Mild traumatic brain injuries (mTBIs) are prevalent worldwide. mTBIs can impair hippocampal-based functions such as memory and cause network hyperexcitability of the dentate gyrus (DG), a key entry point to hippocampal circuitry. One candidate for mediating mTBI-induced hippocampal cognitive and physiological dysfunction is injury-induced changes in the process of DG neurogenesis. There are conflicting results on how TBI impacts the process of DG neurogenesis; this is not surprising given that both the neurogenesis process and the post-injury period are dynamic, and that the quantification of neurogenesis varies widely in the literature. Even within the minority of TBI studies focusing specifically on mild injuries, there is disagreement about if and how mTBI changes the process of DG neurogenesis. Here we utilized a clinically relevant rodent model of mTBI (lateral fluid percussion injury, LFPI), gold-standard markers and quantification of the neurogenesis process, and three time points post-injury to generate a comprehensive picture of how mTBI affects adult hippocampal DG neurogenesis. Male C57BL/6J mice (6-8 weeks old) received either sham surgery or mTBI via LFPI. Proliferating cells, neuroblasts/immature neurons, and surviving cells were quantified via stereology in DG subregions (subgranular zone [SGZ], outer granule cell layer [oGCL], molecular layer, and hilus) at short-term (3 days post-injury, dpi), intermediate (7 dpi), and long-term (31 dpi) time points. The data show this model of mTBI induces transient, sequential increases in ipsilateral SGZ/GCL proliferating cells, neuroblasts/immature neurons, and surviving cells which is suggestive of mTBI-induced neurogenesis. In contrast to these ipsilateral hemisphere findings, measures in the contralateral hemisphere were not increased in key neurogenic DG subregions after LFPI. Our work in this mTBI model is in line with most literature on other and more severe models of TBI in showing TBI stimulates the process of DG neurogenesis. However, as our DG data in mTBI provide temporal, subregional, and neurogenesis-stage resolution, these data are important to consider in regard to the functional importance of TBI-induction of the neurogenesis process and future work assessing the potential of replacing and/or repairing DG neurons in the brain after TBI.

Adipose-derived stem cells (ADSCs) have the capacity to differentiate into neural precursor cells which can be used for nerve regeneration. However, their inherently low neurogenic differentiation efficiency limits further clinical applications. This study was designed to promote neurogenic differentiation efficacy of ADSCs by integrating conductive hydrogel-based microwells with electrical stimulation (ES). We hypothesize that ADSCs will differentiate more efficiently into neural precursor cells when electrically stimulated in conductive hydrogel microwells. To make the conductive hydrogel-based microwell, polyethylene glycol (PEG) diacrylate aqueous solution mixed with poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) was patterned with the polydimethylsiloxane mold and exposed to UV light to induce photo-cross-linking of the conductive hydrogel. After seeding the ADSCs in the microwells, the cells formed distinct cell spheres in PEG microwells and wide disks in the PEG/PEDOT:PSS microwells. Although the microwells yielded varying three-dimensional (3D) cell aggregate structure, cell viability was not affected. After neurogenic differentiation with ES, the ADSC aggregates in PEG/PEDOT:PSS microwells with ES expressed greater positive neuronal differentiation markers compared to nonstimulated PEG/PEDOT:PSS microwells. Although all neuronal gene expression levels were greater in PEG microwells with ES, the increased rates of gene expression levels between treated and untreated PEG/PEDOT:PSS microwells were much higher compared to PEG microwells. This would mean that electrically stimulating ADSC aggregates in conductive microwells is an effective method in increasing neurogenic differentiation. Therefore, we propose a most effective strategy taking advantage of a 3D conductive culture system which can be useful in a wide variety of electrical application.

Mild traumatic brain injuries (mTBIs) are prevalent worldwide. mTBIs can impair hippocampal-based functions such as memory and cause network hyperexcitability of the dentate gyrus (DG), a key entry point to hippocampal circuitry. One candidate for mediating mTBI-induced hippocampal cognitive and physiological dysfunction is injury-induced changes in DG neurogenesis, a process that mediates spatial/contextual memory. There are conflicting results on how TBI impacts DG neurogenesis; this is not surprising given that both the neurogenesis process and the post-injury period are dynamic, and that neurogenesis quantification varies widely in the literature. Even within the minority of TBI studies focusing specifically on mild injuries, there is disagreement about if and how mTBI changes DG neurogenesis. Here we utilized a clinically-relevant rodent model of mTBI (lateral fluid percussion injury, LFPI), gold-standard neurogenesis markers and quantification approaches, and three time points post-injury to generate a comprehensive picture of how mTBI affects adult hippocampal DG neurogenesis. Male C57BL/6J mice (6-8 weeks old) received either sham surgery or mTBI via LFPI. Proliferating cells, neuroblasts/immature neurons, and surviving cells were quantified via stereology in DG subregions (subgranular zone [SGZ], outer granule cell layer [GCL], molecular layer, and hilus) at short-term (3 days post-injury, dpi), intermediate (7 dpi), and long-term (31 dpi) time points. The data suggest this model of mTBI induces transient, sequential increases in ipsilateral SGZ/GCL proliferating cells, immature neurons, and surviving cells which are indicative of mTBI-induced neurogenesis. In contrast to these ipsilateral hemisphere findings, measures in the contralateral hemisphere show no increase in neurogenesis indices in the key neurogenic DG subregions. Our work in this mTBI model is in line with the large fraction of literature that reports increased DG neurogenesis in other and more severe models of TBI. As our DG neurogenesis data in this mTBI model provide temporal, subregional, and neurogenesis-stage resolution, these data are important to consider in regard to the functional importance of TBI-induced neurogenesis and future work assessing the potential of replacing and/or repairing DG neurons in the brain after TBI.