Biology subjects

Stoica, B. A.

Publications and source records attributed to Stoica, B. A..

3 recordsLinked to original sources

bioRxiv2023

Interaction of high-fat diet and brain trauma alters adipose tissue macrophages and brain microglia associated with exacerbated cognitive dysfunction.

Obesity increases the morbidity and mortality of traumatic brain injury (TBI). We performed a detailed analysis of transcriptomic changes in the brain and adipose tissue to examine the interactive effects between high-fat diet-induced obesity (DIO) and TBI in relation to central and peripheral inflammatory pathways, as well as neurological function. Adult male mice were fed a high-fat diet (HFD) for 12 weeks prior to experimental TBI and continuing after injury. Combined TBI and HFD resulted in additive dysfunction in the Y-Maze, novel object recognition (NOR), and Morris water maze (MWM) cognitive function tests. We also performed high-throughput transcriptomic analysis using Nanostring panels of cellular compartments in the brain and total visceral adipose tissue (VAT), followed by unsupervised clustering, principal component analysis, and IPA pathway analysis to determine shifts in gene expression programs and molecular pathway activity. Analysis of cellular populations in the cortex and hippocampus as well as in visceral adipose tissue during the chronic phase after combined TBI-HFD showed amplification of central and peripheral microglia/macrophage responses, including superadditive changes in select gene expression signatures and pathways. These data suggest that HFD-induced obesity and TBI can independently prime and support the development of altered states in brain microglia and visceral adipose tissue macrophages, including the disease-associated microglia/macrophage (DAM) phenotype observed in neurodegenerative disorders. The interaction between HFD and TBI promotes a shift toward chronic reactive microglia/macrophage transcriptomic signatures and associated pro-inflammatory disease-altered states that may, in part, underlie the exacerbation of cognitive deficits. Targeting of HFD-induced reactive cellular phenotypes, including in peripheral adipose tissue macrophages, may serve to reduce microglial maladaptive states after TBI, attenuating post-traumatic neurodegeneration and neurological dysfunction.

neuroscience↗

bioRxiv2022

Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with hyperphagocytosis and inflammatory neurodegeneration

Lipofuscin is an autofluorescent (AF) pigment formed by lipids and misfolded proteins that accumulates in post-mitotic cells with advanced age. Here we immunophenotyped microglia in the brain of old C57BL/6 mice (>18 months-old) and demonstrate that in comparison to young mice, one third of old microglia are AF, characterized by profound changes in lipid and iron content, phagocytic activity, and oxidative stress. Pharmacological depletion of microglia in old mice eliminated the AF microglia following repopulation and reversed microglial dysfunction. Age-related neurological deficits and neurodegeneration after traumatic brain injury (TBI) were attenuated in old mice lacking AF microglia. Furthermore, hyperphagocytic activity and lipid accumulation in microglia persisted for up to one year after TBI, were modified by Apoe4 genotype, and chronically driven by phagocyte-mediated oxidative stress. Thus, AF may reflect a pathological state in aging microglia associated with hyperphagocytosis and inflammatory neurodegeneration that can be further accelerated by TBI. TeaserTraumatic brain injury accelerates age-related pathological phagocytosis and lipofuscin formation in microglia.

neuroscience↗

bioRxiv2019

Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

Chronic neuroinflammation with sustained microglial activation occurs following moderate-to-severe traumatic brain injury (TBI) and is believed to contribute to subsequent neurodegeneration and neurological deficits. Microglia, the primary innate immune cells in brain, are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for their survival. In this translational study, we examined the effects of delayed depletion and subsequent repopulation of microglia on chronic neurodegeneration and functional recovery up to three months posttrauma. A CSF1R inhibitor, PLX5622, was administered to injured adult male C57Bl/6 mice at one month after controlled cortical impact to remove chronically activated microglia, and the inihibitor was withdrawn 1 week later to allow microglial repopulation. Following TBI, the repopulated microglia displayed a ramified morphology, similar to that of sham control uninjured animals, whereas microglia in untreated injured animals showed the typical chronic posttraumatic hypertrophic morphology. PLX5622 treatment limited TBI-associated neuropathological changes at 3 months posttrauma; these included a smaller cortical lesion, reduced neuronal cell death in the injured cortex and ipsilateral hippocampus, and decreased NOX2-dependent reactive microgliosis. Furthermore, delayed depletion of microglia led to widespread changes in the cortical transcriptome, including alterations in gene pathways involved in neuroinflammation, oxidative stress, and neuroplasticity. PLX5622 treated animals showed significantly improved neurological recovery using a variety of complementary neurobehavioral evaluations. These included beam walk and rotorod tests for sensori-motor function, as well as Y-maze, novel object recognition, and Morris water maze tests to evaluate cognitive function. Together, our findings show that chronic phase removal of neurotoxic microglia using CSF1R inhibitors after experimental TBI can markedly reduce chronic neuroinflammation and neurodegeneration, as well as related long-term motor and cognitive deficits. Thus, CSF1R inhibition may provide a clinically feasible approach to limit posttraumatic neurodegeneration and neurological dysfunction following head injury.

neuroscience↗