Frontiers in Cellular Neuroscience最新文献

Microglia, the innate immune cells of the central nervous system (CNS), play essential roles in maintaining neural homeostasis through dynamic interactions with neurons and other brain structures. While their protective functions are well-established, recent studies have illuminated the detrimental consequences of sustained microglial activation in the context of neurodegeneration. In particular, overactivated microglia contribute to neuroinflammation and induce synaptic alterations through the release of pro-inflammatory cytokines and engagement of specific receptors. These interactions disrupt synaptic structure and function, compromising connectivity, plasticity, and cognitive processes. Notably, neuronal synapses are primary targets of such inflammation-driven dysfunction, where prolonged exposure to cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and signaling via receptor systems including cluster of differentiation-200 (CD200)/CD200 receptor (CD200R), C-X3-C motif chemokine ligand 1 (CX3CL1)/CX3C receptor 1 (CX3CR1), colony-stimulating factor 1 (CSF1)/CSF1 receptor (CSF1R), and interferon-γ (IFN-γ)/IFN-γ receptor (IFN-γR), lead to impaired learning, excitotoxicity, and neurodegenerative progression. This review synthesizes emerging evidence on the mechanisms by which microglia-mediated immune responses regulate synaptic remodeling, emphasizing the roles of pro-inflammatory cytokines and their receptors in neurodegenerative disorders.

Cognitive impairment is a frequent but underrecognized complication of neurodegenerative and traumatic central nervous system disorders. Although research on Alzheimer's disease (AD) revealed that microglial triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in inhibiting neuroinflammation and improving cognition, its contribution to cognitive impairment following spinal cord injury (SCI) is unclear. Evidence from AD shows that TREM2 drives microglial activation, promotes pathological protein clearance, and disease-associated microglia (DAM) formation. SCI patients also experience declines in attention, memory, and other functions, yet the specific mechanism of these processes remains unclear. In SCI, microglia and TREM2 are involved in inflammation and repair, but their relationship with higher cognitive functions has not been systematically examined. We infer that TREM2 might connect injury-induced neuroinflammation in the SCI with cognitive deficits, providing a new treatment target. Artificial intelligence (AI) offers an opportunity to accelerate this endeavor by incorporating single-cell transcriptomics, neuroimaging, and clinical data for the identification of TREM2-related disorders, prediction of cognitive trajectories, and applications to precision medicine. Novel approaches or modalities of AI-driven drug discovery and personalized rehabilitation (e.g., VR, brain-computer interface) can more precisely steer these interventions. The interface between lessons learned from AD and SCI for generating new hypotheses and opportunities for translation.

Background: Vesicular monoamine transporter 2 (VMAT-2) plays a vital role in packaging cytosolic monoamine transmitters into axon terminal vesicles, which can be released in response to action potentials. Reserpine (RSP), a classical irreversible inhibitor of the monoamine transporter, is an alkaloid used as an antihypertensive drug. However, its use in medicine was very short-lived because of side effects (depression, Parkinsonism). Tetrabenazine (TBZ) and valbenazine (VBZ), biochemically non-competitive and reversible VMAT-2 inhibitors, are both used in the treatment of Tardive Dyskinesia (TD). The aim of this study was to directly compare the effects of RSP, TBZ, and VBZ on vesicular storage and exocytotic release of monoamines in hippocampal slices, and to clarify whether their actions differ in terms of reversibility and persistence. Our work addresses the biological question of how these clinically relevant VMAT-2 inhibitors modulate monoaminergic neurotransmission at the synaptic level.

Materials and methods: Vesicular storage capacity and release of [³H] noradrenaline ([³H] NA), [³H] serotonin ([³H] 5-HT), and [³H] acetylcholine ([³H] ACh) were studied in mouse hippocampus ex vivo slice preparations using electrical field stimulation.

