Microglia, the resident immune cells of the brain, play a pivotal role in neuroinflammation and neurodegenerative diseases. Recent studies have elucidated the genetic underpinnings of microglial function, particularly in the context of Alzheimer's disease (AD). For instance, research has identified 21 AD risk loci through transcriptome and chromatin accessibility profiling in primary human microglia, refining these loci to single genes, including three novel candidates (ref: Kosoy doi.org/10.1038/s41588-022-01149-1/). Additionally, the dual ontogeny of microglia and inflammatory macrophages has been characterized, revealing distinct populations that contribute to brain homeostasis and pathology in aging and neurodegeneration (ref: Silvin doi.org/10.1016/j.immuni.2022.07.004/). The role of apolipoprotein E4 (APOE4) has also been highlighted, showing that it impairs microglial responses in glaucoma models, suggesting a complex interplay between genetic risk factors and microglial activation (ref: Margeta doi.org/10.1016/j.immuni.2022.07.014/). Furthermore, the inhibition of neuroinflammation via targeting ubiquitin-specific protease 7 (USP7) has emerged as a promising therapeutic strategy, with small molecules like eupalinolide B demonstrating efficacy in modulating microglial activation (ref: Zhang doi.org/10.1126/sciadv.abo0789/). Overall, these studies underscore the multifaceted roles of microglia in neuroinflammation and their potential as therapeutic targets in neurodegenerative diseases.

The genetic landscape of microglia has been further elucidated through expression quantitative trait loci (eQTL) studies, which have identified significant cell-type-specific effects in microglia. A comprehensive analysis involving single-nuclei RNA sequencing revealed 7,607 eGenes, with 46% exhibiting microglia-specific expression patterns, highlighting their unique regulatory mechanisms (ref: Bryois doi.org/10.1038/s41593-022-01128-z/). Additionally, the impact of diet on microglial function has been explored, revealing that high-fat diets can induce compulsive behaviors through microglial activation in the anterior paraventricular thalamus (ref: Cheng doi.org/10.1038/s41593-022-01129-y/). The study of MCT1 haploinsufficiency has also provided insights into the relationship between metabolic disorders and brain dysfunction, suggesting that targeting metabolic pathways may offer new therapeutic avenues for conditions like non-alcoholic fatty liver disease (ref: Hadjihambi doi.org/10.1016/j.jhep.2022.08.008/). Furthermore, the evolution of the primate dorsolateral prefrontal cortex has been examined, revealing species-specific molecular differences that may influence cognitive functions and microglial roles in neurodevelopment (ref: Ma doi.org/10.1126/science.abo7257/). Collectively, these findings emphasize the intricate genetic and molecular mechanisms governing microglial behavior and their implications for neurological disorders.

Microglia are increasingly recognized for their dual roles in neuroprotection and neurodegeneration, particularly in the context of diseases like Alzheimer's and glaucoma. The APOE4 allele has been shown to impair microglial surveillance and promote a neurodegenerative phenotype, leading to neuronal loss in glaucoma models (ref: Margeta doi.org/10.1016/j.immuni.2022.07.014/). Additionally, lipid accumulation associated with APOE4 has been linked to compromised microglial communication with neurons, further exacerbating neurodegenerative processes (ref: Victor doi.org/10.1016/j.stem.2022.07.005/). The inhibition of neuroinflammation through targeting USP7 has emerged as a potential therapeutic strategy, with small molecules demonstrating the ability to modulate microglial activation and mitigate neuronal damage (ref: Zhang doi.org/10.1126/sciadv.abo0789/). Moreover, prenatal environmental stressors have been shown to impair microglial function and influence adult behavior, particularly in males, indicating that early-life exposures can have lasting effects on neurodevelopment and microglial activity (ref: Block doi.org/10.1016/j.celrep.2022.111161/). These studies highlight the complex interplay between microglial function, genetic risk factors, and environmental influences in the pathogenesis of neurodegenerative diseases.

