This review systematically synthesizes current evidence on hippocampal alterations in chronic pain across multiple levels and proposes a multiscale integrative framework in which synaptic imbalance, neuroimmune activation, and neurotrophic dysregulation interact to drive hippocampal dysfunction, forming a bidirectional loop that links pain, emotion, and cognition.
Abstract
Chronic pain is a multifaceted condition characterized by persistent nociceptive signaling and maladaptive central nervous system plasticity, in which the hippocampus has emerged as a critical hub of structural, functional, metabolic, and molecular remodeling. This review systematically synthesizes current evidence on hippocampal alterations in chronic pain across multiple levels, including structural remodeling (e.g., gray matter atrophy and impaired neurogenesis), functional and circuit-level disruptions, metabolic dysregulation, and cellular and molecular mechanisms. In particular, we highlight convergent pathways involving neurotransmitter and receptor dysregulation, cytokine-driven neuroinflammation, neurotrophic signaling deficits, and additional molecular alterations that collectively impair synaptic plasticity and hippocampal network stability. Importantly, we propose a multiscale integrative framework in which synaptic imbalance, neuroimmune activation, and neurotrophic dysregulation interact to drive hippocampal dysfunction, forming a bidirectional loop that links pain, emotion, and cognition. We further discuss therapeutic strategies targeting hippocampal remodeling, including pharmacological, metabolic, neuroimmune, and circuit-level neuromodulation approaches, as well as emerging precision medicine strategies. By integrating preclinical and clinical evidence, this review positions the hippocampus as a central node in chronic pain pathophysiology and a promising target for developing interventions that address both nociceptive and comorbid affective and cognitive symptoms. These insights support a unified model of hippocampal remodeling in chronic pain that may guide future precision diagnostics and targeted interventions.
BACKGROUND
Microglia, the resident immune cells of the central nervous system, are key regulators of synaptic plasticity and neural circuit homeostasis.
MAIN BODY
This review summarizes the mechanisms by which microglia shape synaptic structure and function, including dynamic synaptic interactions, selective pruning, epigenetic regulation, extracellular matrix remodeling, metabolic adaptation, and communication with other glial cells. Under physiological conditions, these processes support circuit refinement, synaptic stability, and cognition, which are modulated by circadian rhythms and the microbiota-gut-brain axis. In Alzheimer's disease, schizophrenia, and related disorders, microglial dysfunction can shift synaptic pruning from a controlled homeostatic process to pathological synapse loss. Excessive complement-mediated pruning, disrupted excitation-inhibition balance, neuroinflammation, and metabolic dysregulation may jointly impair synaptic integrity and circuit function.
CONCLUSION
This review highlights microglial heterogeneity, state transitions, and targeted modulation as important directions for understanding synaptic remodeling and developing therapeutic strategies for neurological diseases.
Zheng Liu, Wu-lan Ao, Ai-Di Luo et al.· BMC Medicine· 0 citations
Type 2 diabetes mellitus (T2DM) increases vulnerability to cognitive decline through interacting disturbances in insulin signaling, mitochondrial energetics, redox and lipid homeostasis, neuroimmune regulation, neurovascular coupling, and experience-dependent plasticity. This review integrates molecular, cellular, preclinical, and clinical evidence linking these processes to altered gene expression, glial dysfunction, synaptic instability, and impaired cognition. We distinguish well-supported mechanisms from unresolved questions concerning causality, cell-type specificity, human hippocampal remodeling, context-dependent pharmacological effects, and the translational limitations of experimental models. On this basis, we propose an integrative framework in which metabolic flexibility acts as a permissive gatekeeper for neural adaptation. AMPK-centered signaling supports mitochondrial quality control, autophagy, antioxidant defenses, and restraint of NF-kB/NLRP3-associated inflammation, but is considered necessary rather than sufficient for cognitive recovery. Durable plasticity additionally requires activity-dependent CREB-BDNF signaling and adequate neurovascular support to match energy delivery with circuit demand. Exercise, cognitive training, environmental enrichment, metformin, and incretin-based therapies engage complementary components of this network, although their efficacy is likely to vary with age, metabolic state, inflammatory burden, vascular reserve, treatment timing, and adherence. The framework predicts that metabolic activation without circuit engagement will provide limited cognitive benefit, whereas plasticity-promoting interventions will be constrained by persistent metabolic or vascular dysfunction. We therefore argue for multimodal, biomarker-informed strategies that integrate metabolic stabilization, vascular support, and structured physical and cognitive stimulation. Long-term randomized studies combining neuroimaging with molecular and metabolic profiling are required to test these predictions and define precision approaches for preserving cognitive resilience in T2DM.
