physical activity, exploration, etc.) can have different effects on the underlying neurobiology (see The Different Components of Environmental Enrichment), simply changing an animal’s environment can have a major impact on the proliferation, differentiation, and survival of these newborn neurons (van Praag, Kempermann, & Gage, 1999). The addition of newborn neurons to the hippocampal circuitry is a prime example of neuroplasticity; exposure to an enriched environment has been shown to influence neuroplasticity at a synaptic level (Faherty, Kerley, & Smeyne, 2003; Gogolla, Galimberti, Deguchi, & Caroni, 2009; Moser, Trommald, & Andersen, 1994; Rampon et al., 2000; van Praag, Christie, Sejnowski, & Gage, 1999). Several studies have shown increased synaptogenesis (Gogolla et al., 2009; Rampon et al., 2000), density and complexity of dendrites (Faherty et al., 2003; Gonçalves et al., 2016; Moser et al., 1994; Rampon et al., 2000; Zhao, Jou, Wolff, Sun, & Gage, 2014), enhanced long-term potentiation (LTP) (Farmer et al., 2004; van Praag, Christie, et al., 1999), and increased expression of synaptic proteins (Nithianantharajah, Levis, & Murphy, 2004) following enrichment. Although the duration of enrichment varied across studies, longer exposures to enriched environments led to comparatively more newborn neurons in the dentate gyrus (Kempermann, Gast, & Gage, 2002; van Praag, Kempermann, et al., 1999). In addition, animals living in an enriched environment for half of their life (10 months) demonstrated a five-fold increase in newborn neurons (Kempermann et al., 2002). Interestingly, even short exposures to an enriched environment (e.g., seven days) can also produce a measurable effect on hippocampal neurogenesis. We should note, however, that the timing of the enrichment exposure relative to the maturation of the newborn neurons may be important for their survival and function (Tashiro, Makino, & Gage, 2007).
Environmental enrichment can have a robust impact on neuroplasticity within the hippocampus, and these changes are associated with improvements in hippocampus-dependent behavior. However, whether this link is truly causal is still unclear. For example, it has long been known that the hippocampus plays a pivotal role in spatial learning and memory (Morris, 1984; O’Keefe & Dostrovsky, 1971; O’Keefe & Nadel, 1978; Tolman, 1948). Exposing animals to an enriched environment resulted in improved performance on the classic hippocampus-dependent spatial memory task, the Morris water maze (Garthe, Roeder, & Kempermann, 2016; Kempermann et al., 1997; Nilsson, Perfilieva, Johansson, Orwar, & Eriksson, 1999; Schrijver, Pallier, Brown, & Würbel, 2004; van Praag et al., 2002; van Praag, Christie, et al., 1999). Improvements in spatial learning and memory were also observed in the radial arm maze (Leggio et al., 2005; Mora-Gallegos et al., 2015; Sampedro-Piquero, Begega, Zancada-Menendez, Cuesta, & Arias, 2013). In addition, the dentate gyrus of the hippocampus itself is thought to perform a computation known as pattern separation in the service of memory (Yassa & Stark, 2011, for review). Several studies have shown that this pattern separation ability is particularly sensitive to hippocampal neurogenesis (Aimone, Wiles, & Gage, 2009; Clelland et al., 2009; Gilbert, Kesner, & Lee, 2001; Leutgeb, Leutgeb, Moser, & Moser, 2007; McHugh et al., 2007; Sahay et al., 2011). A recent meta-analysis of hippocampal neurogenesis and pattern separation found that the literature consistently supports a correlation between hippocampal neurogenesis and behavioral pattern separation (França, Bitencourt, Maximilla, Barros, & Monserrat, 2017). Accordingly, several studies have also shown that environmental enrichment can increase performance on behavioral tasks of pattern separation (Clemenson et al., 2015; Creer, Romberg, Saksida, van Praag, & Bussey, 2010). Whether the improvements in these behaviors are causally linked to the increase in hippocampal neurogenesis with environmental enrichment has yet to be conclusively shown (Bruel-Jungerman, Laroche, & Rampon, 2005; Clemenson et al., 2015; Meshi et al., 2006; Shors, Townsend, Zhao, Kozorovitskiy, & Gould, 2002; Zeleznikow-Johnston, Burrows, Renoir, & Hannan, 2017). However, it is important to note that there are multiple components of enriched environments that are responsible for the benefits of environmental enrichment and these may work through distinct mechanisms (Olson, Eadie, Ernst, & Christie, 2006).
The Different Components of Environmental Enrichment
There are many ways that environments have been “enriched.” For example, experimental manipulations of enrichment have included varying the size of the enriched environment, the types of toys or tunnels chosen, the presence of a running wheel, and even the length of exposure to the enriched environment. These inconsistencies between studies can lead to a range of results that make it difficult to truly assess the positive, negative, or sometimes null effects of an enriched environment. Despite these inconsistencies, there are specific aspects of environmental enrichment that are particularly robust and have been shown to specifically influence hippocampal neuroplasticity and behavior.
Probably the most widely studied aspect of environmental enrichment is the physical activity associated with a running wheel placed inside the enrichment cages (van Praag, Kempermann, et al., 1999; Vivar, Potter, & van Praag, 2013). The initial study exploring the different aspects of enriched environments divided animals into various conditions: learners, swimmers, runners, and enriched (van Praag, Kempermann, et al., 1999). Using bromodeoxyuridine (BrdU) as a marker for dividing cells, researchers discovered that simply placing a running wheel inside the home cages was sufficient to induce cell proliferation in the dentate gyrus. Four weeks after BrdU injections, they found an increased number of BrdU-positive neurons in both the enriched and runner groups, suggesting that physical activity increased not only the proliferation of newborn neurons, but their survival as well. Furthermore, running enhanced LTP in the dentate gyrus, and the newborn neurons whose survival was dependent on the running experience were functionally integrated into the existing hippocampal circuitry (van Praag et al., 2002; van Praag, Christie, et al., 1999). This overall increase in neurogenesis was also associated with an improvement in performance on the Morris water maze. Since this pivotal study, the research exploring the effect of physical activity on hippocampal neuroplasticity has been extensive (Vivar et al., 2013). Without a doubt, the increased physical activity associated with enriched environments is an important component.
Physical Activity vs Environmental Enrichment
The effects of physical activity on hippocampal neuroplasticity are undeniable. In fact, several studies have even suggested that physical activity is the sole contributor to the neurogenic and neurotropic effects of environmental enrichment (Kobilo et al., 2011; Mustroph et al., 2012). After all, giving a rodent a large arena that it explores or toys that it plays with are not only associated with increased exploration and play, respectively, but also with increased physical activity as it explores and plays. However, a number of studies have suggested that the environment itself can provide meaningful effects even outside of physical activity (Birch, McGarry, & Kelly, 2013; Clemenson et al., 2015; Freund et al., 2013; Kronenberg et al., 2003; Steiner, Zurborg, Hörster, Fabel, & Kempermann, 2008; van Praag, Kempermann, et al., 1999). In truth, physical activity and environmental enrichment may have distinct effects and mechanisms (Olson et al., 2006), as exercise has been shown to have a greater impact on proliferation, whereas environmental enrichment has a greater influence on survival (van Praag, Kempermann, et al., 1999). Furthermore, exercise and environmental enrichment have an additive effect; the combination increases hippocampal neurogenesis beyond exercise alone (Fabel et al., 2009).
Recently, one specific difference between enrichment- and exercise-induced neurogenesis was demonstrated in a difficult task of pattern separation (Figure 1) (Clemenson et al., 2015). “Pattern separation” refers to the ability to discriminate between two closely related but distinct pieces of information and is thought to critically involve the dentate gyrus (Yassa & Stark, 2011, for review). Thus, when testing an animal’s ability to discriminate between two highly similar contexts, improvements in performance would be consistent with enhanced dentate gyrus functioning. When groups of animals exposed to either environmental enrichment (Fig. 1C) or physical exercise (Fig. 1B) were tested, only the group exposed to an enriched environment was able to discriminate between the two similar contexts (Fig. 1D), despite the finding that the exercised group showed greater levels of neurogenesis relative to the enriched group (Fig. 1E) (Clemenson et al., 2015). Furthermore, knocking down neurogenesis in the enrichment group eliminated their ability to discriminate, implicating the enrichment-induced newborn neurons in the pattern separation behavior. These data suggest that, although the influence of the environment on hippocampal neuroplasticity is not as pronounced as exercise alone, it may still be relevant under certain circumstances.
The available evidence therefore suggests that not only does physical activity affect neurogenesis, but some aspect of being exposed to an enriched environment also impacts neurogenesis and memory. At least one study found that a critical aspect of enriched environments is the spatial exploration that occurs while animals are living in these environments (Freund et al., 2013). In this study, mice were tagged with radio frequency identification transponders (RFID) and lived in a large, enriched environment for four months. Antennas were placed around the environment so exploratory behavior could be monitored over the course of the four months. Using an exploratory behavior measure, researchers found that mice with higher roaming entropy (randomly distributed spatial coverage over the entire environment) had increased neurogenesis compared to mice with low roaming entropy (stable and small spatial coverage). Furthermore, while there was a significant correlation between neurogenesis levels and roaming entropy values, there was no such correlation between neurogenesis and total distance traveled (Freund et al., 2013), suggesting that spatial exploration is an important component of enriched environments.
Other Components of Environmental Enrichment
There are several additional components commonly associated with environmental enrichment that can be difficult to relate to effects of environmental enrichment on hippocampal neuroplasticity. Numerous forms of learning are often associated with the hippocampus and, in some cases (e.g., trace conditioning), have even been shown to increase hippocampal neurogenesis in animals (Gould, Beylin, Tanapat, Reeves, & Shors, 1999; Leuner et al., 2004). While the presentation of a novel enriched environment is likely to provide many learning experiences for the animals, including spatial and contextual learning, it is difficult to isolate the type of learning that occurs. Some environmental enrichment setups include multiple-mouse housing and mixing of cages to provide a certain amount of social enrichment to animals. While it is clear that social isolation has an extremely negative effect on hippocampal neuroplasticity and the overall health of animals, the addition of extra animals to the socially isolated animal does not appear to influence neurogenesis beyond what is seen in control animals that are reared in groups (Ibi et al., 2008; Leasure & Decker, 2009; Lu et al., 2003). However, social enrichment may play more of a role in the mediation of olfactory neurogenesis, consistent with the animals’ use of olfactory cues as dominant signals for social identification and communication (Monteiro, Moreira, Massensini, Moraes, & Pereira, 2014).
Neurotrophic Factors Involved in Environmental Enrichment
In addition to its effects on hippocampal plasticity, environmental enrichment interacts strongly with neurotrophic factors, many of which support the development and maintenance of neurons in the brain (Barde, 1994). Here we will discuss a few of the most important neurotrophic factors that are closely coupled with environmental enrichment.
Brain-Derived Neurotrophic Factor (BDNF)
Brain-derived neurotrophic factor (BDNF) is a protein found in both the central (e.g., hippocampus and cortex) and peripheral (e.g., dorsal root ganglion) nervous systems and supports the survival and differentiation of neurons, neurite growth, and synapse formation (Acheson et al., 1995; Huang & Reichardt, 2001). Given its role in plasticity, it should come as little surprise that BDNF plays a critical role in learning and memory and is one of the most common molecules associated with environmental enrichment (Bekinschtein, Oomen, Saksida, & Bussey, 2011; Rossi et al., 2006). BDNF has a well-established role in adult hippocampal neurogenesis and is directly tied to the proliferation, differentiation, and survival of newborn neurons (Bergami et al., 2008; Li et al., 2008; Scharfman et al., 2005). Infusion of BDNF into the hippocampus of the brain results in an increase in neurogenesis (Scharfman et al., 2005), and mice designed to overexpress BDNF have increased dendritic complexity in the dentate gyrus (Tolwani et al., 2002). The disruption of BDNF and its receptor, tropomyosin receptor kinase B (TrkB), decreased the survival of newborn neurons as they transitioned from immature to mature neurons (Bergami et al., 2008).
BDNF also interacts with environmental enrichment, which has been shown to modulate the expression of BDNF in the hippocampus (Falkenberg et al., 1992; Farmer et al., 2004; Ickes et al., 2000; Neeper, Gómez-Pinilla, Choi, & Cotman, 1996; Rossi et al., 2006). Supporting a causal role, in a heterozygous knockout mouse for BDNF, exposure to an enriched environment failed to induce hippocampal neurogenesis, contrary to what was observed in controls (Rossi et al., 2006). Furthermore, the proliferative effects of exercise-induced neurogenesis were impaired in mice lacking TrkB in their hippocampal NPCs (Li et al., 2008). These data suggest that BDNF and the BDNF-TrkB signaling pathway play a critical role in environmental enrichment-induced neuroplasticity.
Vascular Endothelial Growth Factor (VEGF)
Vascular endothelial growth factor (VEGF) is a strong promoter of vasculogenesis and angiogenesis, both of which are strongly associated with hippocampal neurogenesis (Goldberg & Hirschi, 2013; Palmer, Willhoite, & Gage, 2000). The vasculature of the hippocampus is important for the neurogenic niche that promotes hippocampal neurogenesis (Palmer et al., 2000). Exposure to an enriched environment, and to physical activity in particular, has been shown to increase vasculature and increase expression of VEGF in the hippocampus (Cao et al., 2004; Fabel et al., 2003; Pereira et al., 2007; Van der Borght et al., 2009). Interestingly, VEGF has a direct effect on neurogenesis such that the overexpression of VEGF in the hippocampus, in the absence of environmental enrichment, leads to an overall increase in hippocampal neurogenesis (Cao et al., 2004; Jin et al., 2002). Importantly, knocking down hippocampal VEGF with the use of RNA interference and a VEGF antagonist blocked the effects of environmental enrichment, suggesting that VEGF mediates the effects of environmental enrichment on adult hippocampal neurogenesis (Cao et al., 2004; Fabel et al., 2003; Jin et al., 2002).
