Giving birth gives birth to neurons.

In mice, pregnancy results in new neurons that support recognition of pups.

The embodied mind in motion: a neuroscientific and philosophical perspective on prevention and therapy of dementia.

The embodied mind in motion is a concept in which health and well-being, prevention and therapy, as well as lifestyle and habits meet. The mind changes profoundly in the course of dementias, affecting daily living and resulting in reduced quality of life. Interdisciplinary approaches are required for a holistic understanding of how the mind is affected by dementia. We here explore what such a holistic theory of dementia might look like and propose the idea of "embodied mind in motion". The paradigm is biopsychosocial or biocultural, the theoretical anchor point is the lifeworld, and the guiding concept is "embodiment," as body and mind are constantly in motion. Physical activity is, hence, central for the experience of health and well-being, beyond being "exercise" and "health behavior". We discuss the embodied mind in motion referring to phenomenology, enactivism and (philosophical) anthropology. In our view, habits are embodied long-term memories and a philosophical equivalent to lifestyle. They unfold the meaningfulness of moving the body, complementing the objectifiable benefits of physical exercise. Empirical studies on "holistic activities" like hiking, yoga, music and dance illustrate improved integration into everyday life. Their meaningfulness enhances compliance and increases the preventive and even therapeutic potential. A crucial factor for this is the emotional dimension of lifestyle, exemplified by the virally popularized performance of "Swan Lake" by wheel-chair bound ex-ballerina Marta Cinta González Saldaña, suffering from Alzheimer's disease. A number of epistemological and ontological consequences anchor "embodied movement" as a valuable principle for dementia research.

High-resolution CMOS-based biosensor for assessing hippocampal circuit dynamics in experience-dependent plasticity.

Experiential richness creates tissue-level changes and synaptic plasticity as patterns emerge from rhythmic spatiotemporal activity of large interconnected neuronal assemblies. Despite numerous experimental and computational approaches at different scales, the precise impact of experience on network-wide computational dynamics remains inaccessible due to the lack of applicable large-scale recording methodology. We here demonstrate a large-scale multi-site biohybrid brain circuity on-CMOS-based biosensor with an unprecedented spatiotemporal resolution of 4096 microelectrodes, which allows simultaneous electrophysiological assessment across the entire hippocampal-cortical subnetworks from mice living in an enriched environment (ENR) and standard-housed (SD) conditions. Our platform, empowered with various computational analyses, reveals environmental enrichment's impacts on local and global spatiotemporal neural dynamics, firing synchrony, topological network complexity, and large-scale connectome. Our results delineate the distinct role of prior experience in enhancing multiplexed dimensional coding formed by neuronal ensembles and error tolerance and resilience to random failures compared to standard conditions. The scope and depth of these effects highlight the critical role of high-density, large-scale biosensors to provide a new understanding of the computational dynamics and information processing in multimodal physiological and experience-dependent plasticity conditions and their role in higher brain functions. Knowledge of these large-scale dynamics can inspire the development of biologically plausible computational models and computational artificial intelligence networks and expand the reach of neuromorphic brain-inspired computing into new applications.

Presymptomatic Reduction of Individuality in the AppNL-F Knockin Model of Alzheimer's Disease.

