RESUMEN
Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow in distinct directions, embryonic MG accumulate, display a state resembling post-natal axon-tract-associated microglia (ATM) and prevent the progression of microcavities into large cavitary lesions, in part via a mechanism involving the ATM-factor Spp1. MG and Spp1 furthermore contribute to the rapid repair of lesions, collectively highlighting protective functions that preserve the fetal brain from physiological morphogenetic stress and injury. Our study thus highlights key major roles for embryonic MG and Spp1 in maintaining structural integrity during morphogenesis, with major implications for our understanding of MG functions and brain development.
Asunto(s)
Encéfalo , Microglía , Axones , Encéfalo/citología , Encéfalo/crecimiento & desarrollo , Macrófagos/fisiología , Microglía/patología , MorfogénesisRESUMEN
Psychostimulants induce stable changes in neural plasticity and behavior in a transcription-dependent manner. Further, stable cellular changes require transcription that is regulated by epigenetic mechanisms that alter chromatin structure, such as histone acetylation. This mechanism is typically catalyzed by enzymes with histone acetyltransferase or histone deacetylase (HDAC) activity. Class IIa HDACs are notable for their high expression in important regions of the brain reward circuitry and their neural activity-dependent shuttling in and out of the cell nucleus. In particular, HDAC5 has an important modulatory function in cocaine-induced behaviors and social defeat stress-induced effects. Although a mutation in HDAC5 has been shown to cause hypersensitive responses to chronic cocaine use whether this response worsens during chronic early life stress has not been examined yet. In this study, we exposed mouse pups to two different early life stress paradigms (social isolation, ESI, and social threat, EST) to determine whether the heterozygous null mutation in HDAC5 (HDAC5+/-) moderated the effects of exposure to stress in early life on adult cocaine-induced conditioned place preference (CPP). Notably, HDAC5+/- mice that had been exposed to ESI were more susceptible to developing cocaine-induced CPP and more resistant to extinguishing this behavior. The same effect was not observed for HDAC5+/- mice experiencing EST, suggesting that only ESI induces behavioral changes by acting precisely through HDAC5-related biological pathways. Finally, an analysis of c-Fos expression performed to discover the neurobiological substrates that mediated this phenotype, identified the dorsolateral striatum as an important structure that mediates the interaction between HDAC5 mutation and ESI. Our data demonstrate that decreased HDAC5 function is able to exacerbate the long-term behavioral effects of adverse rearing environment in mouse.