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

Abstract

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.

Exploring social modulation: Microglia as a key mediator of individual immune response, plasticity and pathology in App-NL-G-F mouse model of Alzheimer’s disease

“…Two clusters are of critical importance: First the proliferative cluster (7) validated the histological data and affirmed the heightened proliferative capacity in App-NL-G-F and increased variance in following ENR in both genotypes. Second, interferon (INF)-responsive microglia (5) displayed susceptibility to housing conditions in ENR, pointing towards a reduction of their inflammatory microenvironment, even in the NL background.…”

“…Grasping the intricate interplay between behavioral activity and brain plasticity is a pivotal stride towards comprehending the intricate dynamics of neurobiology. Behavioral activity has been linked to brain plasticity, while adult hippocampal neurogenesis seems to be necessary to form stable behavioral trajectories 7 and enhancing memory consolidation 8-10 . Moreover, the plasticity influenced by adult neurogenesis, which is dependent on activity and experience, is linked to the individualization of the hippocampal circuitry 11 .…”

“…Grasping the intricate interplay between behavioral activity and brain plasticity is a pivotal stride towards comprehending the intricate dynamics of neurobiology. Behavioral activity has been linked to brain plasticity, while adult hippocampal neurogenesis seems to be necessary to form stable behavioral trajectories 7 and enhancing memory consolidation [8][9][10] .…”

Environmental enrichment: a systematic review on the effect of a changing spatial complexity on hippocampal neurogenesis and plasticity in rodents, with considerations for translation to urban and built environments for humans

“…An approach that can be particularly useful to understand such links is the adoption of experimental paradigms in which EE is provided to mice with suppressed neurogenesis. For instance, Bogado Lopes and colleagues employed cyclin D2 knockout mice, which constitutively have extremely low levels of adult hippocampal neurogenesis, and housed them for 3 months in a highly-complex enriched environment consisting of 70 connected cages, finding that in D2 knockout mice there is a reduction of the EE-induced enhancement of spatial cognition ( Bogado Lopes et al, 2023 ). On the other hand, when mice that had underwent hippocampal X-Ray irradiation, which annihilates hippocampal neurogenesis, were exposed to EE, it was seen that hippocampal neurogenesis was not required for the EE-induced cognitive enhancement, suggesting that there may be independent mechanisms mediating the effects of EE on cognition, for example the upregulation of growth factors such as BDNF ( Meshi et al, 2006 ).…”

Adult neurogenesis in the hippocampus

“…Here, a focus on epigenetic changes has brought a new perspective on how an impairment of precursor cell function might affect the aging process Zocher and Toda (2023). New longitudinal studies as the one by Lopes et al (2023) highlight the emerging role of adult neurogenesis in establishing individual behavioral trajectories and related levels of brain plasticity over the life course. An extensive review by Gao et al (2023) summarizes the state‐of‐the‐art of how physical activity stimulates adult hippocampal neurogenesis.…”