BACKGROUND: One-third of the risk for Alzheimer's disease is explained by environment and lifestyle, but Alzheimer's disease pathology might also affect lifestyle and thereby impair the individual potential for health behavior and prevention. METHODS: We examined in mice how the AppNL-F/NL-F (NL-F) knockin mutation affects the presymptomatic response to environmental enrichment (ENR) as an experimental paradigm addressing nongenetic factors. We assessed the emergence of interindividual phenotypic variation under the condition that both the genetic background and the shared environment were held constant, thereby isolating the contribution of individual behavior (nonshared environment). RESULTS: After 4 months of ENR, the mean and variability of plasma ApoE were increased in NL-F mice, suggesting a presymptomatic variation in pathogenic processes. Roaming entropy as a measure of behavioral activity was continuously assessed with radiofrequency identification (RFID) technology and revealed reduced habituation and variance in NL-F mice compared with control animals, which do not carry a Beyreuther/Iberian mutation. Intraindividual variation decreased, while behavioral stability was reduced in NL-F mice. Seven months after discontinuation of ENR, we found no difference in plaque size and number, but ENR increased variance in hippocampal plaque counts in NL-F mice. A reactive increase in adult hippocampal neurogenesis in NL-F mice, known from other models, was normalized by ENR. CONCLUSIONS: Our data suggest that while NL-F has early effects on individual behavioral patterns in response to ENR, there are lasting effects on cellular plasticity even after the discontinuation of ENR. Hence, early behavior matters for maintaining individual behavioral trajectories and brain plasticity even under maximally constrained conditions.

Loss of individualized behavioral trajectories in adult neurogenesis-deficient cyclin D2 knockout mice.

There is still limited mechanistic insight into how the interaction of individuals with their environment results in the emergence of individuality in behavior and brain structure. Nevertheless, the idea that personal activity shapes the brain is implicit in strategies for healthy cognitive aging as well as in the idea that individuality is reflected in the brain's connectome. We have shown that even isogenic mice kept in a shared enriched environment (ENR) developed divergent and stable social and exploratory trajectories. As these trajectories-measured as roaming entropy (RE)-positively correlated with adult hippocampal neurogenesis, we hypothesized that a feedback between behavioral activity and adult hippocampal neurogenesis might be a causal factor in brain individualization. We used cyclin D2 knockout mice with constitutively extremely low levels of adult hippocampal neurogenesis and their wild-type littermates. We housed them for 3 months in a novel ENR paradigm, consisting of 70 connected cages equipped with radio frequency identification antennae for longitudinal tracking. Cognitive performance was evaluated in the Morris Water Maze task (MWM). With immunohistochemistry we confirmed that adult neurogenesis correlated with RE in both genotypes and that D2 knockout mice had the expected impaired performance in the reversal phase of the MWM. But whereas the wild-type animals developed stable exploratory trajectories with increasing variance, correlating with adult neurogenesis, this individualizing phenotype was absent in D2 knockout mice. Here the behaviors started out more random and revealed less habituation and low variance. Together, these findings suggest that adult neurogenesis contributes to experience-dependent brain individualization.

Individual behavioral trajectories shape whole-brain connectivity in mice.

It is widely assumed that our actions shape our brains and that the resulting connections determine who we are. To test this idea in a reductionist setting, in which genes and environment are controlled, we investigated differences in neuroanatomy and structural covariance by ex vivo structural magnetic resonance imaging in mice whose behavioral activity was continuously tracked for 3 months in a large, enriched environment. We confirmed that environmental enrichment increases mouse hippocampal volumes. Stratifying the enriched group according to individual longitudinal behavioral trajectories, however, revealed striking differences in mouse brain structural covariance in continuously highly active mice compared to those whose trajectories showed signs of habituating activity. Network-based statistics identified distinct subnetworks of murine structural covariance underlying these differences in behavioral activity. Together, these results reveal that differentiated behavioral trajectories of mice in an enriched environment are associated with differences in brain connectivity.

