Social isolation produces a sex- and brain region-specific alteration of microglia state.

Social isolation is a profound form of psychological stress that impacts the mental health of a large proportion of society. Other experimental models of stress have demonstrated a microglia response that serves either a protective or pathological function. However, the effect of adult social isolation on microglia has not been thoroughly investigated. We measured microglia territory, branching, end points and phagocytic-lysosomal activity in group housed C57Bl/6 mice and mice that were socially isolated for 2 weeks. Our results show that the dorsomedial hypothalamus and hippocampal CA2 region of adult male mice undergo increased microglia volume, territory and endpoints following social isolation, whereas females exhibit this increase in the hypothalamus only. Males exhibited decreases in the phagocytic-lysosomal marker CD68 in microglia in these regions, whereas females showed an increase in CD68 in the hypothalamus suggesting sexually dimorphic and brain region-specific change in microglia state in response to social isolation. The prefrontal cortex, central amygdala, nucleus accumbens shell and visual cortex did not exhibit changes in microglia structure in either male or female mice. These data show that microglia in different brain regions undergo a distinct response to social isolation which may account for changes in cognition and behaviour associated with this prevalent form of psychological stress.

Adult neurogenesis mediates forgetting of multiple types of memory in the rat.

The formation and retention of hippocampus-dependent memories is impacted by neurogenesis, a process that involves the production of new neurons in the dentate gyrus of the hippocampus. Recent studies demonstrate that increasing neurogenesis after memory formation induces forgetting of previously acquired memories. Neurogenesis-induced forgetting was originally demonstrated in mice, but a recent report suggests that the same effect may be absent in rats. Although a general species difference is possible, other potential explanations for these incongruent findings are that memories which are more strongly reinforced become resilient to forgetting or that perhaps only certain types of memories are affected. Here, we investigated whether neurogenesis-induced forgetting occurs in rats using several hippocampus-dependent tasks including contextual fear conditioning (CFC), the Morris Water Task (MWT), and touchscreen paired associates learning (PAL). Neurogenesis was increased following training using voluntary exercise for 4 weeks before recall of the previous memory was assessed. We show that voluntary running causes forgetting of context fear memories in a neurogenesis-dependent manner, and that neurogenesis-induced forgetting is present in rats across behavioral tasks despite differences in complexity or reliance on spatial, context, or object memories. In addition, we asked whether stronger memories are less susceptible to forgetting by varying the strength of training. Even with a very strong training protocol in the CFC task, we still observed enhanced forgetting related to increased neurogenesis. These results suggest that forgetting due to neurogenesis is a conserved mechanism that aids in the clearance of memories.

Disrupted Neurogenesis in Germ-Free Mice: Effects of Age and Sex.

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.