Human immunodeficiency virus (HIV) infection induces neuronal injuries, with almost 50% of infected individuals developing HIV-associated neurocognitive disorders (HAND). Although highly activate antiretroviral therapy (HAART) has significantly reduced the incidence of severe dementia, the overall prevalence of HAND remains high. Synaptic degeneration is emerging as one of the most relevant neuropathologies associate with HAND. Previous studies have reported critical roles of viral proteins and inflammatory responses in this pathogenesis. Infected cells, including macrophages, microglia and astrocytes, may release viral proteins and other neurotoxins to stimulate neurons and cause excessive calcium influx, overproduction of free radicals and disruption of neurotransmitter hemostasis. The dysregulation of neural circuits likely leads to synaptic damage and loss. Identification of the specific mechanism of the synaptic degeneration may facilitate the development of effective therapeutic approaches to treat HAND.
and coverslips were applied with ProLong Gold Antifade Mountant (Thermo Fisher Scientific). Immunofluorescence was captured using a Zeiss LSM 510 laser-scanning confocal microscope. Statistics. Survival curve comparisons were performed using GraphPad Prism software, which uses the log-rank test. Values for viral burden, cytokine production, and antibody and T cell response experiments are presented as the mean ± SEM. P values for these experiments were calculated with an unpaired, 2-tailed Student's t test. Statistical significance was accepted at a P value of less than 0.05. Study approval. All experiments were performed in compliance with and under the approval of the IACUC of UTMB.
HIV-1 infection of the nervous system causes various neurological diseases, and synaptic degeneration is likely a critical step in the neuropathogenesis. Our prior studies revealed a significant decrease of synaptic protein, specifically in the spinal dorsal horn of patients with HIV-1 in whom pain developed, suggesting a potential contribution of synaptic degeneration to the pathogenesis of HIV-associated pain. However, the mechanism by which HIV-1 causes the spinal synaptic degeneration is unclear. Here, we identified a critical role of microglia in the synaptic degeneration. In primary cortical cultures (day in vitro 14) and spinal cords of 3-to 5-month-old mice (both sexes), microglial ablation inhibited gp120-induced synapse decrease. Fractalkine (FKN), a microglia activation chemokine specifically expressed in neurons, was upregulated by gp120, and knockout of the FKN receptor CX3CR1, which is predominantly expressed in microglia, protected synapses from gp120-induced toxicity. These results indicate that the neuron-to-microglia intercellular FKN/ CX3CR1 signaling plays a role in gp120-induced synaptic degeneration. To elucidate the mechanism controlling this intercellular signaling, we tested the role of the Wnt/-catenin pathway in regulating FKN expression. Inhibition of Wnt/-catenin signaling blocked both gp120-induced FKN upregulation and synaptic degeneration, and gp120 stimulated Wnt/-catenin-regulated FKN expression via NMDA receptors (NMDARs). Furthermore, NMDAR antagonist APV, Wnt/-catenin signaling suppressor DKK1, or knockout of CX3CR1 alleviated gp120-induced mechanical allodynia in mice, suggesting a critical contribution of the Wnt/-catenin/FKN/CX3R1 pathway to gp120-induced pain. These findings collectively suggest that HIV-1 gp120 induces synaptic degeneration in the spinal pain neural circuit by activating microglia via Wnt3a/-catenin-regulated FKN expression in neurons.Synaptic degeneration develops in the spinal cord dorsal horn of HIV patients with chronic pain, but the patients without the pain disorder do not show this neuropathology, indicating a pathogenic contribution of the synaptic degeneration to the development of HIV-associated pain. However, the mechanism underlying the synaptic degeneration is unclear. We report here that HIV-1 gp120, a neurotoxic protein that is specifically associated with the manifestation of pain in HIV patients, induces synapse loss via microglia. Further studies elucidate that gp120 activates microglia by stimulating Wnt/-catenin-regulated fractalkine in neuron. The results demonstrate a critical role of microglia in the pathogenesis of HIV-associated synaptic degeneration in the spinal pain neural circuit.
While astrocytes have been traditionally described as passive supportive cells, studies during the last decade have shown they are active players in many aspects of cnS physiology and function both in normal and disease states. However, the precise mechanisms regulating astrocytes function and interactions within the cnS are still poorly understood. this knowledge gap is due in large part to the limitations of current image analysis tools that cannot process astrocyte images efficiently and to the lack of methods capable of quantifying their complex morphological characteristics. to provide an unbiased and accurate framework for the quantitative analysis of fluorescent images of astrocytes, we introduce a new automated image processing pipeline whose main novelties include an innovative module for cell detection based on multiscale directional filters and a segmentation routine that leverages deep learning and sparse representations to reduce the need of training data and improve performance. extensive numerical tests show that our method performs very competitively with respect to state-of-the-art methods also in challenging images where astrocytes are clustered together. Our code is released open source and freely available to the scientific community.The human brain is a complex network of over 2 × 10 11 neural cells comprising neurons and glial cells. Neuroglia comprise astrocytes, oligodendrocytes, NG2 glia, microglia and all peripheral glia 1 . Astrocytes, a subtype of glial cells with a complex star-shaped morphology, are the most abundant cells in most part of the human brain 2 . Although they were long characterized as supportive cells only involved in maintaining neuron homeostasis and survival, a number of studies during the last decade have revealed that astrocytes play an active role in fundamental brain processes underlying neuronal development and function. Several studies have implicated astrocytes in controlling the development of the nervous system through axon guidance and synaptogenesis. During neural circuit development, astrocytes are responsible for the regularization of the neuronal network by pruning abnormal or dysfunctioning synapses 3 . In addition, together with the pre-and post-synaptic parts of two neuronal synapses, astrocytes can form a so-called "tripartite" synapse that helps modulate synaptic transmission via the release of neurotransmitters such as glutamate and ATP 4,5 . The critical roles of astrocytes in neuronal development and connectivity make them among the most promising targets for innovative therapies designed to treat a range of brain disorders or neurological injuries 6 . As a result, the attention on astrocytes has dramatically increased in recent years.Astrocytes have been shown to reflect their diverse abilities and functions on their special structural design, and alterations in astrocyte morphology are known to correlate to traumatic brain injury, infection, ischemia, autoimmune responses, and neurodegenerative diseases 5,7,8 . For instance, their intricate ar...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.