An individual's experiences and behavior shape their brain, thereby building and refining a network of connections between neurons. This unique network may affect an individual's brain resilience in the face of aging, injury or disease. Understanding how individual experiences shape brain connections could help scientists develop personalized treatments. It may also have important implications for preventing brain disease. Studying mice can provide a window into some of these brain processes. By using inbred mice, scientists can rule out the role of genetics in brain differences. Scientists can also control the animals' environments and track the activity of individuals to study their behavior. Bogado Lopes et al. show that more active mice living in enriched environments have signs of more complex networks of brain connections. In the experiments, the researchers placed genetically identical mice in either standard laboratory mouse housing or in enriched environments. Mice in the enriched housing had access to multi-level enclosures connected with tubes and supplied with a rotating array of toys. A tiny tracking device was inserted under the skin of the mice to follow their movements. Finally, all mice underwent structural magnetic resonance imaging to assess their brain anatomy and connections. This revealed that the most active and adventurous mice in the enriched enclosures had the most robust signs of increased brain connectivity. However, mice with declining activity levels in the enriched enclosures had fewer brain connections. Brain connection patterns in these creatures of habit were nearly identical to the ones in mice housed in small unenriched enclosures. The results show that how individual mice respond to their environments affects their brain structure. More active behavior patterns lead to more robust networks of brain connections. Larger studies in mice could provide more about lifestyle-dependent brain resilience. It may also help scientists to develop individualized approaches to optimizing brain health.

The individuality paradigm: Automated longitudinal activity tracking of large cohorts of genetically identical mice in an enriched environment.

Personalized medicine intensifies interest in experimental paradigms that delineate sources of phenotypic variation. The paradigm of environmental enrichment allows for comparisons among differently housed laboratory rodents to unravel environmental effects on brain plasticity and related phenotypes. We have developed a new longitudinal variant of this paradigm, which allows to investigate the emergence of individuality, the divergence of individual behavioral trajectories under a constant genetic background and in a shared environment. We here describe this novel method, the "Individuality Paradigm," which allows to investigate mechanisms that drive individuality. Various aspects of individual activity are tracked over time to identify the contribution of the non-shared environment, that is the extent to which the experience of an environment differs between individual members of a population. We describe the design of this paradigm in detail, lay out its scientific potential beyond the published studies and discuss how it differs from other approaches to study individuality. The custom-built cage system, commercially marketed as "ColonyRack", allows mice to roam freely between 70 cages through connector tubes equipped with ring antennas that detect each animal's ID from an RFID transponder implanted in the animal's neck. The system has a total floor area of 2.74 m2 and its spatial resolution corresponds to the size of the individual cages. Spatiotemporally resolved antenna contacts yield longitudinal measures of individual behavior, including the powerful measure of roaming entropy (RE). The Individuality Paradigm provides a rodent model of the making of individuality and the impact of the 'non-shared' environment on life-course development.

Musical Activity During Life Is Associated With Multi-Domain Cognitive and Brain Benefits in Older Adults.

Regular musical activity as a complex multimodal lifestyle activity is proposed to be protective against age-related cognitive decline and Alzheimer's disease. This cross-sectional study investigated the association and interplay between musical instrument playing during life, multi-domain cognitive abilities and brain morphology in older adults (OA) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Participants reporting having played a musical instrument across three life periods (n = 70) were compared to controls without a history of musical instrument playing (n = 70), well-matched for reserve proxies of education, intelligence, socioeconomic status and physical activity. Participants with musical activity outperformed controls in global cognition, working memory, executive functions, language, and visuospatial abilities, with no effects seen for learning and memory. The musically active group had greater gray matter volume in the somatosensory area, but did not differ from controls in higher-order frontal, temporal, or hippocampal volumes. However, the association between gray matter volume in distributed frontal-to-temporal regions and cognitive abilities was enhanced in participants with musical activity compared to controls. We show that playing a musical instrument during life relates to better late-life cognitive abilities and greater brain capacities in OA. Musical activity may serve as a multimodal enrichment strategy that could help preserve cognitive and brain health in late life. Longitudinal and interventional studies are needed to support this notion.

What Is Adult Hippocampal Neurogenesis Good for?

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.

Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose.

Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetics methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN-Lx/Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular diseases and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival on Chromosome 16: 62.1-66.3 Mb. We subsequently fine-mapped the key phenotype to a locus that includes the Telo2-interacting protein 2 gene (Tti2)-a chaperone that modulates the activity and stability of PIKK kinases. To verify the hypothesis that differences in neurogenesis and glucose levels are caused by a polymorphism in Tti2, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia.