The activation of microglia is intricately linked to behavioral outcomes, particularly in the context of neurodevelopmental and psychiatric disorders. Recent research has demonstrated that prenatal environmental stressors can significantly impair microglial function, leading to altered behavior in male offspring, which may contribute to the development of neurodevelopmental disorders such as autism (ref: Block doi.org/10.1016/j.celrep.2022.111161/). Additionally, eQTL studies have identified novel risk genes for psychiatric and neurological disorders, with a notable emphasis on microglial-specific effects, suggesting that genetic predispositions can influence microglial behavior and, consequently, cognitive functions (ref: Bryois doi.org/10.1038/s41593-022-01128-z/). The dual ontogeny of microglia and inflammatory macrophages has also been characterized, providing insights into how different microglial populations contribute to neuroinflammation and behavior across the lifespan (ref: Silvin doi.org/10.1016/j.immuni.2022.07.004/). Furthermore, the impact of APOE4 on microglial surveillance of neuronal networks has been explored, revealing that lipid accumulation can impair microglial responses, potentially influencing cognitive decline in Alzheimer's disease (ref: Victor doi.org/10.1016/j.stem.2022.07.005/). These findings underscore the critical role of microglial activation in shaping behavior and highlight the need for further investigation into the mechanisms underlying these relationships.

Identifying therapeutic targets within microglial pathways has become a focal point in neurodegenerative disease research. The inhibition of neuroinflammation through small molecules targeting USP7 has shown promise in modulating microglial activation and protecting against neuronal damage, presenting a potential therapeutic avenue for neurodegenerative conditions (ref: Zhang doi.org/10.1126/sciadv.abo0789/). Additionally, the role of MCT1 haploinsufficiency in protecting against diet-induced non-alcoholic fatty liver disease and associated brain dysfunction highlights the metabolic pathways that could be targeted for therapeutic intervention (ref: Hadjihambi doi.org/10.1016/j.jhep.2022.08.008/). The spatiotemporal dynamics of microglia across the human lifespan have also been characterized, providing insights into how microglial behavior changes with age and how these changes may be leveraged for therapeutic purposes (ref: Menassa doi.org/10.1016/j.devcel.2022.07.015/). Furthermore, the investigation of lactate receptor HCAR1 in regulating neurogenesis and microglial activation after neonatal hypoxia-ischemia suggests that targeting metabolic receptors may enhance tissue repair and recovery following injury (ref: Kennedy doi.org/10.7554/eLife.76451/). Collectively, these studies emphasize the potential for targeting microglial pathways to develop novel therapeutic strategies for neurodegenerative diseases.

Microglia are highly responsive to environmental factors, which can significantly influence their function and behavior. Prenatal exposure to environmental stressors has been shown to impair microglial function, particularly in the anterior cingulate cortex, leading to altered adult behavior in males, which may contribute to neurodevelopmental disorders (ref: Block doi.org/10.1016/j.celrep.2022.111161/). Additionally, the genetic landscape of microglia has been explored through eQTL studies, revealing that specific genetic variants can modulate microglial responses to environmental stimuli, highlighting the interplay between genetics and environment in shaping microglial behavior (ref: Bryois doi.org/10.1038/s41593-022-01128-z/). The impact of APOE4 on microglial surveillance of neuronal networks has also been investigated, suggesting that lipid accumulation can impair microglial responses, potentially exacerbating the effects of environmental stressors on cognitive decline (ref: Victor doi.org/10.1016/j.stem.2022.07.005/). Furthermore, the role of lactate receptor HCAR1 in regulating microglial activation after neonatal hypoxia-ischemia underscores the importance of metabolic pathways in microglial responses to environmental challenges (ref: Kennedy doi.org/10.7554/eLife.76451/). These findings illustrate the critical role of environmental factors in modulating microglial function and their implications for neurodevelopmental and neurodegenerative disorders.

Microglia play a crucial role in cognitive functions, with their activation and behavior significantly influencing neural development and cognitive outcomes. Recent studies have demonstrated that lipid accumulation induced by the APOE4 allele impairs microglial surveillance of neuronal networks, which may contribute to cognitive decline in Alzheimer's disease (ref: Victor doi.org/10.1016/j.stem.2022.07.005/). Additionally, the spatiotemporal dynamics of microglia across the human lifespan have been characterized, revealing how microglial behavior changes with age and its potential impact on cognitive functions (ref: Menassa doi.org/10.1016/j.devcel.2022.07.015/). The inhibition of neuroinflammation through targeting USP7 has also shown promise in enhancing cognitive functions by modulating microglial activation (ref: Zhang doi.org/10.1126/sciadv.abo0789/). Furthermore, prenatal environmental stressors have been linked to impaired microglial function and altered behavior in males, indicating that early-life exposures can have lasting effects on cognitive development (ref: Block doi.org/10.1016/j.celrep.2022.111161/). These findings highlight the intricate relationship between microglial function and cognitive processes, emphasizing the need for further research into the mechanisms underlying these interactions.