Results: In this study, for the first time, direct neurochemical evidence was obtained that RSP reduces the vesicular storage capacity and the exocytotic release of [³H] NA and [³H] 5-HT evoked by axonal stimulation from the ex vivo hippocampal slice preparations and failed to influence the plasma membrane uptake of monoamines and exocytotic release of [³H] ACh. The inhibitory effect of RSP on vesicular release, neurochemically proven to be irreversible, was not accompanied by a recovery in VMAT-2 enzyme activity, as observed in biochemical studies. TBZ and VBZ are compared to RSP in that they also inhibit the vesicular release of neurotransmitters and storage capacity; however, their activity is less effective and is of much shorter duration, leaving some time for vesicle refilling.

Discussion: The difference observed between the two types of VMAT-2 inhibitors might give some explanation of why, in response to TBZ or VBZ treatment, the occurrence of depression or Parkinsonism as side effects is seen very rarely or not at all, and in the case of RSP, it is relatively frequent.

Dopamine released from the axon terminals of dopaminergic neurons is central to behaviors like reward learning and complex motor output. The dynamic control of dopamine release canonically occurs through two main mechanisms: the modulation of somatic excitability and the regulation of vesicular release at presynaptic boutons. However, there is also a third mechanism: the precise and local control of axonal excitability. Together, these three mechanisms control the amplitude and timing of dopamine release from terminal axons. In this review, we examine the intrinsic properties and dynamic modulation of dopaminergic axons. First, we will examine their intrinsic properties, including membrane biophysics and morphological features. Second, we will focus on the modulation of axonal excitability through receptor signaling. Finally, we will review how drugs of abuse directly influence axonal physiology, and how axonal excitability influences the progression and etiology of Parkinson's disease. Through this review we hope to highlight the important role that modulation of axonal excitability plays in controlling dopamine release, beyond action potential propagation.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive dysfunction, motor abnormalities, and memory disorders, with a persistently high and rising incidence. The pathological features of AD include the extracellular deposition of the amyloid beta peptide (Aβ), the accumulation of neurofibrillary tangles (NFTs), and neuroinflammation. Microglia (MG), the main immune cells in the central nervous system (CNS), can transform into different phenotypes. An imbalance in their phenotypic transformation may induce neuroinflammation and lead to neurological diseases, playing a central role in the onset and progression of AD.

Purpose: This article aims to briefly review the key role of microglia-mediated neuroinflammation in the pathogenesis of AD and to summarize and analyze the strategies of traditional Chinese medicine (TCM) for targeting microglia in AD treatment.

Methods: Literature review and analysis were conducted to summarize the role of microglia-mediated neuroinflammation in AD pathogenesis and to collate TCM therapeutic strategies aimed at modulating microglia.

Results and conclusion: Microglia-mediated neuroinflammation plays a central role in the pathological progression of AD. TCM demonstrates potential in intervening in AD neuroinflammation by regulating the microglial phenotype and function. These related therapeutic strategies warrant further summary and analysis.

Insulin-like growth factor-1 (IGF-1) is a single chain polypeptide hormone that plays an essential role in intrauterine and postnatal growth. Recent studies suggest that IGF-1 and its receptor IGF-1R are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IGF-1 signaling in neonatal hypoxic-ischemic (HI) brain injury and elucidate the underlying mechanisms of action. We found that the expression levels of IGF-1 were markedly enhanced in astrocytes post HI. Delivery of IGF-1 significantly alleviates neonatal brain insult and improves neurobehavioral disorders in neonatal mice after HI challenge. Through binding to IGF-1 receptor (IGF-1R), IGF-1 inhibited the apoptosis of neuronal cells following HI exposure. IGF-1 improved neuronal cell survival and proliferation through activation of phosphorylated AKT signaling. Of note, the protective property of IGF-1 against ischemic neuronal insults was dependent on suppression of the FoXO3a-PUMA signaling pathway. Taken together, these findings suggest that IGF-1 may represent a new neuroprotectant for newborns with hypoxic-ischemic encephalopathy.

