In previous work with young adult mice we found that microglia within the ventral tegmental area (VTA), nucleus accumbens (NAc), substantia nigra pars compacta (SNc), and substantia nigra pars reticulata (SNr) exhibited significant regional variation in anatomical features, lysosome content, electrophysiological membrane properties, and transcriptome. Together, these observations demonstrate that microglia in the healthy brain exist along a spectrum of distinct functional states and these data provide a critical foundation for defining microglial contributions to BG circuit function. To expand on these findings and begin to define the regulatory factors responsible for establishing and maintaining these region-specific microglial phenotypes, we examined BG microglia in early postnatal mice. These experiments indicated that microglial regional specialization emerges during the second postnatal week and suggested that local cues are responsible for shaping microglial properties. To determine whether these regulatory cues continue to inform microglial phenotype in adulthood, we used genetic and pharmacological approaches to ablate microglia in adult mice and then examined BG microglial properties following microglial repopulation. These experiments indicated that local regulatory cues capable of programming multiple diverse microglial attributes continue to be active in the adult. Collectively, these findings were recently published in Neuron. In a separate project, we have carried out extensive analysis of microglial colonization of the BG during postnatal development. These experiments provided evidence that microglia are overproduced and then refined to adult levels of abundance through programmed cell death, similar to other CNS cell populations. These studies provide a foundation for defining the impact of early life drug exposure and other insults on these cells and their contributions to circuit maturation. Work to define how BG microglia are impacted by chronic drug exposure and the process of normal aging is ongoing. This includes bioinformatics analysis for whole transcriptome RNAseq of microglia isolated from the NAc, PFC, and VTA of mice following chronic self-administration of saline or cocaine. We are also using imaging, RT-PCR analysis of gene expression, and microglial ablation to quantify aging-induced changes in BG microglia and analyze contributions of these cells to aging-induced alterations in cognitive function.
| De Biase, Lindsay M; Schuebel, Kornel E; Fusfeld, Zachary H et al. (2017) Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia. Neuron 95:341-356.e6 |