Additional Growth Factors
In addition to BDNF and VEGF, several other neurotrophic factors have been shown to increase with environmental enrichment. However, while direct, causal roles are supported for BDNF and VEGF, the role of these other factors is not clear. Nerve growth factor (NGF) is a trophic factor involved in the growth, differentiation, and survival of cholinergic neurons (Conner et al., 2009; Frielingsdorf, Simpson, Thal, & Pizzo, 2007). In the absence of environmental enrichment, exogenous NGF is sufficient to improve behavior and survival of newborn neurons in the dentate gyrus of young animals (Frielingsdorf et al., 2007), and blocking endogenous NGF leads to reduced hippocampal LTP and impaired spatial memory performance (Conner et al., 2009). NGF expression is increased in response to environmental enrichment exposure, suggesting that NGF may also mediate enrichment-induced neuroplasticity (Birch et al., 2013; Ickes et al., 2000; Neeper et al., 1996). Unlike NGF, increased expression of fibroblast growth factor 2 (FGF-2) and insulin-like growth factor 1 (IGF-1) appears to be more specifically attributable to physical activity rather than to the enrichment manipulation as a whole (Carro, Nuñez, Busiguina, & Torres-Aleman, 2000; Gomez-Pinilla & Hillman, 2013; Trejo, Carro, & Torres-Aleman, 2001). Both FGF-2 and IGF-1 have been implicated in hippocampal neurogenesis (Aberg, Aberg, Hedbäcker, Oscarsson, & Eriksson, 2000; Rai, Hattiangady, & Shetty, 2007; Yoshimura et al., 2001); however, the role of IGF-1 appears to be stronger. IGF-1 mediates changes in vasculature induced by exercise (Lopez-Lopez, LeRoith, & Torres-Aleman, 2004) and interacts with BDNF, further confirming its role in exercise-induced neuroplasticity. Thus, while each of these factors impacts neurogenesis, their roles and how they interact with enrichment are less direct or more complex.
Environmental Enrichment and Aging
Aging is associated with a decline in hippocampal function, with alterations in both neurogenesis and connectivity being key factors in this decline (Stark & Stark, 2016). Both physical activity and environmental enrichment have been shown to ameliorate these effects (Kempermann et al., 2002; Segovia, Yagüe, García-Verdugo, & Mora, 2006; Speisman et al., 2013; van Praag, Shubert, Zhao, & Gage, 2005). For example, older animals that lived in an enriched environment for 10 months showed increased proliferation, differentiation, and survival of newborn neurons in the dentate gyrus and improved performance on a spatial task (Kempermann et al., 2002). While these animals were on the younger side of the age spectrum (10 months old), living in an enriched environment for over half their life resulted in a five-fold increase in the number of surviving adult-born neurons compared to aged controls. Similarly, (even older animals (20–25 months) that received a shorter (8–10-week) exposure to an enriched environment were found to have an increase in hippocampal neurogenesis and improved spatial memory (Segovia et al., 2006; Speisman et al., 2013).
While most studies allow animals to live in the enrichment cages (a chronic approach to enrichment), multiple short, intermittent exposures to an enriched environment over a long period of time can have a similar effect. Weekly three-hour exposures to an enriched environment for 18 months resulted in increased cell proliferation and improvements in object-recognition memory (Leal-Galicia, Castañeda-Bueno, Quiroz-Baez, & Arias, 2008), which have been tied to hippocampal function (Broadbent, Gaskin, Squire, & Clark, 2010).
In addition to changes in hippocampal neurogenesis and behavior, environmental enrichment in aged animals has been shown to induce neuroplasticity at the synapse. Specifically, environmental enrichment increased dendritic branching and spine density in the hippocampus of aged animals (Darmopil, Petanjek, Mohammed, & Bogdanović, 2009; Kolb, Gorny, Söderpalm, & Robinson, 2003; Mirmiran, Van Gool, Van Haaren, & Polak, 1986). At the synapse, enrichment is associated with increased expression of the presynaptic protein synaptophysin (Frick & Fernandez, 2003; Leal-Galicia et al., 2008; Saito et al., 1994), increased release of the neurotransmitters glutamate and gamma-aminobutyric acid (GABA) (Segovia et al., 2006), and changes in synaptic plasticity (enhanced long-term potentiation and depression) in the hippocampus (Kumar, Rani, Tchigranova, Lee, & Foster, 2012; Stein, O’Dell, Funatsu, Zorumski, & Izumi, 2016). Interestingly, in aged animals, the effects of environmental enrichment and exercise on the neurotrophic factor BDNF are less clear (Adlard, Perreau, & Cotman, 2005; Aguiar et al., 2011; Barrientos et al., 2011). Some studies suggest that the effect of exercise on BDNF decreases with age (Adlard et al., 2005), whereas others do not (Aguiar et al., 2011). Together, these data suggest that, even at advanced stages of aging, when structural and cognitive impairments are present, environmental enrichment can induce increased neuroplasticity in the hippocampus and ameliorate cognitive and structural deficits associated with aging.
Environmental Enrichment and Neurodegenerative Disease
Given the potency of the effects of environmental enrichment and the ease of implementing it, environmental enrichment has been explored as an intervention in several animal models of neurodegenerative diseases, stroke, and traumatic brain injury. The neurodegenerative diseases discussed in the following section are characterized by the loss of brain cells, leading to a progressive decline in memory, motor functions, and overall cognition, and to dementia, often resulting in death. Although many of the neurodegenerative diseases share symptoms, the underlying neurobiology and mechanisms are distinct, even if they share common neurobiological components such as inflammation. In many cases, environmental enrichment has been shown to be neuroprotective, delaying the progression, improving the neuropathology, and ameliorating many of the symptoms and cognitive deficits associated with each disease.
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by a slow, progressive loss of memory and other cognitive functions. Rodents do not naturally develop AD, but a number of transgenic models have been developed to replicate the classic neuropathology found in humans: beta-amyloid (Aß) plaques and neurofibrillary tangles (Webster, Bachstetter, Nelson, Schmitt, & Van Eldik, 2014). In such transgenic models, environmental enrichment has been shown to reduce the presence of both the Aß plaques and the neurofibrillary tangles (Hu et al., 2010; Hu, Long, Pigino, Brady, & Lazarov, 2013; Lazarov et al., 2005), rescue deficits in hippocampal neurogenesis and synaptic plasticity (Hu et al., 2010; Rodríguez & Verkhratsky, 2011; Valero et al., 2011), improve hippocampal cognition (Arendash et al., 2004; Jankowsky et al., 2005), and upregulate neurotrophic factors important to environmental enrichment and hippocampal neurogenesis (Hu et al., 2010; Wolf et al., 2006).
Parkinson’s Disease (PD)
Parkinson’s disease (PD) is often described by deficits in motor functions, characterized by a loss of dopamine neurons in the substantia nigra, and can lead to cognitive deficits and dementia during later stages (Regensburger, Prots, & Winner, 2014). In rodent models, environmental enrichment has been shown to improve motor function (Jadavji, Kolb, & Metz, 2006; Tillerson, Caudle, Reverón, & Miller, 2003) and ameliorate the loss of these dopaminergic neurons (Faherty, Raviie Shepherd, Herasimtschuk, & Smeyne, 2005; Goldberg, Haack, & Meshul, 2011; Jungling et al., 2017). Interestingly, one study found that the social interaction provided by an enriched environment could improve deficits in rearing behaviors and reduce neurodegeneration, resulting in an improvement in motor behavior deficits associated with PD (Goldberg, Fields, Pflibsen, Salvatore, & Meshul, 2012).
Huntington’s Disease (HD)
Huntington’s disease (HD) is an autosomal dominant disease that causes the death of nerve cells in the brain, leading to deficits in cognition, to mood and motor symptoms, and to dementia. In multiple rodent models of HD, environmental enrichment has been shown to ameliorate and delay the onset of both motor and cognitive deficits associated with HD (Hockly et al., 2002; Kreilaus, Spiro, Hannan, Garner, & Jenner, 2016; Nithianantharajah, Barkus, Murphy, & Hannan, 2008; Pang, Stam, Nithianantharajah, Howard, & Hannan, 2006; Schilling et al., 2004; Spires et al., 2004), as well as rescue deficits in hippocampal neurogenesis (Lazic et al., 2006). Additionally, physical activity, and in some cases, environmental enrichment were shown to rescue deficits in BDNF gene expression in mouse models of HD (Zajac et al., 2010).
A stroke occurs when there is poor blood flow to the brain, either through lack of blood flow (ischemic stroke) or bleeding (hemorrhagic), resulting in cell death. Importantly, environmental enrichment has been shown to improve sensorimotor deficits associated with stroke in rodents (Janssen et al., 2010; Johansson, 1996; Johansson & Ohlsson, 1996). In addition, environmental enrichment has been shown to ameliorate deficits in spatial learning and memory (Buchhold et al., 2007; Dahlqvist, Rönnbäck, Bergström, Söderström, & Olsson, 2004; Puurunen, Jolkkonen, Sirviö, Haapalinna, & Sivenius, 2001; Rönnbäck et al., 2005; Sonninen, Virtanen, Sivenius, & Jolkkonen, 2006; Wurm, Keiner, Kunze, Witte, & Redecker, 2007). Improvements in spatial memory were associated with an increase in hippocampal neurogenesis (Wurm et al., 2007), dendritic spine density (Rojas et al., 2013), and BDNF expression (Risedal et al., 2002). Interestingly, pre-exposure to an enriched environment prior to stroke induction improved the recovery of motor function and spatial learning and memory in stroke animal models as well (Xie et al., 2013; Yu et al., 2013), highlighting the neuroprotective effects of environmental enrichment.
Although there are general overall improvements in post-stroke recovery with environmental enrichment, there are several variables, such as age, timing of the enrichment exposure, and type of stroke model, that could account for observed differences in the efficacy of environmental enrichment as a therapy for stroke (Biernaskie, Chernenko, & Corbett, 2004; Leasure & Decker, 2009; Leasure & Grider, 2010; Risedal et al., 2002; Rönnbäck et al., 2005). For example, following focal ischemia, multiple groups of rats were exposed to an enriched rehabilitation therapy (six hours a day) starting at 5, 14, or 30 days after ischemic stroke (Biernaskie et al., 2004). Enrichment beginning at day 5 resulted in significant improvements in dendritic growth and complexity within the motor cortex, which correlated with improvements in locomotor function. Although animals in the 14-day group did not exhibit a change in dendritic growth or complexity, they did demonstrate a modest improvement in behavior. At 30 days’ delay prior to beginning enrichment rehabilitation, rats with ischemic stroke were no different than stroke controls. Results of this study suggest that a critical period exists after stroke in which the brain is most responsive to the effects of environmental enrichment. Interestingly, one study suggested that the improvement in motor function related to environmental enrichment post-stroke was not a result of functional restitution but rather of the facilitated use of an alternate and effective strategy that was promoted by environmental enrichment (Knieling, Metz, Antonow-Schlorke, & Witte, 2009).
Traumatic Brain Injury (TBI)
Traumatic brain injury (TBI) is commonly caused by an external force and can lead to both temporary and permanent damage to the brain. While the symptoms of TBI vary, depending on the location of the injury, animal models of TBI can reproduce the long-term cognitive and histological deficits associated with TBI in humans (Bramlett & Dietrich, 2002; Lindner et al., 1998; Pierce, Smith, Trojanowski, & McIntosh, 1998; Smith et al., 1997). Importantly, these animal models consistently reproduce cognitive and structural damage to the hippocampus (Creed, DiLeonardi, Fox, Tessler, & Raghupathi, 2011; Hamm, Temple, O’Dell, Pike, & Lyeth, 1996; Hicks, Smith, Lowenstein, Saint Marie, & McIntosh, 1993; Wakade, Sukumari-Ramesh, Laird, Dhandapani, & Vender, 2010).
After TBI, animals exposed to an enriched environment showed improvements in performance in the Morris water maze (Briones, Woods, & Rogozinska, 2013; Hamm et al., 1996; Passineau, Green, & Dietrich, 2001) and another spatial memory task, the Barnes maze (Kovesdi et al., 2011). Like stroke, the timing of the enrichment exposure and the severity of the TBI are important factors in recovery (Griesbach, Gómez-Pinilla, & Hovda, 2007). Pre-exposing animals to an enriched environment reduced the deficits in sensory, motor, and spatial behaviors, demonstrating the neuroprotective effects of environmental enrichment (Held, Gordon, & Gentile, 1985; Johnson, Traver, Hoffman, Harrison, & Herman, 2013; Yu et al., 2013).
In the few examples listed here, environmental enrichment has been shown to positively benefit both cognitive and structural deficits associated with neurodegenerative disease and brain injuries. Importantly, the effects of environmental enrichment extend beyond the hippocampus. While the exact underlying mechanisms through which environmental enrichment works are not fully understood, the benefits are comprehensive, and enrichment represents an extremely effective therapeutic intervention for a wide range of diseases and impairments.