C. G. Diniz, Natáli Valím Oliver Bento-Torres, Emanuel Ramos da Costa et al.· Neuroscience and Biobehavior...· 0 citations
The mechanisms linking systemic inflammation to brain dysfunction are evaluated and emerging translational opportunities are highlighted, including the therapeutic repurposing of cytokine-targeting and immunomodulatory agents for neuropsychiatric interventions.
Yelin Lee, Jaewon Ko, J. Um· Experimental and Molecular M...· 0 citations
Overall, the gut microbiota functions as a dynamic regulator of brain plasticity and cognitive resilience across the lifespan, suggesting shared systems-level vulnerabilities across conditions and highlighting the translational potential of microbiota-targeted interventions such as probiotics, dietary modulation, postbiotics, and precision microbiome-based strategies.
Major depressive disorder (MDD) is associated with reduced hippocampal volume, altered connectivity and negative memory bias, suggesting disrupted hippocampal plasticity. Dysregulated adult hippocampal neurogenesis is a potential contributor, but its relevance in humans and role in MDD remain unclear. Here we investigated the molecular basis of hippocampal dysfunction in nonmedicated individuals with MDD by integrating analyses of neurogenic trajectories, cell-type- and subfield-specific gene expression, chromatin accessibility and protein expression. We identify a neurogenic lineage in the adult human hippocampal subgranular zone and provide evidence for a stalled neurogenic process in MDD, associated with transcriptional regulation, stress-related reprogramming and interferon signaling across developmental stages. Excitatory and inhibitory neurons show dysregulation of transcription factor networks affecting cell states. Cellular stress, excitatory-inhibitory imbalance, impaired synaptic plasticity, reduced metabolic capacity and immune activation, underlie impaired neurogenesis and reduced hippocampus circuit plasticity. Findings indicate genetic and epigenetic regulation of gene expression in MDD, and overlapping pathogenetic mechanisms with autoimmune, neurodevelopmental and neurodegenerative diseases. This work provides a new understanding of the pathogenesis of hippocampus-dependent cognitive symptoms in MDD and suggests potential therapeutic targets.
Madeleine S Peng, Jia-Jia Jiang, Luciana Polizzi et al.· Nature Medicine· 1 citation
Synaptic dysfunction is the earliest and most critical pathological feature of Alzheimer's disease (AD), directly contributing to cognitive decline. This review provides an integrative overview of the molecular and biochemical modulators governing synaptic plasticity and their disruption in AD. We discuss how the collective impairment of Aβ aggregation, tau pathology, calcium imbalance, oxidative stress, and neuroinflammation affects dendritic spine morphology and synaptic connectivity. Particular attention is given to neurotrophins such as brain-derived neurotrophic factor and TrkB signaling, hormonal influences, likewise glucocorticoids, estrogens, testosterone, endocannabinoid pathways, lipid and cholesterol regulators like ApoE and lipid rafts, and epigenetic mechanisms that modulate synaptic resilience. We further evaluate the therapeutic potential of pharmacological agents, including cholinesterase inhibitors, NMDA receptor modulators, and multi-target directed ligands alongside nutraceuticals such as resveratrol, curcumin, omega-3 fatty acids, Withania somnifera, and Bacopa monnieri. Emerging technologies, including iPSC-derived neuronal models, optogenetics, and advanced neuroimaging biomarkers like SV2A PET, cerebrospinal fluid/plasma neurogranin, are also highlighted for their role in elucidating and monitoring synaptic integrity. Ultimately, targeting the biochemical modulators of synaptic plasticity offers a promising avenue for AD therapy, especially through combinatorial and precision-medicine strategies aimed at restoring synaptic function and cognitive performance.
I. Farzeen, Muhammad Muzammil Nazir, Zunaira Jaan et al.· Journal of Alzheimer's Disea...· 0 citations