Embodied Prevention.

Evidence-based recommendations for lifestyles to promote healthy cognitive aging (exercise, education, non-smoking, balanced diet, etc.) root in reductionistic studies of mostly physical measurable factors with large effect sizes. In contrast, most people consider factors like autonomy, purpose, social participation and engagement, etc. as central to a high quality of life in old age. Evidence for a direct causal impact of these factors on healthy cognitive aging is still limited, albeit not absent. Ultimately, however, individual lifestyle is a complex composite of variables relating to both body and mind as well as to receiving input and generating output. The physical interventions are tied to the more subjective and mind-related aspects of lifestyle and wellbeing in the idea of the "embodied mind," which states that the mind is shaped by and requires the body. The causality is reciprocal and the process is dynamic, critically requiring movement: the "embodied mind" is a "embodied mind in motion." Hiking, playing musical instruments, dancing and yoga are examples of body-mind activities that assign depth, purpose, meaning, social embedding, etc. to long-term beneficial physical "activities" and increase quality of life not only as delayed gratification. The present motivational power of embodied activities allows benefiting from the side-effects of late-life resilience. The concept offers an access point for unraveling the mechanistic complexity of lifestyle-based prevention, including their neurobiological foundations.

Selenium mediates exercise-induced adult neurogenesis and reverses learning deficits induced by hippocampal injury and aging.

Although the neurogenesis-enhancing effects of exercise have been extensively studied, the molecular mechanisms underlying this response remain unclear. Here, we propose that this is mediated by the exercise-induced systemic release of the antioxidant selenium transport protein, selenoprotein P (SEPP1). Using knockout mouse models, we confirmed that SEPP1 and its receptor low-density lipoprotein receptor-related protein 8 (LRP8) are required for the exercise-induced increase in adult hippocampal neurogenesis. In vivo selenium infusion increased hippocampal neural precursor cell (NPC) proliferation and adult neurogenesis. Mimicking the effect of exercise through dietary selenium supplementation restored neurogenesis and reversed the cognitive decline associated with aging and hippocampal injury, suggesting potential therapeutic relevance. These results provide a molecular mechanism linking exercise-induced changes in the systemic environment to the activation of quiescent hippocampal NPCs and their subsequent recruitment into the neurogenic trajectory.

De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis.

Adult neurogenesis enables the life-long addition of functional neurons to the hippocampus and is regulated by both cell-intrinsic molecular programs and behavioral activity. De novo DNA methylation is crucial for embryonic brain development, but its role during adult hippocampal neurogenesis has remained unknown. Here, we show that de novo DNA methylation is critical for maturation and functional integration of adult-born neurons in the mouse hippocampus. Bisulfite sequencing revealed that de novo DNA methyltransferases target neuronal enhancers and gene bodies during adult hippocampal neural stem cell differentiation, to establish neuronal methylomes and facilitate transcriptional up-regulation of neuronal genes. Inducible deletion of both de novo DNA methyltransferases Dnmt3a and Dnmt3b in adult neural stem cells did not affect proliferation or fate specification, but specifically impaired dendritic outgrowth and synaptogenesis of newborn neurons, thereby hampering their functional maturation. Consequently, abolishing de novo DNA methylation modulated activation patterns in the hippocampal circuitry and caused specific deficits in hippocampus-dependent learning and memory. Our results demonstrate that proper establishment of neuronal methylomes during adult neurogenesis is fundamental for hippocampal function.

Adult-born neurons promote cognitive flexibility by improving memory precision and indexing.

Adult neurogenesis in the hippocampal dentate gyrus (DG) is an extraordinary form of plasticity fundamental for cognitive flexibility. Recent evidence showed that newborn neurons differentially modulate input to the infra- and supra-pyramidal blades of the DG during the processing of spatial and contextual information, respectively. However, how this differential regulation by neurogenesis is translated into different aspects contributing cognitive flexibility is unclear. Here, we increased adult-born neurons by a genetic expansion of neural stem cells and studied their influence during navigational learning. We found that increased neurogenesis improved both memory precision and flexibility. Interestingly, each of these gains was associated with distinct subregional patterns of activity and better separation of memory representations in the DG-CA3 network. Our results highlight the role of adult-born neurons in promoting memory precision and indexing and suggests their anatomical allocation within specific DG-CA3 compartments, together contributing to cognitive flexibility.

Notch3-Dependent Effects on Adult Neurogenesis and Hippocampus-Dependent Learning in a Modified Transgenic Model of CADASIL.

We and others have reported that Notch3 is a regulator of adult hippocampal neurogenesis. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), the most common genetic form of vascular dementia, is caused by mutations in Notch3. The present study intended to investigate whether there is a correlation between altered adult hippocampal neurogenesis and spatial memory performance in CADASIL transgenic mice. To overcome visual disabilities that hampered behavioral testing of the original mice (on an FVB background) we back-crossed the existing TgN3 R169C CADASIL mouse model onto the C57BL/6J background. These animals showed an age-dependent increase in the pathognomonic granular osmiophilic material (GOM) deposition in the hippocampus. Analysis in the Morris water maze task at an age of 6 and 12 months revealed deficits in re-learning and perseverance in the CADASIL transgenic mice. Overexpression of Notch3 alone resulted in deficits in the use of spatial strategies and diminished adult neurogenesis in both age groups. The additional CADASIL mutation compensated the effect on strategy usage but not on adult neurogenesis. In brain bank tissue samples from deceased CADASIL patients we found signs of new neurons, as assessed by calretinin immunohistochemistry, but no conclusive quantification was possible. In summary, while our study confirmed the role of Notch3 in adult neurogenesis, we found a specific effect of the CADASIL mutation only on the reversion of the Notch3 effect on behavior, particularly visible at 6 months of age, consistent with a loss of function. The mutation did not revert the Notch3-dependent changes in adult neurogenesis or otherwise affected adult neurogenesis in this model.

Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus.

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.

Generation of mouse hippocampal neural precursor cell lines with CRISPR/Cas9-mediated gene knockouts.

Genetic manipulation of neural precursor cells is an important tool to study mechanisms underlying proliferation, fate specification, and neuron formation. The CRISPR/Cas9 system enables efficient genome editing but requires the clonal expansion of cells containing the desired mutation. Here, we describe a protocol for the effective generation of clonal mouse hippocampal neural precursor lines with CRISPR/Cas9-based gene knockouts. Edited cell lines can be used to investigate gene regulatory networks driving neuronal differentiation and for modeling of diseases that involve hippocampal neurogenesis. For complete details on the use and execution of this protocol, please refer to Pötzsch et al. (2021).

L-lactate exerts a pro-proliferative effect on adult hippocampal precursor cells in vitro.

L-lactate has energetic and signaling properties, and its availability is modulated by activity-dependent stimuli, which also regulate adult hippocampal neurogenesis. Studying the effects of L-lactate on neural precursor cells (NPCs) in vitro, we found that L-lactate is pro-proliferative and that this effect is dependent on the active lactate transport by monocarboxylate transporters. Increased proliferation was not linked to amplified mitochondrial respiration. Instead, L-lactate deviated glucose metabolism to the pentose phosphate pathway, indicated by increased glucose-6-phosphate dehydrogenase activity while glycolysis decreased. Knockout of Hcar1 revealed that the pro-proliferative effect of L-lactate was not dependent on receptor activity although phosphorylation of ERK1/2 and Akt was increased following L-lactate treatment. Together, we show that availability of L-lactate is linked to the proliferative potential of NPCs and add evidence to the hypothesis that lactate influences cellular homeostatic processes in the adult brain, specifically in the context of adult hippocampal neurogenesis.