Humans and Environmental Enrichment
The robust beneficial effects of environmental enrichment in rodents are undeniable and naturally lead to the question of whether this manipulation has relevance to humans. At first glance, the comparison may seem irrelevant, as we already live in an enriched environment compared to the standard laboratory rodent. However, as noted in The Different Components of Environmental Enrichment, even in rodents, it is not clear exactly what aspects of environmental enrichment drive the observed effects and whether these effects would map directly onto humans. What is clear is that people vary in how much they expose themselves to these environmental enrichments, and the physical and mental changes associated with a wide range of disorders can be affected by enrichment.
Perhaps the most common attempt to translate environmental enrichment to humans can be seen in the promotion of a physically and cognitively active lifestyle for successful brain aging (https://www.nia.nih.gov/health/cognitive-health-and-older-adults). It is well known that aging is accompanied by memory loss and accelerated cognitive decline. The current consensus in the field is that leading a healthy physical and mentally active lifestyle is beneficial for the brain and body and is the key to successful healthy aging (Mora, 2013). Supported by the large amount of rodent data that exist demonstrating the positive effects of enriched environment on the cognitive deficits and neurobiological changes associated with aging, an active and all-around healthy lifestyle can be seen as a direct human parallel of environmental enrichment.
In fact, several studies in older adults have shown that engagement in both novel activities (Park et al., 2014) and more directed cognitive training (Rebok et al., 2014) could reduce the cognitive decline associated with aging. For example, the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) Study (Rebok et al., 2014) was a 10-year intervention study of more than 2,800 older participants who underwent a cognitive training intervention with a “kitchen sink” approach, focusing on memory, reasoning, and speed-of-processing skills. Although participants demonstrated clear improvements in the cognitive abilities for which they trained, there was only a modest improvement in performance-based measures of daily function. On the face of it, these studies appear to utilize at least some form of enrichment, yet gains were modest at best. Unpacking how an enriched environment influences the animal models may paint a clearer picture of why gains were not larger in humans and what might be done in future studies that attempt to use enrichment more directly as a treatment.
Animal models provide us with a vivid understanding of the underlying neurobiology of our brain and how our brain changes with experience. By understanding how our knowledge of animal models translates to humans, perhaps we can gain a better understanding of what a human correlate of environmental enrichment is. In the following section, we will explore how environmental enrichment relates to humans and we will specifically address this topic from the perspective of animal research. Furthermore, because the impact of environmental enrichment on brain neuroplasticity is so robust, we will specifically focus on human studies that explore the impact of the environment on brain structure and function.
Neurobiological Effects in Humans
Before we do this, however, it is worth explicitly noting that the studies in humans are necessarily more indirect. We have neither the experimental control over the environmental history in human studies, nor access to the wealth of neurobiological manipulations and measures that we can use in animal models. Thus, the goal of the human studies is often to determine the degree of concordance with findings in animal models rather than to resolutely test the underlying neurobiological mechanisms.
General Examples of Changes in Neuroplasticity with Experience
“Neuroplasticity” refers to the growth of new cells and synapses, and the rewiring of entire neural networks in response to experiences. It can occur in many regions of the brain, and changes in neuroplasticity are often associated with the domain in which learning has occurred. While neuroplasticity cannot be readily observed directly in humans, indirect evidence in the form of changes in magnetic resonance imaging (MRI) scans designed to assess structure (volume, gray matter density, etc.) or connectivity (white matter diffusion, functional connectivity, etc.) is readily available. For example, motor skill learning, from juggling (Boyke, Driemeyer, Gaser, Büchel, & May, 2008; Draganski et al., 2004; Gerber et al., 2014; Scholz, Klein, Behrens, & Johansen-Berg, 2009), to golfing (Bezzola, Mérillat, Gaser, & Jäncke, 2011), to balancing (Taubert et al., 2010), has been found to induce neuroplasticity in brain regions associated with the type of skill learned. There are even observations of plasticity associated with learning of more abstract knowledge such as medical knowledge (Draganski et al., 2006), mirror reading (Ilg et al., 2008), meditation (Tang et al., 2010), Morse code (Schmidt-Wilcke, Rosengarth, Luerding, Bogdahn, & Greenlee, 2010), new color names (Kwok et al., 2011), and working memory (Engvig et al., 2010). In addition, experts who have mastered specific skills and abilities have been shown to have alterations in the associated brain regions. Such effects have been observed in musicians (Bengtsson et al., 2005; Bermudez, Lerch, Evans, & Zatorre, 2009; Gaser & Schlaug, 2003), typists (Cannonieri, Bonilha, Fernandes, Cendes, & Li, 2007), London taxi drivers (Maguire et al., 2000), dancers (Hüfner et al., 2011), divers (Wei, Zhang, Jiang, & Luo, 2011), handball players (Hänggi et al., 2015), golfers (Jäncke, Koeneke, Hoppe, Rominger, & Hänggi, 2009), endurance athletes (Schlaffke et al., 2014), and martial artists (Jacini et al., 2009; Schlaffke et al., 2014). We should note that most (but not all) of these studies suffer from being purely correlational; therefore, we cannot reject the possibility that the differences observed in brain structure were preexisting conditions that enabled individuals to pursue these activities better. The presence in several of these many studies of clear “dose effects” (Bengtsson et al., 2005; Bezzola et al., 2011; Cannonieri et al., 2007; Gaser & Schlaug, 2003; Hänggi et al., 2015; Hüfner et al., 2011; Wei et al., 2011) and the use of several random trial designs (Boyke et al., 2008; Draganski et al., 2004; Engvig et al., 2010; Ilg et al., 2008; Schmidt-Wilcke et al., 2010; Scholz et al., 2009; Tang et al., 2010) suggest that we can put aside the hypothesis that preexisting differences are the sole source of the effects; the studies are clearly consistent with the hypothesis that even the adult human brain shows evidence of this form of neuroplasticity.
Even when viewing these results as examples of neuroplasticity driven by experience, their link to the effects in animal models of environmental enrichment is not entirely clear, given their indirect measures and the unclear mapping between these examples of skill learning and environmental enrichment. To gain a better understanding of how our knowledge of the environmental enrichment manipulation in animals translates to humans, we will take a closer look at the similarities between humans and animal models. Recognizing these similarities might provide insight into what environmental enrichment is in humans.
Adult Hippocampal Neurogenesis in Humans
As in animals, adult hippocampal neurogenesis exists in humans. The first piece of evidence suggesting that new neurons exist in the hippocampus of humans came from a study of postmortem tissue collected from patients diagnosed with skin cancer (Eriksson et al., 1998). These patients were treated with BrdU to assess the proliferative activity of the tumorous cells. Using immunohistochemistry, BrdU cells co-labeled with the mature neuronal marker NeuN were found near the granule cell layer of the dentate gyrus in the hippocampus in a postmortem histological analysis. This finding suggested that these cells divided at the time of BrdU injection and differentiated into mature neurons. As this study presented a snapshot of neurogenesis at a single time point, it did not address questions as to the dynamics of hippocampal neurogenesis in humans.
At least two other studies have observed dividing cells in the hippocampus using markedly different techniques (Manganas et al., 2007; Spalding et al., 2013). While the analyses are controversial (Friedman, 2008; Jansen, Gearhart, & Bulte, 2008), researchers identified a metabolic biomarker that is enriched in NPCs and, using magnetic resonance spectroscopy (MRS), were able to detect and quantify low concentrations of NPCs in vivo (Manganas et al., 2007). A second study observed the age of dividing cells in the hippocampus by measuring concentrations of radioactive carbon-14 (14C) in the genomic DNA of humans who lived during the Cold War (Spalding et al., 2013). Nuclear bomb testing resulted in a huge increase in atmospheric 14C, leading to the incorporation of 14C into the genomic DNA of dividing cells. The different concentrations of 14C in cells corresponded to their time of birth, allowing the retrospective dating of these cells (Bergmann et al., 2009; Spalding, Bhardwaj, Buchholz, Druid, & Frisén, 2005). These studies are consistent with the idea that, as in other mammals, adult neurogenesis exists in humans; they also serve to highlight the difficulty of carrying out this style of research in humans.
Exercise in Humans
As previously discussed (see The Different Components of Environmental Enrichment), physical exercise has been singled out as one of the most important components of an enriched environment; it has a particularly robust effect on adult hippocampal neurogenesis. Just as physical exercise enhances cognition and hippocampal neurogenesis in rodents, several studies have suggested that physical activity has a similar effect in humans (Bugg & Head, 2011; Colcombe et al., 2006, 2006; Erickson et al., 2009, 2010, 2011; Pereira et al., 2007; Ruscheweyh et al., 2011). In a side-by-side study comparing mice and humans, researchers showed that exercise had a similar effect on cerebral blood volume (CBV) in both humans and mice (Pereira et al., 2007). Although CBV is not a direct measure of neurogenesis, CBV is highly associated with angiogenesis (Dunn et al., 2004; Lin, Sun, Cheung, Li, & Chang, 2002), which is, in turn, associated with neurogenesis and the surrounding neurogenic niche (Louissaint, Rao, Leventhal, & Goldman, 2002; Palmer et al., 2000). In this study, researchers first demonstrated a correlation between exercise-induced CBV and neurogenesis (BrdU labeling) in the dentate gyrus of animals. After establishing this relationship, they showed that physical exercise selectively increased CBV in the dentate gyrus of humans, and this increase was correlated with aerobic fitness (V02max) and cognition (Rey Auditory Verbal Learning Test; RAVLT). Although this study did not directly measure neurogenesis in humans, it provides a powerful side-by-side comparison of humans and animal models and demonstrates similarities in the underlying neurobiology correlating with neurogenesis.
In a more direct comparison of hippocampal structure and physical activity, several studies have observed a strong correlation between the size of the hippocampus (in addition to other brain regions) and physical activity (Bugg & Head, 2011; Erickson et al., 2009, 2010). Higher levels of cardiovascular fitness, as measured by V02peak, were associated with an increase in hippocampal volume and spatial memory (Erickson et al., 2009) and predicted greater volumes of frontal, occipital, entorhinal, and hippocampal regions nine years later (Erickson et al., 2010). In older adults in whom age-related brain degeneration was well characterized, physical activity was shown to ameliorate the effects of aging, resulting in no brain atrophy in the medial temporal lobe when compared to controls (Bugg & Head, 2011). Importantly, age, sex, and years of education were controlled for in these studies. Although two studies (Bugg & Head, 2011; Erickson et al., 2010) observed a correlation between physical activity and other brain regions in addition to the hippocampus, it should be noted that they assessed physical activity with a questionnaire that spanned either nine or 10 years, making it difficult to dismiss other influential life experiences that occurred over that period.
To further understand the effects of physical activity on brain neuroplasticity, several studies have performed randomized exercise interventions (Colcombe et al., 2006; Erickson et al., 2011; Ruscheweyh et al., 2011). In a particularly influential study, 120 inactive older adults were recruited for a 12-month physical activity intervention study (Figure 2) (Erickson et al., 2011). Participants were randomly distributed into either an active (aerobic walking) or control (stretching) group. Following the intervention, participants in the physical activity group showed increases in hippocampal gray matter (Fig. 2A and 2B) when compared to controls, and an improvement in spatial memory (Fig. 2E and 2F). Interestingly, when looking at BDNF levels in serum, although researchers did not find an overall increase in BDNF in the physical activity group, they did observe that a greater change in BDNF levels was associated with a greater increase in hippocampal volume (Fig. 2C and 2D). Considering the pivotal role BDNF plays in the interaction between exercise and neurogenesis, these data suggest that exercise-induced changes in BDNF are associated with exercise-induced changes in the hippocampus. Several additional studies have examined the effects of physical activity within neurodegenerative clinical populations using randomized intervention studies (Krogh et al., 2014; Pajonk et al., 2010; ten Brinke et al., 2015). Although each of these studies observed an increase in hippocampal gray matter volume, results on symptoms and overall cognition were mixed.
Given the close relationship between physical exercise and hippocampal neurogenesis in the rodent model (see The Different Components of Environmental Enrichment), the behavioral impact of physical exercise may be more pronounced in more sensitive tasks of behavioral pattern separation. In rodents, long-term voluntary wheel-running increased pattern separation performance, an effect that was mediated at least in part by newborn neurons in the hippocampus (Creer et al., 2010). While several studies have explored behavioral pattern separation and exercise in humans, the length and intensity of training vary considerably, making the results difficult to interpret (Basso, Shang, Elman, Karmouta, & Suzuki, 2015; Déry et al., 2013; Suwabe et al., 2017). Six weeks of a high-intensity interval training program led to an improvement in behavioral pattern separation performance (Déry et al., 2013). Although there was no control group, researchers found a positive correlation between a change in V02peak and performance in the behavioral pattern separation task. Shorter, more acute exercise protocols have also been shown to impact hippocampus-related behavior; however, given the extremely short duration of exercise (10 minutes), these results are more likely to be an effect of exercise independent of hippocampal neurogenesis (Basso et al., 2015; Suwabe et al., 2017).
Spatial Knowledge of Real-World Environments in Humans
The critical involvement of the hippocampus in spatial memory has been studied in the rodent for over half a century (O’Keefe & Dostrovsky, 1971; O’Keefe & Nadel, 1978; Tolman, 1948). Not only is it clear that the hippocampus is necessary for spatial learning in rodents, but there are also underlying neural networks in the hippocampus that are dedicated to physical space (Hafting, Fyhn, Molden, Moser, & Moser, 2005; Morris, 1984; Moser, Rowland, & Moser, 2015; O’Keefe & Dostrovsky, 1971). Importantly, evidence exists to suggest that the hippocampus is also involved in humans during spatial learning, memory, and navigation (Maguire et al., 1998, 2000; Woollett, Spiers, & Maguire, 2009). Grid- and place-like cells have even been identified in humans (Ekstrom et al., 2003; Jacobs et al., 2013). As mentioned in The Different Components of Environmental Enrichment, an important aspect of enriched environments is the spatial exploration that the novel environments afford, and exploration of these environments is correlated with neuroplasticity in the hippocampus (Freund et al., 2013).
