The gut microbiome has profound effects on development and function of the nervous system. Recent evidence indicates that disruption of the gut microbiome leads to altered hippocampal neurogenesis. Here, we examined whether the effects of gut microbiome disruption on neurogenesis are age-dependent, given that both neurogenesis and the microbiome show age-related changes. Additionally, we examined memory induced functional connectivity of hippocampal networks. Control and germ-free mice at three different ages (4, 8, and 12 weeks) were trained in contextual fear-conditioning, then subsequently tested the following day. Hippocampal neurogenesis, quantified via BrdU and doublecortin, exhibited age-dependent changes relative to controls, with the established age-dependent decrease in neurogenesis being delayed in germ-free mice. Moreover, we found sex-dependent effects of germ-free status on neurogenesis, with 4 week old male germ-free mice having decreased neurogenesis and 8 week old female germ-free mice having increased neurogenesis. To assess systems-level consequences of disrupted neurogenesis, we assessed functional connectivity of hippocampal networks by inducing c-Fos expression with contextual memory retrieval and applying a previously described network analysis. Our results indicate impaired connectivity of the dentate gyrus in germ-free mice in a pattern highly correlated with adult neurogenesis. In control but not germ-free mice, functional connectivity became more refined with age, indicating that age dependent network refinement is disrupted in germ-free mice. Overall, the results show that disruption of the gut microbiome affects hippocampal neurogenesis in an age-and sex-dependent manner and that these changes are also related to changes in the dentate gyrus functional network.
Adult neurogenesis, the proliferation and integration of newly generated neurons, has been observed in the adult mammalian hippocampus of many species. Numerous studies have also found adult neurogenesis in the human hippocampus, but several recent high-profile studies have suggested that this process is considerably reduced in humans, occurring in children but not in adults. In comparison, rodent studies also show age-related decline but a greater degree of proliferation of new neurons in adult animals. These differences may represent biological species differences or could alternatively be explained by methodological differences in tissue handling and fixation. Here, we examine whether differences in the post-mortem interval between death and tissue fixation might impact subsequent detection of adult neurogenesis due to increased tissue degradation. Because there are fewer new neurons present in older subjects to begin with we hypothesized that, subject age might interact significantly with post-mortem interval in the detection of adult neurogenesis. We analyzed neurogenesis in the hippocampus of rats that were either perfusion-fixed or the brains extracted and immersion-fixed at various post-mortem intervals. We observed an interaction between animal age and the time delay between death and tissue fixation. While similar levels of neurogenesis were observed in young rats regardless of fixation, older rats had significantly fewer labeled neurons when fixation was not immediate. Furthermore, the morphological detail of the labeled neurons was significantly reduced in the delayed fixation conditions at all ages. This study highlights critical concerns that must be considered when using post-mortem tissue to quantify adult neurogenesis.
Postnatal hippocampal neurogenesis has been demonstrated to affect learning and memory in numerous ways. Several studies have now demonstrated that increased neurogenesis can induce forgetting of memories acquired prior to the manipulation of neurogenesis and, as a result of this forgetting can also facilitate new learning. However, the mechanisms mediating neurogenesis-induced forgetting are not well understood. Here, we used a subregion-based analysis of the immediate early gene c-Fos as well as in vivo fiber photometry to determine changes in activity corresponding with neurogenesis induced forgetting. We found that increasing neurogenesis led to reduced CA1 activity during context memory retrieval. We also demonstrate here that perineuronal net expression in areas CA1 is bidirectionally altered by the levels or activity of postnatally generated neurons in the dentate gyrus. These results suggest that neurogenesis may induce forgetting by disrupting perineuronal nets in CA1 which may otherwise protect memories from degradation.
To better understand complex systems, such as the brain, studying the interactions between multiple brain regions is imperative. Such experiments often require delineation of multiple brain regions on microscopic images based on preexisting brain atlases. Experiments examining the relationships of multiple regions across the brain have traditionally relied on manual plotting of regions. This process is very intensive and becomes untenable with a large number of regions of interest (ROIs). To reduce the amount of time required to process multi-region datasets, several tools for atlas registration have been developed; however, these tools are often inflexible to tissue type, only supportive of a limited number of atlases and orientation, require considerable computational expertise, or are only compatible with certain types of microscopy. To address the need for a simple yet extensible atlas registration tool, we have developed FASTMAP, a Flexible Atlas Segmentation Tool for Multi-Area Processing. We demonstrate its ability to register images efficiently and flexibly to custom mouse brain atlas plates, to detect differences in the regional numbers of labels of interest, and to conduct densitometry analyses. This open-source and user-friendly tool will facilitate the atlas registration of diverse tissue types, unconventional atlas organizations, and a variety of tissue preparations.
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