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‘Enriched environments’ are a key experimental paradigm to decipher how interactions between genes and environment change the structure and function of the brain across the lifespan of an animal. The regulation of adult hippocampal neurogenesis by environmental enrichment is a prime example of this complex interaction. As each animal in an enriched environment will have a slightly different set of experiences that results in downstream differences between individuals, enrichment can be considered not only as an external source of rich stimuli but also to provide the room for individual behaviour that shapes individual patterns of brain plasticity and thus function.Environmental enrichment is a classical experimental paradigm for the study of the interaction between genes and the environment. In this Opinion, Kempermann discusses how this paradigm can be further developed in order to capture the essence of interindividual differences in brain function.

Adult hippocampal neurogenesis is a unique and exceptional process in the mammalian brain that in a lifelong and activity-dependent way generates new excitatory principal neurons. A comprehensive view on their function in greater contexts has now emerged, revealing to which extent the hippocampus (and hence brain and mind) depend on these neurons. Due to a postmitotic period of heightened synaptic plasticity they bias incoming excitation to the dentate gyrus to non-overlapping subnetworks, resulting in pattern separation and the avoidance of catastrophic interference. Temporally, this promotes the flexible integration of novel information into familiar contexts and contributes to episodic memory, which in humans would be critical for autobiographic memory. Together these local effects represent a unique strategy to solve the plasticity-stability dilemma that all learning neuronal networks are facing. Neurogenesis-dependent plasticity also improves memory consolidation. This relates to the surprising involvement of adult neurogenesis in forgetting, which is also hypothesized to be critically relevant for negative plasticity, for example in post-traumatic stress disorder. In addition, adult-born neurons also directly mediate stress-resilience and take part in affective behaviors. Finally, the activity- and experience-dependent plasticity that is contributed by adult neurogenesis is associated with an individualization of the hippocampal circuitry. While a solid and largely consensual understanding of how new neurons contribute to hippocampal function has been reached, an overarching unifying theory that embeds neurogenesis-dependent functionality and effects on connectomics is still missing. More sophisticated multi-electrode electrophysiology, advanced ethologically relevant behavioral tests, and next-generation computational modeling will let us take the next steps.

The Cynefin scheme is a concept of knowledge management, originally devised to support decision making in management, but more generally applicable to situations, in which complexity challenges the quality of insight, prediction, and decision. Despite the fact that life itself, and especially the brain and its diseases, are complex to the extent that complexity could be considered their cardinal feature, complex problems in biomedicine are often treated as if they were actually not more than the complicated sum of solvable sub-problems. Because of the emergent properties of complex contexts this is not correct. With a set of clear criteria Cynefin helps to set apart complex problems from \"simple/obvious,\" \"complicated,\" \"chaotic,\" and \"disordered\" contexts in order to avoid misinterpreting the relevant causality structures. The distinction comes with the insight, which specific kind of knowledge is possible in each of these categories and what are the consequences for resulting decisions and actions. From student's theses over the publication and grant writing process to research politics, misinterpretation of complexity can have problematic or even dangerous consequences, especially in clinical contexts. Conceptualization of problems within a straightforward reference language like Cynefin improves clarity and stringency within projects and facilitates communication and decision-making about them.

The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracts age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is critical to neuronal function. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the stimulating effects of environmental enrichment on hippocampal plasticity at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions. Decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Here the authors provide evidence that environmental enrichment delays age-related DNA methylation alterations in the mouse hippocampus.

Functional plasticity of the brain decreases during ageing causing marked deficits in contextual learning, allocentric navigation and episodic memory. Adult neurogenesis is a prime example of hippocampal plasticity promoting the contextualisation of information and dramatically decreases during ageing. We found that a genetically-driven expansion of neural stem cells by overexpression of the cell cycle regulators Cdk4/cyclinD1 compensated the age-related decline in neurogenesis. This triggered an overall inhibitory effect on the trisynaptic hippocampal circuit resulting in a changed profile of CA1 sharp-wave ripples known to underlie memory consolidation. Most importantly, increased neurogenesis rescued the age-related switch from hippocampal to striatal learning strategies by rescuing allocentric navigation and contextual memory. Our study demonstrates that critical aspects of hippocampal function can be reversed in old age, or compensated throughout life, by exploiting the brain’s endogenous reserve of neural stem cells. Ageing affects several brain areas causing a decrease in cognitive abilities and memory. We find that increasing the endogenous potential of the hippocampus to generate new neurons throughout life rejuvenates learning and memory, indicating that neural reserves can be exploited during ageing to compensate for age- or disease-related cognitive impairments.

Some immature neurons in the cerebral cortex of mammals might wait for years before they become activated and finish their development.Some immature neurons in the cerebral cortex of mammals might wait for years before they become activated and finish their development.

To effectively promote life-long health and resilience against - for example - neurodegenerative diseases, evidence-based recommendations must acknowledge the complex multidimensionality not only of the diseases but also of personal lifestyle. In a straightforward descriptive and heuristic framework, more than 50 potential lifestyle factors cluster around diet (D), education (E), exercise (E), and purpose (P), unveiling their many relationships across domains and scales. The resulting systematics and its visualization might be a small but helpful step toward the development of more comprehensive, interdisciplinary models of lifestyle-dependent risk and resilience and a means to explain the opportunities and limitations of preventive measures to the public and other stakeholders. Most importantly, this perspective onto the subject implies that not all lifestyle factors are created equal but that there is a hierarchy of values and needs that influences the success of lifestyle-based interventions.

Despite enormous progress in the past few years the specific contribution of newly born granule cells to the function of the adult hippocampus is still not clear. We hypothesized that in order to solve this question particular attention has to be paid to the specific design, the analysis, and the interpretation of the learning test to be used. We thus designed a behavioral experiment along hypotheses derived from a computational model predicting that new neurons might be particularly relevant for learning conditions, in which novel aspects arise in familiar situations, thus putting high demands on the qualitative aspects of (re-)learning.In the reference memory version of the water maze task suppression of adult neurogenesis with temozolomide (TMZ) caused a highly specific learning deficit. Mice were tested in the hidden platform version of the Morris water maze (6 trials per day for 5 days with a reversal of the platform location on day 4). Testing was done at 4 weeks after the end of four cycles of treatment to minimize the number of potentially recruitable new neurons at the time of testing. The reduction of neurogenesis did not alter longterm potentiation in CA3 and the dentate gyrus but abolished the part of dentate gyrus LTP that is attributed to the new neurons. TMZ did not have any overt side effects at the time of testing, and both treated mice and controls learned to find the hidden platform. Qualitative analysis of search strategies, however, revealed that treated mice did not advance to spatially precise search strategies, in particular when learning a changed goal position (reversal). New neurons in the dentate gyrus thus seem to be necessary for adding flexibility to some hippocampus-dependent qualitative parameters of learning.Our finding that a lack of adult-generated granule cells specifically results in the animal's inability to precisely locate a hidden goal is also in accordance with a specialized role of the dentate gyrus in generating a metric rather than just a configurational map of the environment. The discovery of highly specific behavioral deficits as consequence of a suppression of adult hippocampal neurogenesis thus allows to link cellular hippocampal plasticity to well-defined hypotheses from theoretical models.

The Morris water maze represents the de-facto standard for testing hippocampal function in laboratory rodents. In the field of adult hippocampal neurogenesis, however, using this paradigm to assess the functional relevance of the new neurons yielded surprisingly inconsistent results. While some authors found aspects of water maze performance to be linked to adult neurogenesis, others obtained different results or could not demonstrate any effect of manipulating adult neurogenesis. In this review we discuss evidence that the large diversity of protocols and setups used is an important aspect in interpreting the differences in the results that have been obtained. Even simple parameters such as pool size, number, and configuration of visual landmarks, or number of trials can become highly relevant for getting the new neurons involved at all. Sets of parameters are often chosen with implicit or explicit concepts in mind and these might lead to different views on the function of adult-generated neurons. We propose that the classical parameters usually used to measure spatial learning performance in the water maze might not be particularly well-suited to sensitively and specifically detect the supposedly highly specific functional changes elicited by the experimental modulation of adult hippocampal neurogenesis. As adult neurogenesis is supposed to affect specific aspects of information processing only in the hippocampus, any claim for a functional relevance of the new neurons has to be based on hippocampus-specific parameters. We also placed a special emphasis on the fact that the dentate gyrus (DG) facilitates the differentiation between contexts as opposed to just differentiating places. In conclusion, while the Morris water maze has proven to be one of the most effective testing paradigms to assess hippocampus-dependent spatial learning, new and more specific questions ask for new parameters. Therefore, the full potential of the water maze task remains to be tapped.

Brain plasticity as a neurobiological reflection of individuality is difficult to capture in animal models. Inspired by behavioral-genetic investigations of human monozygotic twins reared together, we obtained dense longitudinal activity data on 40 inbred mice living in one large enriched environment. The exploratory activity of the mice diverged over time, resulting in increasing individual differences with advancing age. Individual differences in cumulative roaming entropy, indicating the active coverage of territory, correlated positively with individual differences in adult hippocampal neurogenesis. Our results show that factors unfolding or emerging during development contribute to individual differences in structural brain plasticity and behavior. The paradigm introduced here serves as an animal model for identifying mechanisms of plasticity underlying nonshared environmental contributions to individual differences in behavior.