One of the most compelling demonstrations of increased hippocampal neuroplasticity with spatial expertise is the series of experiments performed on London taxi drivers. Obtaining a license as a London taxi cab driver is notoriously difficult and unique among taxi drivers anywhere in the world. The process of obtaining a London taxi driver license can take anywhere from three to four years to complete. Using structural MRI and voxel-based morphology (VBM), licensed London taxi drivers were compared with age-, education-, and intelligence-matched controls. Researchers found that the taxi drivers had increased gray matter volumes in the posterior hippocampus region compared to both controls (Maguire et al., 2000) and bus drivers (Maguire, Nannery, & Spiers, 2006) who follow a constrained route. This increase in gray matter volume correlated with the number of years spent as a taxi driver. In addition, increases in hippocampal volume were not observed in the intensive acquisition of large amounts of medical knowledge, such as gained by medical doctors, suggesting a certain amount of specificity for spatial knowledge (Woollett, Glensman, & Maguire, 2008).
To investigate whether the spatial knowledge gained from becoming a London taxi driver was responsible for the increase in hippocampal volume, the authors followed aspiring London taxi cab drivers as they obtained “the Knowledge” over the three to four years it took to obtain their license. Structural MRI scans of 79 trainees were taken before and after qualifying for the taxi driver license (39 received their London taxi driver license), and of 31 controls. Of these three groups (31 controls, 40 non-qualified taxi drivers, and 39 qualified taxi drivers), only the group that received their London taxi driver license demonstrated an increase in spatial knowledge and a specific increase in gray matter volume of the posterior hippocampi (Woollett & Maguire, 2011).
Combining Physical and Cognitive Training
Recently, several studies have taken a “kitchen-sink” approach and designed intervention studies with both cognitive and physical exercise, as well as diet and social experiences (Consortium, 2017; Lövdén et al., 2012; Ngandu et al., 2015; Rosen, Sugiura, Kramer, Whitfield-Gabrieli, & Gabrieli, 2011). Cognitive training included visual attention, auditory attention, verbal word lists, working memory, facial memory, logic, spatial memory, and more. Although the studies varied widely in participant number, participant age, type of cognitive intervention, intensity of the physical activity, and length of the intervention, all showed a positive benefit of the intervention on behavior, with a few studies even demonstrating increases in hippocampal cerebral blood flow (CBF) (Consortium, 2017) and blood oxygenation level dependent (BOLD) signal activation in the hippocampus (Consortium, 2017; Rosen et al., 2011). Results of structural changes in the hippocampus, however, were mixed. Hippocampal volume in patients with mild-cognitive impairment (MCI) patients did not increase despite an observed increase in BOLD activity and CBF (Consortium, 2017). In healthy young and older adults, a combination of spatial training and physical activity resulted in stable hippocampal volume compared to controls, whose hippocampal volume declined over the period of the intervention (Lövdén et al., 2012). However, the physical demands of this intervention were mild.
Cognitive Effects in Humans
In addition to the complementary effects of environmental enrichment on the underying neurobiology of both humans and animals, several human studies have demonstrated cognitive effects of enrichment which parallel the effects described in animals.
Spatial Knowledge of Virtual Environments in Humans
The studies presented here support the idea that real-world spatial knowledge is associated with hippocampal neuroplasticity; however, an additional field of spatial research lies within the virtual realm. It is important to point out that, even though there are clear differences between how humans perceive real and virtual environments (Ziemer, Plumert, Cremer, & Kearney, 2009), a large amount of research that has implicated the role of the hippocampus in spatial knowledge was performed in a virtual environment of some kind (Bohbot, Iaria, & Petrides, 2004; Bohbot, Lerch, Thorndycraft, Iaria, & Zijdenbos, 2007; Maguire et al., 1998). Importantly, components of the spatial-neural network are active even within these virtual environments, suggesting that, at a very basic level, the hippocampus treats virtual environments with some degree of similarity to real-world environments (Ekstrom et al., 2003; Harvey, Collman, Dombeck, & Tank, 2009; Jacobs et al., 2013; Schmidt-Hieber & Häusser, 2013).
While virtual environments are often used as a tool to explore spatial memory and the involvement (activity) of the hippocampus (as well as other regions of the medial temporal lobe), a few studies have used these environments to observe a correlation between spatial knowledge and hippocampal volume. When acquiring spatial knowledge of an environment, there are two common strategies used to navigate: a place strategy and a response strategy. Place strategies have been shown to rely more on the hippocampus (Maguire et al., 1998), whereas response strategies are more closely associated with the caudate nucleus (Hartley, Maguire, Spiers, & Burgess, 2003; Iaria, Petrides, Dagher, Pike, & Bohbot, 2003; Packard, Hirsh, & White, 1989). In one study, participants who naturally relied more on a spatial strategy had increased gray matter volume (assessed via VBM) in the hippocampus and decreased gray matter volume in the caudate nucleus compared to participants who naturally relied on a response strategy (Bohbot et al., 2007). Interestingly, hippocampal gray matter only correlated with the spontaneous navigation strategy used and not actual performance on the behavioral tasks (Konishi & Bohbot, 2013).
A recent study out of our own lab (Clemenson & Stark, 2015) attempted to translate the effects of enrichment via spatial exploration in rodents (e.g., Freund et al., 2013) into effects in humans on memory tasks known to require the hippocampus. Given the cited effects using virtual environments and given that modern 3D video games center around vast virtual environments, we hypothesized that the exploration of these engaging 3D environments could be a human correlate of environmental enrichment (Clemenson & Stark, 2015). Through a series of experiments, we found that participants who played video games that specifically included a 3D environment performed better on a virtual water maze task and a task of behavioral pattern separation. Furthermore, training naïve individuals for two weeks on the 3D video game “Super Mario 3D World” improved performance in both the virtual water maze and behavioral pattern separation task beyond that of both an active and passive control group (Clemenson & Stark, 2015). While this study was strictly behavioral, the tasks used were strongly tied to activity in the hippocampus as well as hippocampal neurogenesis in both rodents and humans (see Environmental Enrichment on Hippocampal Neuroplasticity and Behavior; Yassa & Stark, 2011), and they are consistent with the idea of environmental enrichment. In an independent study, another lab reported that playing the video game “Super Mario 64” for two months led to an increase in hippocampal gray matter (in addition to other regions), and the degree of increase correlated with a shift to a more hippocampal spatial navigation strategy (Kühn, Gleich, Lorenz, Lindenberger, & Gallinat, 2014). Although they did not control for more general aspects of playing video games, together, these studies support the idea that video games centered around 3D virtual environments can lead to structural and functional changes to the hippocampus, possibly through the spatial exploration that is required to successfully proceed through these video games.
Summary of Environmental Enrichment in Humans
From the foregoing discussion, it is clear that there are many similarities between animal and human studies. Both in terms of physical activity and of spatial exploration, we can see effects in humans that parallel those found in animal models, supporting the notion that the detailed observations we can make in animal models are applicable to us as well. In making the extrapolation from rodents to humans and to real-life applications of enrichment, we should note that isolating the effects of physical activity and spatial exploration may not be imperative. After all, a real-world environment requires a certain amount of physical activity to walk through and explore. In addition, in humans (and perhaps in animal models as well), physical spatial exploration may not be strictly required. Not only can spatial exploration be virtual, but other forms of cognitive enrichment may be effective as well. Such potential effects have not been well tested in animal models to date. But, by exploring more direct comparisons of translations between humans and animal models, we might gain a better understanding of what environmental enrichment means to humans.
While our genetic makeup is generally fixed, our brain is in a constant state of plasticity that is continuously modified by our experiences with the surrounding environment. This chapter highlights many of the studies in both animals and humans that help to bridge the gap and paint a more complete picture of the underlying mechanisms, the individual components, and the applications of environmental enrichment. Research in animals has provided undeniable evidence that simply changing an animal’s environment can enhance neuroplasticity (both at a cellular and synaptic level), increase neurotrophic factors, and ameliorate many of the negative cognitive symptoms associated with aging and other neurodegenerative diseases. Furthermore, human studies have demonstrated that many of the same factors that are critical to environmental enrichment in animals, such as exercise and spatial exploration, can also impact brain structure and behavior in humans. Since Donald Hebb’s day, our knowledge of how the environment can influence behavior, and of the structure and function of the brain, has expanded greatly. While there are obvious differences between animals and humans, there are clear parallels that we can draw upon to better understand the translation of how environmental enrichment can apply to humans and inform us how to live healthier and more cognitively enriching lives.
Aberg, M. A., Aberg, N. D., Hedbäcker, H., Oscarsson, J., & Eriksson, P. S. (2000). Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. Journal of Neuroscience, 20(8), 2896–2903.Find this resource:
Acheson, A., Conover, J. C., Fandl, J. P., DeChiara, T. M., Russell, M., Thadani, A., … Lindsay, R. M. (1995). A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature, 374(6521), 450–453.Find this resource:
Adlard, P. A., Perreau, V. M., & Cotman, C. W. (2005). The exercise-induced expression of BDNF within the hippocampus varies across life-span. Neurobiology of Aging, 26(4), 511–520.Find this resource:
Aguiar, A. S., Castro, A. A., Moreira, E. L., Glaser, V., Santos, A. R., Tasca, C. I., … Prediger, R. D. (2011). Short bouts of mild-intensity physical exercise improve spatial learning and memory in aging rats: Involvement of hippocampal plasticity via AKT, CREB and BDNF signaling. Mechanisms of Ageing and Development, 132(11–12), 560–567.Find this resource:
Aimone, J. B., Li, Y., Lee, S. W., Clemenson, G. D., Deng, W., & Gage, F. H. (2014). Regulation and function of adult neurogenesis: From genes to cognition. Physiological Reviews, 94(4), 991–1026.Find this resource:
Aimone, J. B., Wiles, J., & Gage, F. H. (2009). Computational influence of adult neurogenesis on memory encoding. Neuron, 61(2), 187–202.Find this resource:
Altman, J., & Das, G. D. (1964). Autoradiographic examination of the effects of enriched environment on the rate of glial multiplication in the adult rat brain. Nature, 204, 1161–1163.Find this resource:
Arendash, G. W., Garcia, M. F., Costa, D. A., Cracchiolo, J. R., Wefes, I. M., & Potter, H. (2004). Environmental enrichment improves cognition in aged Alzheimer’s transgenic mice despite stable beta-amyloid deposition. Neuroreport, 15(11), 1751–1754.Find this resource:
Barde, Y. A. (1994). Neurotrophins: A family of proteins supporting the survival of neurons. Progress in Clinical and Biological Research, 390, 45–56.Find this resource:
Barrientos, R. M., Frank, M. G., Crysdale, N. Y., Chapman, T. R., Ahrendsen, J. T., Day, H. E., … Maier, S. F. (2011). Little exercise, big effects: Reversing aging and infection-induced memory deficits, and underlying processes. Journal of Neuroscience, 31(32), 11578–11586.Find this resource:
Basso, J. C., Shang, A., Elman, M., Karmouta, R., & Suzuki, W. A. (2015). Acute exercise improves prefrontal cortex but not hippocampal function in healthy adults. Journal of the International Neuropsychological Society, 21(10), 791–801.Find this resource:
Bekinschtein, P., Oomen, C. A., Saksida, L. M., & Bussey, T. J. (2011). Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable? Seminars in Cell and Developmental Biology, 22(5), 536–542.Find this resource:
Bengtsson, S. L., Nagy, Z., Skare, S., Forsman, L., Forssberg, H., & Ullén, F. (2005). Extensive piano practicing has regionally specific effects on white matter development. Nature Neuroscience, 8(9), 1148–1150.Find this resource:
Bennett, E. L., Rosenzweig, M. R., & Diamond, M. C. (1969). Rat brain: Effects of environmental enrichment on wet and dry weights. Science (New York, N.Y.), 163(3869), 825–826.Find this resource:
Bergami, M., Rimondini, R., Santi, S., Blum, R., Götz, M., & Canossa, M. (2008). Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior. Proceedings of the National Academy of Sciences of the United States of America, 105(40), 15570–15575.Find this resource:
Bergmann, O., Bhardwaj, R. D., Bernard, S., Zdunek, S., Barnabé-Heider, F., Walsh, S., … Frisén, J. (2009). Evidence for cardiomyocyte renewal in humans. Science, 324(5923), 98–102.Find this resource:
Bermudez, P., Lerch, J. P., Evans, A. C., & Zatorre, R. J. (2009). Neuroanatomical correlates of musicianship as revealed by cortical thickness and voxel-based morphometry. Cerebral Cortex, 19(7), 1583–1596.Find this resource:
Bezzola, L., Mérillat, S., Gaser, C., & Jäncke, L. (2011). Training-induced neural plasticity in golf novices. Journal of Neuroscience, 31(35), 12444–12448.Find this resource:
Biernaskie, J., Chernenko, G., & Corbett, D. (2004). Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. Journal of Neuroscience, 24(5), 1245–1254.Find this resource:
Birch, A. M., McGarry, N. B., & Kelly, A. M. (2013). Short-term environmental enrichment, in the absence of exercise, improves memory, and increases NGF concentration, early neuronal survival, and synaptogenesis in the dentate gyrus in a time-dependent manner. Hippocampus, 23(6), 437–450.Find this resource:
Bohbot, V. D., Iaria, G., & Petrides, M. (2004). Hippocampal function and spatial memory: Evidence from functional neuroimaging in healthy participants and performance of patients with medial temporal lobe resections. Neuropsychology, 18(3), 418–425.Find this resource:
Bohbot, V. D., Lerch, J., Thorndycraft, B., Iaria, G., & Zijdenbos, A. P. (2007). Gray matter differences correlate with spontaneous strategies in a human virtual navigation task. Journal of Neuroscience, 27(38), 10078–10083.Find this resource:
Boyke, J., Driemeyer, J., Gaser, C., Büchel, C., & May, A. (2008). Training-induced brain structure changes in the elderly. Journal of Neuroscience, 28(28), 7031–7035.Find this resource:
Bramlett, H. M., & Dietrich, W. D. (2002). Quantitative structural changes in white and gray matter 1 year following traumatic brain injury in rats. Acta Neuropathologica, 103(6), 607–614.Find this resource:
Briones, T. L., Woods, J., & Rogozinska, M. (2013). Decreased neuroinflammation and increased brain energy homeostasis following environmental enrichment after mild traumatic brain injury is associated with improvement in cognitive function. Acta Neuropathologica Communications, 1, 57.Find this resource:
Broadbent, N. J., Gaskin, S., Squire, L. R., & Clark, R. E. (2010). Object recognition memory and the rodent hippocampus. Learning and Memory, 17(1), 5–11.Find this resource:
Bruel-Jungerman, E., Laroche, S., & Rampon, C. (2005). New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. European Journal of Neuroscience, 21(2), 513–521.Find this resource:
Buchhold, B., Mogoanta, L., Suofu, Y., Hamm, A., Walker, L., Kessler, C., & Popa-Wagner, A. (2007). Environmental enrichment improves functional and neuropathological indices following stroke in young and aged rats. Restorative Neurology and Neuroscience, 25(5–6), 467–484.Find this resource:
Bugg, J. M., & Head, D. (2011). Exercise moderates age-related atrophy of the medial temporal lobe. Neurobiology of Aging, 32(3), 506–514.Find this resource:
Cannonieri, G. C., Bonilha, L., Fernandes, P. T., Cendes, F., & Li, L. M. (2007). Practice and perfect: Length of training and structural brain changes in experienced typists. Neuroreport, 18(10), 1063–1066.Find this resource:
Cao, L., Jiao, X., Zuzga, D. S., Liu, Y., Fong, D. M., Young, D., & During, M. J. (2004). VEGF links hippocampal activity with neurogenesis, learning and memory. Nature Genetics, 36(8), 827–835.Find this resource:
Carro, E., Nuñez, A., Busiguina, S., & Torres-Aleman, I. (2000). Circulating insulin-like growth factor I mediates effects of exercise on the brain. Journal of Neuroscience, 20(8), 2926–2933.Find this resource:
Clelland, C. D., Choi, M., Romberg, C., Clemenson, G. D., Fragniere, A., Tyers, P., … Bussey, T. J. (2009). A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science, 325(5937), 210–213.Find this resource:
Clemenson, G. D., Lee, S. W., Deng, W., Barrera, V. R., Iwamoto, K. S., Fanselow, M. S., & Gage, F. H. (2015). Enrichment rescues contextual discrimination deficit associated with immediate shock. Hippocampus, 25(3), 385–392. https://doi.org/10.1002/hipo.22380Find this resource:
Clemenson, G. D., & Stark, C. E. (2015). Virtual environmental enrichment through video games improves hippocampal-associated memory. Journal of Neuroscience, 35(49), 16116–16125.Find this resource:
Colcombe, S. J., Erickson, K. I., Scalf, P. E., Kim, J. S., Prakash, R., McAuley, E., … Kramer, A. F. (2006). Aerobic exercise training increases brain volume in aging humans. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 61(11), 1166–1170.Find this resource:
Conner, J. M., Franks, K. M., Titterness, A. K., Russell, K., Merrill, D. A., Christie, B. R., … Tuszynski, M. H. (2009). NGF is essential for hippocampal plasticity and learning. Journal of Neuroscience, 29(35), 10883–10889.Find this resource:
Consortium, T. the B. (2017). Randomized trial on the effects of a combined physical/cognitive training in aged MCI subjects: The Train the Brain study. Scientific Reports, 7, 39471.Find this resource:
Creed, J. A., DiLeonardi, A. M., Fox, D. P., Tessler, A. R., & Raghupathi, R. (2011). Concussive brain trauma in the mouse results in acute cognitive deficits and sustained impairment of axonal function. Journal of Neurotrauma, 28(4), 547–563.Find this resource:
Creer, D. J., Romberg, C., Saksida, L. M., van Praag, H., & Bussey, T. J. (2010). Running enhances spatial pattern separation in mice. Proceedings of the National Academy of Sciences of the United States of America, 107(5), 2367–2372.Find this resource:
Dahlqvist, P., Rönnbäck, A., Bergström, S. A., Söderström, I., & Olsson, T. (2004). Environmental enrichment reverses learning impairment in the Morris water maze after focal cerebral ischemia in rats. European Journal of Neuroscience, 19(8), 2288–2298.Find this resource:
Darmopil, S., Petanjek, Z., Mohammed, A. H., & Bogdanović, N. (2009). Environmental enrichment alters dentate granule cell morphology in oldest-old rat. Journal of Cellular and Molecular Medicine, 13(8B), 1845–1856.Find this resource:
Déry, N., Pilgrim, M., Gibala, M., Gillen, J., Wojtowicz, J. M., Macqueen, G., & Becker, S. (2013). Adult hippocampal neurogenesis reduces memory interference in humans: Opposing effects of aerobic exercise and depression. Frontiers in Neuroscience, 7, 66.Find this resource:
Diamond, M. C., Law, F., Rhodes, H., Lindner, B., Rosenzweig, M. R., Krech, D., & Bennett, E. L. (1966). Increases in cortical depth and glia numbers in rats subjected to enriched environment. Journal of Comparative Neurology, 128(1), 117–126.Find this resource:
Draganski, B., Gaser, C., Busch, V., Schuierer, G., Bogdahn, U., & May, A. (2004). Neuroplasticity: Changes in grey matter induced by training. Nature, 427(6972), 311–312.Find this resource:
Draganski, B., Gaser, C., Kempermann, G., Kuhn, H. G., Winkler, J., Büchel, C., & May, A. (2006). Temporal and spatial dynamics of brain structure changes during extensive learning. Journal of Neuroscience, 26(23), 6314–6317.Find this resource:
Dunn, J. F., Roche, M. A., Springett, R., Abajian, M., Merlis, J., Daghlian, C. P., … Makki, M. (2004). Monitoring angiogenesis in brain using steady-state quantification of DeltaR2 with MION infusion. Magnetic Resonance in Medicine, 51(1), 55–61.Find this resource:
Ekstrom, A. D., Kahana, M. J., Caplan, J. B., Fields, T. A., Isham, E. A., Newman, E. L., & Fried, I. (2003). Cellular networks underlying human spatial navigation. Nature, 425(6954), 184–188.Find this resource:
Engvig, A., Fjell, A. M., Westlye, L. T., Moberget, T., Sundseth, Ø., Larsen, V. A., & Walhovd, K. B. (2010). Effects of memory training on cortical thickness in the elderly. Neuroimage, 52(4), 1667–1676.Find this resource:
Erickson, K. I., Prakash, R. S., Voss, M. W., Chaddock, L., Hu, L., Morris, K. S., … Kramer, A. F. (2009). Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus, 19(10), 1030–1039.Find this resource:
Erickson, K. I., Raji, C. A., Lopez, O. L., Becker, J. T., Rosano, C., Newman, A. B., … Kuller, L. H. (2010). Physical activity predicts gray matter volume in late adulthood: The Cardiovascular Health Study. Neurology, 75(16), 1415–1422.Find this resource:
Erickson, K. I., Voss, M. W., Prakash, R. S., Basak, C., Szabo, A., Chaddock, L., … Kramer, A. F. (2011). Exercise training increases size of hippocampus and improves memory. Proceedings of the National Academy of Sciences of the United States of America, 108(7), 3017–3022.Find this resource:
Eriksson, P. S., Perfilieva, E., Björk-Eriksson, T., Alborn, A. M., Nordborg, C., Peterson, D. A., & Gage, F. H. (1998). Neurogenesis in the adult human hippocampus. Nature Medicine, 4(11), 1313–1317.Find this resource:
Fabel, K., Tam, B., Kaufer, D., Baiker, A., Simmons, N., Kuo, C. J., & Palmer, T. D. (2003). VEGF is necessary for exercise-induced adult hippocampal neurogenesis. European Journal of Neuroscience, 18(10), 2803–2812.Find this resource:
Fabel, K., Wolf, S. A., Ehninger, D., Babu, H., Leal-Galicia, P., & Kempermann, G. (2009). Additive effects of physical exercise and environmental enrichment on adult hippocampal neurogenesis in mice. Frontiers in Neuroscience, 3, 50.Find this resource:
Faherty, C. J., Kerley, D., & Smeyne, R. J. (2003). A Golgi-Cox morphological analysis of neuronal changes induced by environmental enrichment. Brain Research. Developmental Brain Research, 141(1–2), 55–61.Find this resource:
Faherty, C. J., Raviie Shepherd, K., Herasimtschuk, A., & Smeyne, R. J. (2005). Environmental enrichment in adulthood eliminates neuronal death in experimental Parkinsonism. Brain Research. Molecular Brain Research, 134(1), 170–179.Find this resource:
Falkenberg, T., Mohammed, A. K., Henriksson, B., Persson, H., Winblad, B., & Lindefors, N. (1992). Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment. Neuroscience Letters, 138(1), 153–156.Find this resource:
Farmer, J., Zhao, X., van Praag, H., Wodtke, K., Gage, F. H., & Christie, B. R. (2004). Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. Neuroscience, 124(1), 71–79.Find this resource:
França, T. F. A., Bitencourt, A. M., Maximilla, N. R., Barros, D. M., & Monserrat, J. M. (2017). Hippocampal neurogenesis and pattern separation: A meta-analysis of behavioral data. Hippocampus, 27(9), 937-950.Find this resource:
Freund, J., Brandmaier, A. M., Lewejohann, L., Kirste, I., Kritzler, M., Krüger, A., … Kempermann, G. (2013). Emergence of individuality in genetically identical mice. Science, 340(6133), 756–759.Find this resource:
Frick, K. M., & Fernandez, S. M. (2003). Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice. Neurobiology of Aging, 24(4), 615–626.Find this resource:
Friedman, S. D. (2008). Comment on “Magnetic Resonance Spectroscopy Identifies Neural Progenitor Cells in the Live Human Brain.” Science (New York, N.Y.), 321(5889), 640. https://doi.org/10.1126/science.1153484Find this resource:
Frielingsdorf, H., Simpson, D. R., Thal, L. J., & Pizzo, D. P. (2007). Nerve growth factor promotes survival of new neurons in the adult hippocampus. Neurobiology of Disease, 26(1), 47–55.Find this resource:
Gage, F. H. (2000). Mammalian neural stem cells. Science, 287(5457), 1433–1438.Find this resource:
Garthe, A., Roeder, I., & Kempermann, G. (2016). Mice in an enriched environment learn more flexibly because of adult hippocampal neurogenesis. Hippocampus, 26(2), 261–271.Find this resource:
Gaser, C., & Schlaug, G. (2003). Brain structures differ between musicians and non-musicians. Journal of Neuroscience, 23(27), 9240–9245.Find this resource:
Ge, S., Yang, C. H., Hsu, K. S., Ming, G. L., & Song, H. (2007). A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron, 54(4), 559–566.Find this resource:
Gerber, P., Schlaffke, L., Heba, S., Greenlee, M. W., Schultz, T., & Schmidt-Wilcke, T. (2014). Juggling revisited—a voxel-based morphometry study with expert jugglers. Neuroimage, 95, 320–325.Find this resource:
Gilbert, P. E., Kesner, R. P., & Lee, I. (2001). Dissociating hippocampal subregions: Fouble dissociation between dentate gyrus and CA1. Hippocampus, 11(6), 626–636.Find this resource:
Gogolla, N., Galimberti, I., Deguchi, Y., & Caroni, P. (2009). Wnt signaling mediates experience-related regulation of synapse numbers and mossy fiber connectivities in the adult hippocampus. Neuron, 62(4), 510–525.Find this resource:
Goldberg, J. S., & Hirschi, K. K. (2013). A vascular perspective on neurogenesis. In L. Bonfanti (Ed.), Neural stem cells – new perspectives (pp. 199-239). Rijeka, Croatia: Intech.Find this resource:
Goldberg, N. R., Fields, V., Pflibsen, L., Salvatore, M. F., & Meshul, C. K. (2012). Social enrichment attenuates nigrostriatal lesioning and reverses motor impairment in a progressive 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. Neurobiology of Disease, 45(3), 1051–1067.Find this resource:
Goldberg, N. R., Haack, A. K., & Meshul, C. K. (2011). Enriched environment promotes similar neuronal and behavioral recovery in a young and aged mouse model of Parkinson’s disease. Neuroscience, 172, 443–452.Find this resource:
Gomez-Pinilla, F., & Hillman, C. (2013). The influence of exercise on cognitive abilities. Comprehensive Physiology, 3(1), 403–428.Find this resource:
Gonçalves, J. T., Schafer, S. T., & Gage, F. H. (2016). Adult neurogenesis in the hippocampus: From stem cells to behavior. Cell, 167(4), 897–914.Find this resource:
Gould, E., Beylin, A., Tanapat, P., Reeves, A., & Shors, T. J. (1999). Learning enhances adult neurogenesis in the hippocampal formation. Nature Neuroscience, 2(3), 260–265.Find this resource:
Greenough, W. T., & Volkmar, F. R. (1973). Pattern of dendritic branching in occipital cortex of rats reared in complex environments. Experimental Neurology, 40(2), 491–504.Find this resource:
Greenough, W. T., West, R. W., & DeVoogd, T. J. (1978). Subsynaptic plate perforations: Changes with age and experience in the rat. Science, 202(4372), 1096–1098.Find this resource:
Griesbach, G. S., Gómez-Pinilla, F., & Hovda, D. A. (2007). Time window for voluntary exercise-induced increases in hippocampal neuroplasticity molecules after traumatic brain injury is severity dependent. Journal of Neurotrauma, 24(7), 1161–1171.Find this resource:
Hafting, T., Fyhn, M., Molden, S., Moser, M. B., & Moser, E. I. (2005). Microstructure of a spatial map in the entorhinal cortex. Nature, 436(7052), 801–806.Find this resource:
Hamm, R. J., Temple, M. D., O’Dell, D. M., Pike, B. R., & Lyeth, B. G. (1996). Exposure to environmental complexity promotes recovery of cognitive function after traumatic brain injury. Journal of Neurotrauma, 13(1), 41–47.Find this resource:
Hänggi, J., Langer, N., Lutz, K., Birrer, K., Mérillat, S., & Jäncke, L. (2015). Structural brain correlates associated with professional handball playing. PLoS ONE, 10(4), e0124222.Find this resource:
Hartley, T., Maguire, E. A., Spiers, H. J., & Burgess, N. (2003). The well-worn route and the path less traveled: Distinct neural bases of route following and wayfinding in humans. Neuron, 37(5), 877–888.Find this resource:
Harvey, C. D., Collman, F., Dombeck, D. A., & Tank, D. W. (2009). Intracellular dynamics of hippocampal place cells during virtual navigation. Nature, 461(7266), 941–946.Find this resource:
Hebb, D. . (1947). The effects of early experience on problem solving at maturity. American Psychologist, 2, 306–307.Find this resource:
Held, J. M., Gordon, J., & Gentile, A. M. (1985). Environmental influences on locomotor recovery following cortical lesions in rats. Behavioral Neuroscience, 99(4), 678–690.Find this resource:
Hicks, R. R., Smith, D. H., Lowenstein, D. H., Saint Marie, R., & McIntosh, T. K. (1993). Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. Journal of Neurotrauma, 10(4), 405–414.Find this resource:
Hockly, E., Cordery, P. M., Woodman, B., Mahal, A., van Dellen, A., Blakemore, C., … Bates, G. P. (2002). Environmental enrichment slows disease progression in R6/2 Huntington’s disease mice. Annals of Neurology, 51(2), 235–242.Find this resource:
Holloway, R. L. (1966). Dendritic branching: Some preliminary results of training and complexity in rat visual cortex. Brain Research, 2(4), 393–396.Find this resource:
Hu, Y. S., Long, N., Pigino, G., Brady, S. T., & Lazarov, O. (2013). Molecular mechanisms of environmental enrichment: Impairments in Akt/GSK3β, neurotrophin-3 and CREB signaling. PLoS ONE, 8(5), e64460.Find this resource:
Hu, Y. S., Xu, P., Pigino, G., Brady, S. T., Larson, J., & Lazarov, O. (2010). Complex environment experience rescues impaired neurogenesis, enhances synaptic plasticity, and attenuates neuropathology in familial Alzheimer’s disease-linked APPswe/PS1DeltaE9 mice. FASEB Journal, 24(6), 1667–1681.Find this resource:
Huang, E. J., & Reichardt, L. F. (2001). Neurotrophins: Roles in neuronal development and function. Annual Review of Neuroscience, 24, 677–736. https://doi.org/10.1146/annurev.neuro.24.1.677Find this resource:
Hüfner, K., Binetti, C., Hamilton, D. A., Stephan, T., Flanagin, V. L., Linn, J., … Brandt, T. (2011). Structural and functional plasticity of the hippocampal formation in professional dancers and slackliners. Hippocampus, 21(8), 855–865.Find this resource:
Iaria, G., Petrides, M., Dagher, A., Pike, B., & Bohbot, V. D. (2003). Cognitive strategies dependent on the hippocampus and caudate nucleus in human navigation: Variability and change with practice. Journal of Neuroscience, 23(13), 5945–5952.Find this resource:
Ibi, D., Takuma, K., Koike, H., Mizoguchi, H., Tsuritani, K., Kuwahara, Y., … Yamada, K. (2008). Social isolation rearing-induced impairment of the hippocampal neurogenesis is associated with deficits in spatial memory and emotion-related behaviors in juvenile mice. Journal of Neurochemistry, 105(3), 921–932.Find this resource:
Ickes, B. R., Pham, T. M., Sanders, L. A., Albeck, D. S., Mohammed, A. H., & Granholm, A. C. (2000). Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain. Experimental Neurology, 164(1), 45–52.Find this resource:
Ilg, R., Wohlschläger, A. M., Gaser, C., Liebau, Y., Dauner, R., Wöller, A., … Mühlau, M. (2008). Gray matter increase induced by practice correlates with task-specific activation: A combined functional and morphometric magnetic resonance imaging study. Journal of Neuroscience, 28(16), 4210–4215.Find this resource:
Jacini, W. F., Cannonieri, G. C., Fernandes, P. T., Bonilha, L., Cendes, F., & Li, L. M. (2009). Can exercise shape your brain? Cortical differences associated with judo practice. Journal of Science and Medicine in Sport, 12(6), 688–690.Find this resource:
Jacobs, J., Weidemann, C. T., Miller, J. F., Solway, A., Burke, J. F., Wei, X. X., … Kahana, M. J. (2013). Direct recordings of grid-like neuronal activity in human spatial navigation. Nature Neuroscience, 16(9), 1188–1190.Find this resource:
Jadavji, N. M., Kolb, B., & Metz, G. A. (2006). Enriched environment improves motor function in intact and unilateral dopamine-depleted rats. Neuroscience, 140(4), 1127–1138.Find this resource:
Jäncke, L., Koeneke, S., Hoppe, A., Rominger, C., & Hänggi, J. (2009). The architecture of the golfer’s brain. PLoS ONE, 4(3), e4785.Find this resource:
Jankowsky, J. L., Melnikova, T., Fadale, D. J., Xu, G. M., Slunt, H. H., Gonzales, V., … Savonenko, A. V. (2005). Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer’s disease. Journal of Neuroscience, 25(21), 5217–5224.Find this resource:
Jansen, J. F., Gearhart, J. D., & Bulte, J. W. (2008). Comment on “Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain.” Science, 321(5889), 640.Find this resource:
Janssen, H., Bernhardt, J., Collier, J. M., Sena, E. S., McElduff, P., Attia, J., … Spratt, N. J. (2010). An enriched environment improves sensorimotor function post-ischemic stroke. Neurorehabilitation and Neural Repair, 24(9), 802–813.Find this resource:
Jin, K., Zhu, Y., Sun, Y., Mao, X. O., Xie, L., & Greenberg, D. A. (2002). Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America, 99(18), 11946–11950.Find this resource:
Johansson, B. B. (1996). Functional outcome in rats transferred to an enriched environment 15 days after focal brain ischemia. Stroke, 27(2), 324–326.Find this resource:
Johansson, B. B., & Ohlsson, A. L. (1996). Environment, social interaction, and physical activity as determinants of functional outcome after cerebral infarction in the rat. Experimental Neurology, 139(2), 322–327.Find this resource:
Johnson, E. M., Traver, K. L., Hoffman, S. W., Harrison, C. R., & Herman, J. P. (2013). Environmental enrichment protects against functional deficits caused by traumatic brain injury. Frontiers in Behavioral Neuroscience, 7, 44.Find this resource:
Jungling, A., Reglodi, D., Karadi, Z. N., Horvath, G., Farkas, J., Gaszner, B., & Tamas, A. (2017). Effects of postnatal enriched environment in a model of Parkinson’s disease in adult rats. International Journal of Molecular Sciences, 18(2), 406.Find this resource:
Kempermann, G., Gast, D., & Gage, F. H. (2002). Neuroplasticity in old age: Sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Annals of Neurology, 52(2), 135–143.Find this resource:
Kempermann, G., Kuhn, H. G., & Gage, F. H. (1997). More hippocampal neurons in adult mice living in an enriched environment. Nature, 386(6624), 493–495.Find this resource:
Knieling, M., Metz, G. A., Antonow-Schlorke, I., & Witte, O. W. (2009). Enriched environment promotes efficiency of compensatory movements after cerebral ischemia in rats. Neuroscience, 163(3), 759–769.Find this resource:
Kobilo, T., Liu, Q. R., Gandhi, K., Mughal, M., Shaham, Y., & van Praag, H. (2011). Running is the neurogenic and neurotrophic stimulus in environmental enrichment. Learning and Memory, 18(9), 605–609.Find this resource:
Kolb, B., Gorny, G., Söderpalm, A. H. V., & Robinson, T. E. (2003). Environmental complexity has different effects on the structure of neurons in the prefrontal cortex versus the parietal cortex or nucleus accumbens. Synapse, 48(3), 149–153. https://doi.org/10.1002/syn.10196Find this resource:
Konishi, K., & Bohbot, V. D. (2013). Spatial navigational strategies correlate with gray matter in the hippocampus of healthy older adults tested in a virtual maze. Frontiers in Aging Neuroscience, 5, 1.Find this resource:
Kovesdi, E., Gyorgy, A. B., Kwon, S. K., Wingo, D. L., Kamnaksh, A., Long, J. B., … Agoston, D. V. (2011). The effect of enriched environment on the outcome of traumatic brain injury; a behavioral, proteomics, and histological study. Frontiers in Neuroscience, 5, 42.Find this resource:
Krech, D., Rosenzweig, M. R., & Bennett, E. L. (1960). Effects of environmental complexity and training on brain chemistry. Journal of Comparative and Physiological Psychology, 53, 509–519.Find this resource:
Kreilaus, F., Spiro, A. S., Hannan, A. J., Garner, B., & Jenner, A. M. (2016). Therapeutic effects of anthocyanins and environmental enrichment in R6/1 Huntington’s disease mice. Journal of Huntington’s Disease, 5(3), 285–296.Find this resource:
Krogh, J., Rostrup, E., Thomsen, C., Elfving, B., Videbech, P., & Nordentoft, M. (2014). The effect of exercise on hippocampal volume and neurotrophins in patients with major depression—a randomized clinical trial. Journal of Affective Disorders, 165, 24–30.Find this resource:
Kronenberg, G., Reuter, K., Steiner, B., Brandt, M. D., Jessberger, S., Yamaguchi, M., & Kempermann, G. (2003). Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli. Journal of Comparative Neurology, 467(4), 455–463.Find this resource:
Kühn, S., Gleich, T., Lorenz, R. C., Lindenberger, U., & Gallinat, J. (2014). Playing Super Mario induces structural brain plasticity: Gray matter changes resulting from training with a commercial video game. Molecular Psychiatry, 19(2), 265–271.Find this resource:
Kumar, A., Rani, A., Tchigranova, O., Lee, W. H., & Foster, T. C. (2012). Influence of late-life exposure to environmental enrichment or exercise on hippocampal function and CA1 senescent physiology. Neurobiology of Aging, 33(4), 828.e1–17.Find this resource:
Kwok, V., Niu, Z., Kay, P., Zhou, K., Mo, L., Jin, Z., … Tan, L. H. (2011). Learning new color names produces rapid increase in gray matter in the intact adult human cortex. Proceedings of the National Academy of Sciences of the United States of America, 108(16), 6686–6688.Find this resource:
Lazarov, O., Robinson, J., Tang, Y. P., Hairston, I. S., Korade-Mirnics, Z., Lee, V. M., … Sisodia, S. S. (2005). Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell, 120(5), 701–713.Find this resource:
Lazic, S. E., Grote, H. E., Blakemore, C., Hannan, A. J., van Dellen, A., Phillips, W., & Barker, R. A. (2006). Neurogenesis in the R6/1 transgenic mouse model of Huntington’s disease: Effects of environmental enrichment. European Journal of Neuroscience, 23(7), 1829–1838.Find this resource:
