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A Thin-skull Window Technique for Chronic Two-photon In vivo Imaging of Murine Microglia in Models of Neuroinflammation
Published on: September 19, 2010
Macrophage-induced inflammation affects hippocampal plasticity and neuronal development in a murine model of HIV-1
Larisa Poluektova1, Vakara Meyer, Lisa Walters
1Laboratory of Neuroregeneration, Department of Pharmacology and Experimental Neuroscience, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. lpoluekt@unmc.edu
Abstract:
Cognitive, behavioral, and motor impairments, during progressive human immunodeficiency virus type 1 (HIV-1) infection, are linked to activation of brain mononuclear phagocytes (MP; perivascular macrophages and microglia). Activated MPs effect a giant cell encephalitis and neuroinflammatory responses that are mirrored in severe combined immunodeficient (SCID) mice injected with human monocyte-derived macrophages (MDM). Whether activated human MDMs positioned in the basal ganglia affect hippocampal neuronal plasticity, the brain subregion involved in learning and memory, is unknown. Thus, immunohistochemical techniques were used for detection of newborn neurons (polysialylated neuronal cell adhesion molecule [PSA-NCAM]) and cell proliferation (Ki-67) to assay MDM effects on neuronal development in mouse models of HIV-1 encephalitis. Immunodeficient (C.B.-17/SCID and nonobese diabetic/SCID, NOD/SCID) and immune competent (C.B.-17) mice were injected with uninfected or HIV-1-infected MDM. Sham-operated or unmanipulated mice served as controls. Neuronal plasticity was evaluated in the hippocampal dentate gyrus (DG) at days 7 and 28. By day 7, increased numbers of Ki-67+ cells, PSA-NCAM+ cells and dendrites in DG were observed in sham-operated animals. In contrast, significant reductions in neuronal precursors and altered neuronal morphology paralleled increased microglial activation in both HIV-1-infected and uninfected MDM-injected animals. DG cellular composition was restored at day 28. We posit that activated MDM induce inflammation and diminish DG neuronal plasticity. These data provide novel explanations for the cognitive impairments manifested during advanced HIV-1 infection.
Insights
Activated human macrophages in the brain reduce neuronal plasticity and development in mouse models of HIV-1 infection, potentially explaining cognitive decline. This impacts learning and memory functions.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Human immunodeficiency virus type 1 (HIV-1) infection causes cognitive, behavioral, and motor impairments linked to brain mononuclear phagocyte (MP) activation.
- Activated MPs contribute to giant cell encephalitis and neuroinflammation, which can be modeled in severe combined immunodeficient (SCID) mice injected with human monocyte-derived macrophages (MDM).
Purpose of the Study:
- To investigate whether activated human MDMs in the basal ganglia affect hippocampal neuronal plasticity, a region crucial for learning and memory.
- To utilize mouse models to assay MDM effects on neuronal development and plasticity in the context of HIV-1 encephalitis.
Main Methods:
- Immunohistochemical techniques were employed to detect newborn neurons (polysialylated neuronal cell adhesion molecule [PSA-NCAM]) and cell proliferation (Ki-67).
- Immunodeficient (SCID) and immune competent mice were injected with uninfected or HIV-1-infected MDM, with sham-operated or unmanipulated mice serving as controls.
- Neuronal plasticity was assessed in the hippocampal dentate gyrus (DG) at 7 and 28 days post-injection.
Main Results:
- While sham-operated animals showed increased neuronal markers and dendrites by day 7, MDM-injected animals exhibited reduced neuronal precursors and altered morphology.
- Increased microglial activation was observed in both HIV-1-infected and uninfected MDM-injected groups.
- DG cellular composition and neuronal morphology showed signs of restoration by day 28.
Conclusions:
- Activated MDMs induce inflammation and diminish dentate gyrus neuronal plasticity.
- These findings offer new insights into the mechanisms underlying cognitive impairments observed in advanced HIV-1 infection.
- The study highlights the detrimental impact of activated macrophages on neuroplasticity, even in the absence of direct HIV-1 infection of the host cells.