Post-ischemic brain neurodegeneration with subsequent neuroinflammation is a major cause of mortality, permanent disability, and the development of Alzheimer's disease type dementia in the absence of appropriate treatment. The inflammatory response begins immediately after ischemia and can persist for many years. Post-ischemic neuroinflammation plays a dual role: initially, it is essential for brain repair and maintenance of homeostasis, but when it becomes uncontrolled, it causes secondary damage and worsens neurological outcome. Neuroinflammation is a complex phenomenon involving interactions between infiltrating immune cells from the peripheral circulation and resident immune cells in ischemic brain areas. This review focuses on the complex relationship between non-coding RNAs, amyloid accumulation, tau protein modifications, and the development of neuroinflammation in the post-ischemic brain. In particular, it clarifies whether the cooperation of non-coding RNAs with amyloid and tau protein enhances neuroinflammation and whether the vicious cycle of neuroinflammatory responses affects the production, behavior, and aggregation of these molecules. Ultimately, elucidating these interactions is critical, as they may contribute to resolving the phenomenon of post-ischemic brain neurodegenerative mechanisms. Furthermore, this review highlights the role of neuroinflammation as a functionally complex immune response regulated/mediated by transcription factors and cytokines. Additionally, it examines how the presence of non-coding RNAs, amyloid aggregation, and modified tau protein may shape the inflammatory landscape. This review aims to advance our understanding of post-ischemic neuroinflammation and its implications for long-term brain health.

Border-associated macrophages (BAMs) are tissue-resident macrophages in the central nervous system (CNS) that originate from yolk sac progenitors during primitive hematopoiesis. While much is known about their parenchymal counterparts, microglia, recent evidence indicates that BAMs also play roles in neurodevelopment. Located at CNS interfaces such as the meninges, choroid plexus, and perivascular space, BAMs facilitate immune surveillance, vascular modeling, debris clearance, and cerebrospinal fluid dynamics. Despite their strategic location, BAMs have historically been understudied in developmental contexts. This mini review covers their embryonic origins, regional diversification, and functional roles as development progresses. Offering new insights, we consider BAMs in the context of neurodevelopmental disorders (NDDs). Recent findings from maternal immune activation (MIA) studies suggest that fetal BAMs may contribute to aberrant cortical development through altered inflammatory signaling. We propose that, like microglia, BAMs may play previously unappreciated roles in shaping the developmental trajectory of the brain. To aid future research, we also review current tools for studying BAMs in vivo and in vitro, including new transgenic lines and organoid-based approaches. These tools will be critical for dissecting the molecular functions of BAMs during healthy and disordered development. Understanding BAM biology in early life may reveal novel mechanisms underlying NDDs and inform therapeutic strategies targeting brain-immune interfaces.

State dependent memory (SDM) occurs when memory retrieval varies with the individual's psychological and physiological state at encoding and recall. Growing evidence shows that internal states shape memory performance across all phases of memory. Examples include affective and physiological conditions, medication effects, and disease states. This review examines how these states affect encoding, storage, and retrieval. We argue that internal states modulate activity in brain regions involved in memory by altering neurotransmitter signaling and by inducing plastic organization of neural circuits and networks. We believe this perspective can guide personalized electrical neuromodulation and multimodal intervention strategies for memory disorders.

Diabetic peripheral neuropathy (DPN), a prevalent and debilitating complication of diabetes, involves complex interactions between peripheral nerve damage and central nervous system (CNS) dysfunction. While traditional research has focused on peripheral and spinal mechanisms, emerging evidence highlights that the brain plays a critical role in the development of painful DPN. This review synthesizes recent advances from neuroimaging, spectroscopy, and preclinical studies to delineate structural, functional, and neurochemical alterations in the central nervous system associated with DPN. Patients exhibit cortical thinning, subcortical atrophy, and disrupted connectivity in sensory, affective, and cognitive networks, accompanied by metabolic imbalances and excitatory-inhibitory neurotransmitter shifts. Preclinical models further implicate maladaptive plasticity, microglial activation, and region-specific astrocytic responses in amplifying central sensitization and pain chronicity. These mechanistic insights underscore the central nervous system as a therapeutic target. Non-invasive neuromodulation techniques, such as repetitive transcranial magnetic stimulation, and brain-directed pharmacological strategies show promising but preliminary benefits in alleviating neuropathic pain. Understanding the interplay between peripheral injury and brain dysfunction in DPN not only broadens the conceptual framework of its pathophysiology but also provides a foundation for developing novel interventions aimed at restoring central network balance and improving patient outcomes.