Leal-Galicia, P., Castañeda-Bueno, M., Quiroz-Baez, R., & Arias, C. (2008). Long-term exposure to environmental enrichment since youth prevents recognition memory decline and increases synaptic plasticity markers in aging. Neurobiology of Learning and Memory, 90(3), 511–518.Find this resource:
Leasure, J. L., & Decker, L. (2009). Social isolation prevents exercise-induced proliferation of hippocampal progenitor cells in female rats. Hippocampus, 19(10), 907–912.Find this resource:
Leasure, J. L., & Grider, M. (2010). The effect of mild post-stroke exercise on reactive neurogenesis and recovery of somatosensation in aged rats. Experimental Neurology, 226(1), 58–67.Find this resource:
Leggio, M. G., Mandolesi, L., Federico, F., Spirito, F., Ricci, B., Gelfo, F., & Petrosini, L. (2005). Environmental enrichment promotes improved spatial abilities and enhanced dendritic growth in the rat. Behavioral Brain Research, 163(1), 78–90.Find this resource:
Leuner, B., Mendolia-Loffredo, S., Kozorovitskiy, Y., Samburg, D., Gould, E., & Shors, T. J. (2004). Learning enhances the survival of new neurons beyond the time when the hippocampus is required for memory. Journal of Neuroscience, 24(34), 7477–7481.Find this resource:
Leutgeb, J. K., Leutgeb, S., Moser, M. B., & Moser, E. I. (2007). Pattern separation in the dentate gyrus and CA3 of the hippocampus. Science, 315(5814), 961–966.Find this resource:
Li, Y., Luikart, B. W., Birnbaum, S., Chen, J., Kwon, C. H., Kernie, S. G., … Parada, L. F. (2008). TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron, 59(3), 399–412.Find this resource:
Lin, T. N., Sun, S. W., Cheung, W. M., Li, F., & Chang, C. (2002). Dynamic changes in cerebral blood flow and angiogenesis after transient focal cerebral ischemia in rats. Evaluation with serial magnetic resonance imaging. Stroke, 33(12), 2985–2991.Find this resource:
Lindner, M. D., Plone, M. A., Cain, C. K., Frydel, B., Francis, J. M., Emerich, D. F., & Sutton, R. L. (1998). Dissociable long-term cognitive deficits after frontal versus sensorimotor cortical contusions. Journal of Neurotrauma, 15(3), 199–216.Find this resource:
Lopez-Lopez, C., LeRoith, D., & Torres-Aleman, I. (2004). Insulin-like growth factor I is required for vessel remodeling in the adult brain. Proceedings of the National Academy of Sciences of the United States of America, 101(26), 9833–9838.Find this resource:
Louissaint, A., Rao, S., Leventhal, C., & Goldman, S. A. (2002). Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron, 34(6), 945–960.Find this resource:
Lövdén, M., Schaefer, S., Noack, H., Bodammer, N. C., Kühn, S., Heinze, H. J., … Lindenberger, U. (2012). Spatial navigation training protects the hippocampus against age-related changes during early and late adulthood. Neurobiology of Aging, 33(3), 620.e9–620.e22.Find this resource:
Lu, L., Bao, G., Chen, H., Xia, P., Fan, X., Zhang, J., … Ma, L. (2003). Modification of hippocampal neurogenesis and neuroplasticity by social environments. Experimental Neurology, 183(2), 600–609.Find this resource:
Maguire, E. A., Burgess, N., Donnett, J. G., Frackowiak, R. S., Frith, C. D., & O’Keefe, J. (1998). Knowing where and getting there: A human navigation network. Science, 280(5365), 921–924.Find this resource:
Maguire, E. A., Gadian, D. G., Johnsrude, I. S., Good, C. D., Ashburner, J., Frackowiak, R. S., & Frith, C. D. (2000). Navigation-related structural change in the hippocampi of taxi drivers. Proceedings of the National Academy of Sciences of the United States of America, 97(8), 4398–4403.Find this resource:
Maguire, E. A., Nannery, R., & Spiers, H. J. (2006). Navigation around London by a taxi driver with bilateral hippocampal lesions. Brain, 129(Pt 11), 2894–2907.Find this resource:
Manganas, L. N., Zhang, X., Li, Y., Hazel, R. D., Smith, S. D., Wagshul, M. E., … Maletic-Savatic, M. (2007). Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science, 318(5852), 980–985.Find this resource:
McHugh, T. J., Jones, M. W., Quinn, J. J., Balthasar, N., Coppari, R., Elmquist, J. K., … Tonegawa, S. (2007). Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science, 317(5834), 94–99.Find this resource:
Meshi, D., Drew, M. R., Saxe, M., Ansorge, M. S., David, D., Santarelli, L., … Hen, R. (2006). Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nature Neuroscience, 9(6), 729–731.Find this resource:
Mirmiran, M., Van Gool, W. A., Van Haaren, F., & Polak, C. E. (1986). Environmental influences on brain and behavior in aging and Alzheimer’s disease. Progress in Brain Research, 70, 443–459.Find this resource:
Monteiro, B. M., Moreira, F. A., Massensini, A. R., Moraes, M. F., & Pereira, G. S. (2014). Enriched environment increases neurogenesis and improves social memory persistence in socially isolated adult mice. Hippocampus, 24(2), 239–248.Find this resource:
Mora, F. (2013). Successful brain aging: Plasticity, environmental enrichment, and lifestyle. Dialogues in Clinical Neuroscience, 15(1), 45–52.Find this resource:
Mora-Gallegos, A., Rojas-Carvajal, M., Salas, S., Saborío-Arce, A., Fornaguera-Trías, J., & Brenes, J. C. (2015). Age-dependent effects of environmental enrichment on spatial memory and neurochemistry. Neurobiology of Learning and Memory, 118, 96–104.Find this resource:
Morris, R. (1984). Developments of a water-maze procedure for studying spatial learning in the rat. Journal of Neuroscience Methods, 11(1), 47–60.Find this resource:
Moser, M. B., Rowland, D. C., & Moser, E. I. (2015). Place cells, grid cells, and memory. Cold Spring Harbor Perspectives in Biology, 7(2), a021808.Find this resource:
Moser, M. B., Trommald, M., & Andersen, P. (1994). An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses. Proceedings of the National Academy of Sciences of the United States of America, 91(26), 12673–12675.Find this resource:
Mustroph, M. L., Chen, S., Desai, S. C., Cay, E. B., DeYoung, E. K., & Rhodes, J. S. (2012). Aerobic exercise is the critical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice. Neuroscience, 219, 62–71.Find this resource:
Neeper, S. A., Gómez-Pinilla, F., Choi, J., & Cotman, C. W. (1996). Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Research, 726(1–2), 49–56.Find this resource:
Ngandu, T., Lehtisalo, J., Solomon, A., Levälahti, E., Ahtiluoto, S., Antikainen, R., … Kivipelto, M. (2015). A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): A randomised controlled trial. Lancet, 385(9984), 2255–2263.Find this resource:
Nilsson, M., Perfilieva, E., Johansson, U., Orwar, O., & Eriksson, P. S. (1999). Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. Journal of Neurobiology, 39(4), 569–578.Find this resource:
Nithianantharajah, J., Barkus, C., Murphy, M., & Hannan, A. J. (2008). Gene-environment interactions modulating cognitive function and molecular correlates of synaptic plasticity in Huntington’s disease transgenic mice. Neurobiology of Disease, 29(3), 490–504.Find this resource:
Nithianantharajah, J., Levis, H., & Murphy, M. (2004). Environmental enrichment results in cortical and subcortical changes in levels of synaptophysin and PSD-95 proteins. Neurobiology of Learning and Memory, 81(3), 200–210.Find this resource:
O’Keefe, J., & Dostrovsky, J. (1971). The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Research, 34(1), 171–175.Find this resource:
O’Keefe, J., & Nadel, L. (1978). The hippocampus as a cognitive map. Oxford; New York: Clarendon Press; Oxford University Press.Find this resource:
Olson, A. K., Eadie, B. D., Ernst, C., & Christie, B. R. (2006). Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus, 16(3), 250–260.Find this resource:
Packard, M. G., Hirsh, R., & White, N. M. (1989). Differential effects of fornix and caudate nucleus lesions on two radial maze tasks: Evidence for multiple memory systems. Journal of Neuroscience, 9(5), 1465–1472.Find this resource:
Pajonk, F. G., Wobrock, T., Gruber, O., Scherk, H., Berner, D., Kaizl, I., … Falkai, P. (2010). Hippocampal plasticity in response to exercise in schizophrenia. Archives of General Psychiatry, 67(2), 133–143.Find this resource:
Palmer, T. D., Willhoite, A. R., & Gage, F. H. (2000). Vascular niche for adult hippocampal neurogenesis. Journal of Comparative Neurology, 425(4), 479–494.Find this resource:
Pang, T. Y., Stam, N. C., Nithianantharajah, J., Howard, M. L., & Hannan, A. J. (2006). Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in Huntington’s disease transgenic mice. Neuroscience, 141(2), 569–584.Find this resource:
Park, D. C., Lodi-Smith, J., Drew, L., Haber, S., Hebrank, A., Bischof, G. N., & Aamodt, W. (2014). The impact of sustained engagement on cognitive function in older adults: The Synapse Project. Psychological Science, 25(1), 103–112.Find this resource:
Passineau, M. J., Green, E. J., & Dietrich, W. D. (2001). Therapeutic effects of environmental enrichment on cognitive function and tissue integrity following severe traumatic brain injury in rats. Experimental Neurology, 168(2), 373–384.Find this resource:
Pereira, A. C., Huddleston, D. E., Brickman, A. M., Sosunov, A. A., Hen, R., McKhann, G. M., … Small, S. A. (2007). An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proceedings of the National Academy of Sciences of the United States of America, 104(13), 5638–5643.Find this resource:
Pierce, J. E., Smith, D. H., Trojanowski, J. Q., & McIntosh, T. K. (1998). Enduring cognitive, neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats. Neuroscience, 87(2), 359–369.Find this resource:
Puurunen, K., Jolkkonen, J., Sirviö, J., Haapalinna, A., & Sivenius, J. (2001). Selegiline combined with enriched-environment housing attenuates spatial learning deficits following focal cerebral ischemia in rats. Experimental Neurology, 167(2), 348–355.Find this resource:
Rai, K. S., Hattiangady, B., & Shetty, A. K. (2007). Enhanced production and dendritic growth of new dentate granule cells in the middle-aged hippocampus following intracerebroventricular FGF-2 infusions. European Journal of Neuroscience, 26(7), 1765–1779.Find this resource:
Rampon, C., Jiang, C. H., Dong, H., Tang, Y. P., Lockhart, D. J., Schultz, P. G., … Hu, Y. (2000). Effects of environmental enrichment on gene expression in the brain. Proceedings of the National Academy of Sciences of the United States of America, 97(23), 12880–12884.Find this resource:
Rebok, G. W., Ball, K., Guey, L. T., Jones, R. N., Kim, H. Y., King, J. W., … Group, A. S. (2014). Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. Journal of the American Geriatric Society, 62(1), 16–24.Find this resource:
Regensburger, M., Prots, I., & Winner, B. (2014). Adult hippocampal neurogenesis in Parkinson’s disease: Impact on neuronal survival and plasticity. Neural Plasticity, 2014, 454696.Find this resource:
Risedal, A., Mattsson, B., Dahlqvist, P., Nordborg, C., Olsson, T., & Johansson, B. B. (2002). Environmental influences on functional outcome after a cortical infarct in the rat. Brain Research Bulletin, 58(3), 315–321.Find this resource:
Rodríguez, J. J., & Verkhratsky, A. (2011). Neurogenesis in Alzheimer’s disease. Journal of Anatomy, 219(1), 78–89.Find this resource:
Rojas, J. J., Deniz, B. F., Miguel, P. M., Diaz, R., Hermel, E. o E., Achaval, M., … Pereira, L. O. (2013). Effects of daily environmental enrichment on behavior and dendritic spine density in hippocampus following neonatal hypoxia-ischemia in the rat. Experimental Neurology, 241, 25–33.Find this resource:
Rönnbäck, A., Dahlqvist, P., Svensson, P. A., Jernås, M., Carlsson, B., Carlsson, L. M., & Olsson, T. (2005). Gene expression profiling of the rat hippocampus one month after focal cerebral ischemia followed by enriched environment. Neuroscience Letters, 385(2), 173–178.Find this resource:
Rosen, A. C., Sugiura, L., Kramer, J. H., Whitfield-Gabrieli, S., & Gabrieli, J. D. (2011). Cognitive training changes hippocampal function in mild cognitive impairment: A pilot study. Journal of Alzheimer’s Disease, 26(Suppl 3), 349–357.Find this resource:
Rosenzweig, M. R., Krech, D., Bennett, E. L., & Diamond, M. C. (1962). Effects of environmental complexity and training on brain chemistry and anatomy: A replication and extension. Journal of Comparative and Physiological Psychology, 55, 429–437.Find this resource:
Rossi, C., Angelucci, A., Costantin, L., Braschi, C., Mazzantini, M., Babbini, F., … Caleo, M. (2006). Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. European Journal of Neuroscience, 24(7), 1850–1856.Find this resource:
Ruscheweyh, R., Willemer, C., Krüger, K., Duning, T., Warnecke, T., Sommer, J., … Flöel, A. (2011). Physical activity and memory functions: An interventional study. Neurobiology of Aging, 32(7), 1304–1319.Find this resource:
Sahay, A., Scobie, K. N., Hill, A. S., O’Carroll, C. M., Kheirbek, M. A., Burghardt, N. S., … Hen, R. (2011). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature, 472(7344), 466–470.Find this resource:
Saito, S., Kobayashi, S., Ohashi, Y., Igarashi, M., Komiya, Y., & Ando, S. (1994). Decreased synaptic density in aged brains and its prevention by rearing under enriched environment as revealed by synaptophysin contents. Journal of Neuroscience Research, 39(1), 57–62.Find this resource:
Sampedro-Piquero, P., Begega, A., Zancada-Menendez, C., Cuesta, M., & Arias, J. L. (2013). Age-dependent effects of environmental enrichment on brain networks and spatial memory in Wistar rats. Neuroscience, 248, 43–53.Find this resource:
Scharfman, H., Goodman, J., Macleod, A., Phani, S., Antonelli, C., & Croll, S. (2005). Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Experimental Neurology, 192(2), 348–356.Find this resource:
Schilling, G., Savonenko, A. V., Coonfield, M. L., Morton, J. L., Vorovich, E., Gale, A., … Borchelt, D. R. (2004). Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice. Experimental Neurology, 187(1), 137–149.Find this resource:
Schlaffke, L., Lissek, S., Lenz, M., Brüne, M., Juckel, G., Hinrichs, T., … Schmidt-Wilcke, T. (2014). Sports and brain morphology—a voxel-based morphometry study with endurance athletes and martial artists. Neuroscience, 259, 35–42.Find this resource:
Schmidt-Hieber, C., & Häusser, M. (2013). Cellular mechanisms of spatial navigation in the medial entorhinal cortex. Nature Neuroscience, 16(3), 325–331.Find this resource:
Schmidt-Hieber, C., Jonas, P., & Bischofberger, J. (2004). Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature, 429(6988), 184–187.Find this resource:
Schmidt-Wilcke, T., Rosengarth, K., Luerding, R., Bogdahn, U., & Greenlee, M. W. (2010). Distinct patterns of functional and structural neuroplasticity associated with learning Morse code. Neuroimage, 51(3), 1234–1241.Find this resource:
Scholz, J., Klein, M. C., Behrens, T. E., & Johansen-Berg, H. (2009). Training induces changes in white-matter architecture. Nature Neuroscience, 12(11), 1370–1371.Find this resource:
Schrijver, N. C., Pallier, P. N., Brown, V. J., & Würbel, H. (2004). Double dissociation of social and environmental stimulation on spatial learning and reversal learning in rats. Behavioral Brain Research, 152(2), 307–314.Find this resource:
Segovia, G., Yagüe, A. G., García-Verdugo, J. M., & Mora, F. (2006). Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and GABA in the hippocampus of aged rats. Brain Research Bulletin, 70(1), 8–14.Find this resource:
Shors, T. J., Townsend, D. A., Zhao, M., Kozorovitskiy, Y., & Gould, E. (2002). Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus, 12(5), 578–584.Find this resource:
Smith, D. H., Chen, X. H., Pierce, J. E., Wolf, J. A., Trojanowski, J. Q., Graham, D. I., & McIntosh, T. K. (1997). Progressive atrophy and neuron death for one year following brain trauma in the rat. Journal of Neurotrauma, 14(10), 715–727.Find this resource:
Sonninen, R., Virtanen, T., Sivenius, J., & Jolkkonen, J. (2006). Gene expression profiling in the hippocampus of rats subjected to focal cerebral ischemia and enriched environment housing. Restorative Neurology and Neuroscience, 24(1), 17–23.Find this resource:
Spalding, K. L., Bergmann, O., Alkass, K., Bernard, S., Salehpour, M., Huttner, H. B., … Frisén, J. (2013). Dynamics of hippocampal neurogenesis in adult humans. Cell, 153(6), 1219–1227.Find this resource:
Spalding, K. L., Bhardwaj, R. D., Buchholz, B. A., Druid, H., & Frisén, J. (2005). Retrospective birth dating of cells in humans. Cell, 122(1), 133–143.Find this resource:
Speisman, R. B., Kumar, A., Rani, A., Pastoriza, J. M., Severance, J. E., Foster, T. C., & Ormerod, B. K. (2013). Environmental enrichment restores neurogenesis and rapid acquisition in aged rats. Neurobiology of Aging, 34(1), 263–274.Find this resource:
Spires, T. L., Grote, H. E., Varshney, N. K., Cordery, P. M., van Dellen, A., Blakemore, C., & Hannan, A. J. (2004). Environmental enrichment rescues protein deficits in a mouse model of Huntington’s disease, indicating a possible disease mechanism. Journal of Neuroscience, 24(9), 2270–2276.Find this resource:
Stark, S., & Stark, C. E. L. (2016). The aging hippocampus: Linking animal and human research. In Cognitive Neuroscience of Aging (2nd ed., pp. 273–300). Oxford Scholarship Online. doi:10.1093/acprof:oso/9780199372935.003.0012Find this resource:
Stein, L. R., O’Dell, K. A., Funatsu, M., Zorumski, C. F., & Izumi, Y. (2016). Short-term environmental enrichment enhances synaptic plasticity in hippocampal slices from aged rats. Neuroscience, 329, 294–305.Find this resource:
Steiner, B., Zurborg, S., Hörster, H., Fabel, K., & Kempermann, G. (2008). Differential 24 h responsiveness of Prox1-expressing precursor cells in adult hippocampal neurogenesis to physical activity, environmental enrichment, and kainic acid-induced seizures. Neuroscience, 154(2), 521–529.Find this resource:
Suwabe, K., Hyodo, K., Byun, K., Ochi, G., Yassa, M. A., & Soya, H. (2017). Acute moderate exercise improves mnemonic discrimination in young adults. Hippocampus, 27(3), 229–234.Find this resource:
Tang, Y. Y., Lu, Q., Geng, X., Stein, E. A., Yang, Y., & Posner, M. I. (2010). Short-term meditation induces white matter changes in the anterior cingulate. Proceedings of the National Academy of Sciences of the United States of America, 107(35), 15649–15652.Find this resource:
Tashiro, A., Makino, H., & Gage, F. H. (2007). Experience-specific functional modification of the dentate gyrus through adult neurogenesis: A critical period during an immature stage. Journal of Neuroscience, 27(12), 3252–3259.Find this resource:
Taubert, M., Draganski, B., Anwander, A., Müller, K., Horstmann, A., Villringer, A., & Ragert, P. (2010). Dynamic properties of human brain structure: Learning-related changes in cortical areas and associated fiber connections. Journal of Neuroscience, 30(35), 11670–11677.Find this resource:
ten Brinke, L. F., Bolandzadeh, N., Nagamatsu, L. S., Hsu, C. L., Davis, J. C., Miran-Khan, K., & Liu-Ambrose, T. (2015). Aerobic exercise increases hippocampal volume in older women with probable mild cognitive impairment: A 6-month randomised controlled trial. British Journal of Sports Medicine, 49(4), 248–254.Find this resource:
Tillerson, J. L., Caudle, W. M., Reverón, M. E., & Miller, G. W. (2003). Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson’s disease. Neuroscience, 119(3), 899–911.Find this resource:
Tolman, E. C. (1948). Cognitive maps in rats and men. Psychological Review, 55(4), 189–208.Find this resource:
Tolwani, R. J., Buckmaster, P. S., Varma, S., Cosgaya, J. M., Wu, Y., Suri, C., & Shooter, E. M. (2002). BDNF overexpression increases dendrite complexity in hippocampal dentate gyrus. Neuroscience, 114(3), 795–805.Find this resource:
Trejo, J. L., Carro, E., & Torres-Aleman, I. (2001). Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. Journal of Neuroscience, 21(5), 1628–1634.Find this resource:
Valero, J., España, J., Parra-Damas, A., Martín, E., Rodríguez-Álvarez, J., & Saura, C. A. (2011). Short-term environmental enrichment rescues adult neurogenesis and memory deficits in APP(Sw,Ind) transgenic mice. PLoS ONE, 6(2), e16832.Find this resource:
Van der Borght, K., Kóbor-Nyakas, D. E., Klauke, K., Eggen, B. J., Nyakas, C., Van der Zee, E. A., & Meerlo, P. (2009). Physical exercise leads to rapid adaptations in hippocampal vasculature: Temporal dynamics and relationship to cell proliferation and neurogenesis. Hippocampus, 19(10), 928–936.Find this resource:
van Praag, H., Christie, B. R., Sejnowski, T. J., & Gage, F. H. (1999). Running enhances neurogenesis, learning, and long-term potentiation in mice. Proceedings of the National Academy of Sciences of the United States of America, 96(23), 13427–13431.Find this resource:
van Praag, H., Kempermann, G., & Gage, F. H. (1999). Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neuroscience, 2(3), 266–270.Find this resource:
van Praag, H., Kempermann, G., & Gage, F. H. (2000). Neural consequences of environmental enrichment. Nature Reviews Neuroscience, 1(3), 191–198.Find this resource:
van Praag, H., Schinder, A. F., Christie, B. R., Toni, N., Palmer, T. D., & Gage, F. H. (2002). Functional neurogenesis in the adult hippocampus. Nature, 415(6875), 1030–1034.Find this resource:
van Praag, H., Shubert, T., Zhao, C., & Gage, F. H. (2005). Exercise enhances learning and hippocampal neurogenesis in aged mice. Journal of Neuroscience, 25(38), 8680–8685.Find this resource:
Vivar, C., Potter, M. C., & van Praag, H. (2013). All about running: Synaptic plasticity, growth factors and adult hippocampal neurogenesis. Current Topics in Behavioral Neuroscience, 15, 189–210.Find this resource:
Wakade, C., Sukumari-Ramesh, S., Laird, M. D., Dhandapani, K. M., & Vender, J. R. (2010). Delayed reduction in hippocampal postsynaptic density protein-95 expression temporally correlates with cognitive dysfunction following controlled cortical impact in mice. Journal of Neurosurgery, 113(6), 1195–1201.Find this resource:
Walsh, R. N., Budtz-Olsen, O. E., Penny, J. E., & Cummins, R. A. (1969). The effects of environmental complexity on the histology of the rat hippocampus. Journal of Comparative Neurology, 137(3), 361–366.Find this resource:
Walsh, R. N., & Cummins, R. A. (1979). Changes in hippocampal neuronal nuclei in response to environmental stimulation. International Journal of Neuroscience, 9(4), 209–212.Find this resource:
Webster, S. J., Bachstetter, A. D., Nelson, P. T., Schmitt, F. A., & Van Eldik, L. J. (2014). Using mice to model Alzheimer’s dementia: An overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Frontiers in Genetics, 5, 88.Find this resource:
Wei, G., Zhang, Y., Jiang, T., & Luo, J. (2011). Increased cortical thickness in sports experts: A comparison of diving players with the controls. PLoS ONE, 6(2), e17112.Find this resource:
Wolf, S. A., Kronenberg, G., Lehmann, K., Blankenship, A., Overall, R., Staufenbiel, M., & Kempermann, G. (2006). Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer’s disease. Biological Psychiatry, 60(12), 1314–1323.Find this resource:
Woollett, K., Glensman, J., & Maguire, E. A. (2008). Non-spatial expertise and hippocampal gray matter volume in humans. Hippocampus, 18(10), 981–984.Find this resource:
Woollett, K., & Maguire, E. A. (2011). Acquiring “the Knowledge” of London’s layout drives structural brain changes. Current Biology, 21(24), 2109–2114.Find this resource:
Woollett, K., Spiers, H. J., & Maguire, E. A. (2009). Talent in the taxi: A model system for exploring expertise. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 364(1522), 1407–1416.Find this resource:
Wurm, F., Keiner, S., Kunze, A., Witte, O. W., & Redecker, C. (2007). Effects of skilled forelimb training on hippocampal neurogenesis and spatial learning after focal cortical infarcts in the adult rat brain. Stroke, 38(10), 2833–2840.Find this resource:
Xie, H., Wu, Y., Jia, J., Liu, G., Zhang, F., Zhang, Q., … Hu, R. (2013). Enriched environment preconditioning induced brain ischemic tolerance without reducing infarct volume and edema: The possible role of enrichment-related physical activity increase. Brain Research, 1508, 63–72.Find this resource:
Yassa, M. A., & Stark, C. E. (2011). Pattern separation in the hippocampus. Trends in Neuroscience, 34(10), 515–525.Find this resource:
Yoshimura, S., Takagi, Y., Harada, J., Teramoto, T., Thomas, S. S., Waeber, C., … Moskowitz, M. A. (2001). FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proceedings of the National Academy of Sciences of the United States of America, 98(10), 5874–5879.Find this resource:
Yu, K., Wu, Y., Hu, Y., Zhang, Q., Xie, H., Liu, G., … Jia, J. (2013). Neuroprotective effects of prior exposure to enriched environment on cerebral ischemia/reperfusion injury in rats: The possible molecular mechanism. Brain Research, 1538, 93–103.Find this resource:
Zajac, M. S., Pang, T. Y., Wong, N., Weinrich, B., Leang, L. S., Craig, J. M., … Hannan, A. J. (2010). Wheel running and environmental enrichment differentially modify exon-specific BDNF expression in the hippocampus of wild-type and pre-motor symptomatic male and female Huntington’s disease mice. Hippocampus, 20(5), 621–636.Find this resource:
Zeleznikow-Johnston, A., Burrows, E. L., Renoir, T., & Hannan, A. J. (2017). Environmental enrichment enhances cognitive flexibility in C57BL/6 mice on a touchscreen reversal learning task. Neuropharmacology, 117, 219–226.Find this resource:
Zhao, C., Jou, J., Wolff, L. J., Sun, H., & Gage, F. H. (2014). Spine morphogenesis in newborn granule cells is differentially regulated in the outer and middle molecular layers. Journal of Comparative Neurology, 522(12), 2756–2766.Find this resource:
Zhao, C., Teng, E. M., Summers, R. G., Ming, G. L., & Gage, F. H. (2006). Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. Journal of Neuroscience, 26(1), 3–11.Find this resource:
Ziemer, C. J., Plumert, J. M., Cremer, J. F., & Kearney, J. K. (2009). Estimating distance in real and virtual environments: Does order make a difference? Attention, Perception, and Psychophysics, 71(5), 1095–1106.Find this resource: