Microglia, the resident immune cells of the central nervous system, play multifaceted roles in both health and disease. During development, they regulate neurogenesis and refine neural circuits through synaptic pruning. In adulthood, microglia maintain homeostasis and dynamically respond to pathological insults, where they contribute to responding to neuroinflammatory challenges. This review summarizes microglial contributions to neurodevelopment and also outlines their function across various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, highlighting both protective and detrimental effects. Finally, recent advances in microglial-targeted therapies and lifestyle-based interventions are highlighted, underscoring the translational potential of modulating microglial states. Elucidating the dual roles of microglia in development and disease could guide the design of therapeutic strategies aimed at enhancing neuroprotection while minimizing neurotoxicity.

Value-based decision-making involves weighing costs and benefits. The activity of the medial prefrontal cortex reflects cost–benefit assessments, and the mediodorsal thalamus, reciprocally connected with the medial prefrontal cortex, has increasingly been recognized as an active partner in decision-making. However, the specific role of the interaction between the mediodorsal thalamus and the medial prefrontal cortex in regulating the neuronal activity underlying how costs and benefits influence decision-making remains largely unexplored. We investigated this by training the rats to perform a self-determined decision-making task, where longer nose poke durations resulted in correspondingly larger rewards. Our results showed that the inactivation of either the medial prefrontal cortex or the mediodorsal thalamus significantly impaired rat to invest more nose poke duration for larger rewards. Moreover, optogenetic stimulation of the mediodorsal thalamus–medial prefrontal cortex pathway enhanced rats’ motivation for larger rewards, whereas inhibition of this pathway resulted in decreased motivation. Notably, we identified a specific population of neurons in the medial prefrontal cortex that exhibited firing patterns correlated with motivation, and these neurons were modulated by the mediodorsal thalamus–medial prefrontal cortex projection. These findings suggest that the motivation during decision-making is encoded primarily by activity of particular neurons in the medial prefrontal cortex and indicate the crucial role of the mediodorsal thalamus–medial prefrontal cortex pathway in maintaining motivation.

Depression is one of the leading causes of disability worldwide, yet its underlying mechanisms remain elusive. Both neuroinflammation and ferroptosis are known contributors to the disease, and understanding their interplay is critical for unraveling the pathogenesis of depression. This review explores the relationship between neuroinflammation and ferroptosis in the context of depression. We first delineate the core mechanisms of each process. Subsequently, we focus on the key signaling pathways bridging these processes, including cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING), nuclear factor kappa-B (NF-κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and nuclear factor erythroid 2-related factor 2 (Nrf2), and elucidate how this inflammation-ferroptosis vicious cycle contributes to depression. Finally, we highlight therapeutic agents targeting both processes, suggesting novel treatment directions. By showing that inflammation and ferroptosis form a vicious cycle, this work offers a clearer perspective on the pathogenesis of depression and identifies specific therapeutic targets for breaking this pathological loop.

Microglia are highly dynamic tissue-resident macrophages that continuously adapt their functional states to developmental, environmental, and pathological cues within the central nervous system (CNS). Rather than executing fixed genetic programs, microglial phenotypes emerge from continuous integration of developmental origin, regional niche, metabolic status, neuronal activity, and environmental signals. In early brain development, microglia contribute to neural circuit refinement through phagocytosing apoptotic cells and extraneous synapses in an activity-dependent manner. In contrast, in the mature CNS, they continuously monitor their surroundings, maintaining synaptic homeostasis and rapidly responding to local tissue perturbances. However, perturbations in the spatiotemporal coordination of state transitions, such as ageing, metabolic dysregulation, and chronic disease, can redirect microglia toward maladaptive phenotypes characterized by long-term inflammation, impaired phagocytosis, and neuronal damage. Building upon recent advances in single-cell transcriptomics, spatial biology, and systems neuroscience, this review synthesizes current understanding of how developmental programming, regional specialization, temporal regulation, and metabolic adaptation collectively shape dynamic microglial states across health and disease. Finally, we discuss emerging therapeutic strategies aimed at context-dependent modulation of microglial states while highlighting current challenges and unanswered questions for precision microglial therapies. Graphical Abstract Microglia are highly plastic CNS-resident immune cells whose functional states are continuously shaped by developmental history, spatial niche-derived signals, temporal regulation, metabolic remodeling, and local microenvironmental cues. Rather than progressing through fixed activation programs, microglia dynamically transition among homeostatic, adaptive, and maladaptive states according to physiological demands and disease context. Failure to appropriately regulate these state transitions promotes chronic neuroinflammation, impaired phagocytosis, metabolic dysfunction, and neurodegeneration. Consequently, emerging therapeutic strategies increasingly focus on restoring physiologically coordinated microglial state dynamics through spatiotemporally informed modulation of signaling pathways, immunometabolism, epigenetic programs, and tissue-specific regulatory networks. (This figure was initially generated with the assistance of an AI tool (ChatGPT) and subsequently substantially modified by the authors to ensure scientific accuracy and originality.)