Effect of a multi-strain probiotic mixture consumption on anxiety and depression symptoms induced in adult mice by postnatal maternal separation.

BACKGROUND: Intestinal microbial composition not only affects the health of the gut but also influences centrally mediated systems involved in mood, through the "gut-brain" axis, a bidirectional communication between gut microbiota and the brain. In this context, the modulation of intestinal microbiota and its metabolites through the administration of probiotics seems to represent a very promising approach in the treatment of the central nervous system alterations. Early postnatal life is a critical period during which the brain undergoes profound and essential modulations in terms of maturation and plasticity. Maternal separation (MS), i.e., the disruption of the mother-pup interaction, represents a pivotal paradigm in the study of stress-related mood disorders, by inducing persistent changes in the immune system, inflammatory processes, and emotional behavior in adult mammals. RESULTS: We conducted experiments to investigate whether sustained consumption of a multi-strain probiotic formulation by adult male mice could mitigate the effects of maternal separation. Our data demonstrated that the treatment with probiotics was able to totally reverse the anxiety- and depressive-like behavior; normalize the neuro-inflammatory state, by restoring the resting state of microglia; and finally induce a proneurogenic effect. Mice subjected to maternal separation showed changes in microbiota composition compared to the control group that resulted in permissive colonization by the administered multi-strain probiotic product. As a consequence, the probiotic treatment also significantly affected the production of SCFA and in particular the level of butyrate. CONCLUSION: Gut microbiota and its metabolites mediate the therapeutic action of the probiotic mix on MS-induced brain dysfunctions. Our findings extend the knowledge on the use of probiotics as a therapeutic tool in the presence of alterations of the emotional sphere that significantly impact on gut microbiota composition. Video Abstract.

Essential role of p21Waf1/Cip1 in the modulation of post-traumatic hippocampal Neural Stem Cells response.

BACKGROUND: Traumatic Brain Injury (TBI) represents one of the main causes of brain damage in young people and the elderly population with a very high rate of psycho-physical disability and death. TBI is characterized by extensive cell death, tissue damage and neuro-inflammation with a symptomatology that varies depending on the severity of the trauma from memory loss to a state of irreversible coma and death. Recently, preclinical studies on mouse models have demonstrated that the post-traumatic adult Neural Stem/Progenitor cells response could represent an excellent model to shed light on the neuro-reparative role of adult neurogenesis following damage. The cyclin-dependent kinase inhibitor p21Waf1/Cip1 plays a pivotal role in modulating the quiescence/activation balance of adult Neural Stem Cells (aNSCs) and in restraining the proliferation progression of progenitor cells. Based on these considerations, the aim of this work is to evaluate how the conditional ablation of p21Waf1/Cip1 in the aNSCS can alter the adult hippocampal neurogenesis in physiological and post-traumatic conditions. METHODS: We designed a novel conditional p21Waf1/Cip1 knock-out mouse model, in which the deletion of p21Waf1/Cip1 (referred as p21) is temporally controlled and occurs in Nestin-positive aNSCs, following administration of Tamoxifen. This mouse model (referred as p21 cKO mice) was subjected to Controlled Cortical Impact to analyze how the deletion of p21 could influence the post-traumatic neurogenic response within the hippocampal niche. RESULTS: The data demonstrates that the conditional deletion of p21 in the aNSCs induces a strong increase in activation of aNSCs as well as proliferation and differentiation of neural progenitors in the adult dentate gyrus of the hippocampus, resulting in an enhancement of neurogenesis and the hippocampal-dependent working memory. However, following traumatic brain injury, the increased neurogenic response of aNSCs in p21 cKO mice leads to a fast depletion of the aNSCs pool, followed by declined neurogenesis and impaired hippocampal functionality. CONCLUSIONS: These data demonstrate for the first time a fundamental role of p21 in modulating the post-traumatic hippocampal neurogenic response, by the regulation of the proliferative and differentiative steps of aNSCs/progenitor populations after brain damage.

Age-related changes in layer II immature neurons of the murine piriform cortex.

The recent identification of a population of non-newly born, prenatally generated "immature" neurons in the layer II of the piriform cortex (cortical immature neurons, cINs), raises questions concerning their maintenance or depletion through the lifespan. Most forms of brain structural plasticity progressively decline with age, a feature that is particularly prominent in adult neurogenesis, due to stem cell depletion. By contrast, the entire population of the cINs is produced during embryogenesis. Then these cells simply retain immaturity in postnatal and adult stages, until they "awake" to complete their maturation and ultimately integrate into neural circuits. Hence, the question remains open whether the cINs, which are not dependent on stem cell division, might follow a similar pattern of age-related reduction, or in alternative, might leave a reservoir of young, undifferentiated cells in the adult and aging brain. Here, the number and features of cINs were analyzed in the mouse piriform cortex from postnatal to advanced ages, by using immunocytochemistry for the cytoskeletal marker doublecortin. The abundance and stage of maturation of cINs, along with the expression of other markers of maturity/immaturity were investigated. Despite a marked decrease in this neuronal population during juvenile stages, reminiscent of that observed in hippocampal neurogenesis, a small amount of highly immature cINs persisted up to advanced ages. Overall, albeit reducing in number with increasing age, we report that the cINs are present through the entire animal lifespan.