One manifestation of individualization is a progressively differential response of individuals to the non-shared components of the same environment. Individualization has practical implications in the clinical setting, where subtle differences between patients are often decisive for the success of an intervention, yet there has been no suitable animal model to study its underlying biological mechanisms. Here we show that enriched environment (ENR) can serve as a model of brain individualization. We kept 40 isogenic female C57BL/6JRj mice for 3 months in ENR and compared these mice to an equally sized group of standard-housed control animals, looking at the effects on a wide range of phenotypes in terms of both means and variances. Although ENR influenced multiple parameters and restructured correlation patterns between them, it only increased differences among individuals in traits related to brain and behavior (adult hippocampal neurogenesis, motor cortex thickness, open field and object exploration), in agreement with the hypothesis of a specific activity-dependent development of brain individuality.

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The niche concept of stem cell biology proposes a functional unit between the precursor cells and their local microenvironment, to which several cell types might contribute by cell-cell contacts, extracellular matrix, and humoral factors. We here established three co-culture models (with cell types separated by membrane) for both adherent monolayers and neurospheres to address the potential influence of different niche cell types in the neurogenic zone of the adult hippocampus of mice. Astrocytes and endothelial cells enhanced precursor cell proliferation and neurosphere formation. Endothelial factors also led to a prolonged increase in proliferation after growth factor withdrawal, which otherwise induces differentiation. All niche cell types enhanced cell survival in monolayer cultures, endothelial cells also stimulated neuronal differentiation. A parallel trend elicited by astrocytes did not reach conventional statistical significance. Pericytes had variable effects here. We did not observe changes in differentiation in neurosphere co-cultures. In summary, our data indicate that in precursor cell culture protocols survival could be improved by adding as yet unknown factors physiologically contributed by astrocytes and endothelial cells. Our findings also underscore the complexity of the niche and the differential impact of factors from the different sources on distinct aspects of neuronal development. With the help of the models presented here, identification of these factors and their specific biological activity can now be initiated.

Adult neurogenesis and the neurogenic niche in the dentate gyrus are subjects of much research interest. Enhancing our knowledge of this niche process and the role played by this unique microenvironment would further our understanding of plasticity and its relevance for cognition in health and disease. The complex three-dimensional (3D) nature of the niche microenvironment is poorly recapitulated in current cell culture experimental procedures. Neural precursor cells (NPCs) are cultured either on two-dimensional (2D) surfaces, where cells quickly reach confluency and passaging is required, or as 3D neurospheres, with the limitation of poor diffusion of nutrients and thus partial differentiation of cells over time. Herein, we culture NPCs on microscale scaffolds termed microcarriers, composed of poly(ethylene glycol) and heparin, designed to more closely represent the 3D environment of the neurogenic niche. The interconnected macroporous structure of the microcarriers allows NPCs to attach to their pore walls with subsequent continuous proliferation (analyzed up to 28 days) without formation of a necrotic core. Removal of basic fibroblast growth factor and epidermal growth factor from the culture medium results in differentiation of the NPCs. Unlike 2D culture, a high percentage of neurons was achieved on the microcarriers (22% MAP2 positive cells) indicating that these 3D microscale scaffolds give a more conducive environment for neuronal differentiation. Microcarrier culture of NPCs allows long-term cell expansion and better differentiation, which provides superior culture conditions for studying/modelling the neurogenic niche.