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Exposure to gestational diabetes mellitus induces neuroinflammation, derangement of hippocampal neurons, and cognitive changes in rat offspring

View Article: PubMed Central - PubMed

ABSTRACT

Background: Birth cohort studies link gestational diabetes mellitus (GDM) with impaired cognitive performance in the offspring. However, the mechanisms involved are unknown. We tested the hypothesis that obesity-associated GDM induces chronic neuroinflammation and disturbs the development of neuronal circuitry resulting in impaired cognitive abilities in the offspring.

Methods: In rats, GDM was induced by feeding dams a diet high in sucrose and fatty acids. Brains of neonatal (E20) and young adult (15-week-old) offspring of GDM and lean dams were analyzed by immunohistochemistry, cytokine assay, and western blotting. Young adult offspring of GDM and lean dams went also through cognitive assessment. Cultured microglial responses to elevated glucose and/or fatty acids levels were analyzed.

Results: In rats, impaired recognition memory was observed in the offspring of GDM dams. GDM exposure combined with a postnatal high-fat and sucrose diet resulted in atypical inattentive behavior in the offspring. These cognitive changes correlated with reduced density and derangement of Cornu Ammonis 1 pyramidal neuronal layer, decreased hippocampal synaptic integrity, increased neuroinflammatory status, and reduced expression of CX3CR1, the microglial fractalkine receptor regulating microglial pro-inflammatory responses and synaptic pruning. Primary microglial cultures that were exposed to high concentrations of glucose and/or palmitate were transformed into an activated, amoeboid morphology with increased nitric oxide and superoxide production, and altered their cytokine release profile.

Conclusions: These findings demonstrate that GDM stimulates microglial activation and chronic inflammatory responses in the brain of the offspring that persist into young adulthood. Reactive gliosis correlates positively with hippocampal synaptic decline and cognitive impairments. The elevated pro-inflammatory cytokine expression at the critical period of hippocampal synaptic maturation suggests that neuroinflammation might drive the synaptic and cognitive decline in the offspring of GDM dams. The importance of microglia in this process is supported by the reduced Cx3CR1 expression as an indication of the loss of microglial control of inflammatory responses and phagocytosis and synaptic pruning in GDM offspring.

No MeSH data available.


Related in: MedlinePlus

Gestational diabetes mellitus induces neuroinflammation in the offspring brain (at 20E). Micrographs of immunostaining with Iba1 and GFAP demonstrate elevated neuroinflammation status throughout the rat embryo brain. a, b Iba1 allows visualization of microglial morphology. The microglia of embryos from GDM dams have more activated, amoeboid morphology compared to embryos from dams with healthy pregnancy of which majority possess resting, ramified microglial morphology. d Increase in GFAP expression seen in embryos of GDM dams reflects on astroglial activation and chronic inflammation. Quantitative analysis of hippocampal Iba1-positive cells (c) and GFAP staining (e) confirms the elevated neuroinflammation in GDM offspring. f Cytokine analysis demonstrates increase in pro-inflammatory cytokines (IFNγ, TNFα, IL-1, MCP-1), while only IL-4 was elevated from the anti-inflammatory cytokines (IL-4, IL-10, IL-13). *p ≤ 0.05 compared to lean, n = 6
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Fig3: Gestational diabetes mellitus induces neuroinflammation in the offspring brain (at 20E). Micrographs of immunostaining with Iba1 and GFAP demonstrate elevated neuroinflammation status throughout the rat embryo brain. a, b Iba1 allows visualization of microglial morphology. The microglia of embryos from GDM dams have more activated, amoeboid morphology compared to embryos from dams with healthy pregnancy of which majority possess resting, ramified microglial morphology. d Increase in GFAP expression seen in embryos of GDM dams reflects on astroglial activation and chronic inflammation. Quantitative analysis of hippocampal Iba1-positive cells (c) and GFAP staining (e) confirms the elevated neuroinflammation in GDM offspring. f Cytokine analysis demonstrates increase in pro-inflammatory cytokines (IFNγ, TNFα, IL-1, MCP-1), while only IL-4 was elevated from the anti-inflammatory cytokines (IL-4, IL-10, IL-13). *p ≤ 0.05 compared to lean, n = 6

Mentions: Since GDM can promote a pro-inflammatory environment [14], we evaluated activation of microglia, the resident immune cells of the brain. Iba1 immunohistochemical analysis of the hippocampi from neonates revealed microglial morphological activation, as judged by the reduced proportion of ramified microglia (lean 65 ± 11% vs GDM 19 ± 6%), and an increased proportion of microglia exhibiting amoeboid morphology (lean 8 ± 2% vs GDM 46 ± 8%) (Fig. 3a–c). Increased GFAP expression (Fig. 3d, e) in the GDM neonates indicated elevated hippocampal astogliosis. Increased levels of pro-inflammatory cytokines IFNγ, IL-1α, IL-4, MCP-1, and TNFα were also observed in the brain of the neonatal offspring of GDM dams (Fig. 3f). Overall, our findings show that GDM increased neuroinflammation status in the neonatal offspring.Fig. 3


Exposure to gestational diabetes mellitus induces neuroinflammation, derangement of hippocampal neurons, and cognitive changes in rat offspring
Gestational diabetes mellitus induces neuroinflammation in the offspring brain (at 20E). Micrographs of immunostaining with Iba1 and GFAP demonstrate elevated neuroinflammation status throughout the rat embryo brain. a, b Iba1 allows visualization of microglial morphology. The microglia of embryos from GDM dams have more activated, amoeboid morphology compared to embryos from dams with healthy pregnancy of which majority possess resting, ramified microglial morphology. d Increase in GFAP expression seen in embryos of GDM dams reflects on astroglial activation and chronic inflammation. Quantitative analysis of hippocampal Iba1-positive cells (c) and GFAP staining (e) confirms the elevated neuroinflammation in GDM offspring. f Cytokine analysis demonstrates increase in pro-inflammatory cytokines (IFNγ, TNFα, IL-1, MCP-1), while only IL-4 was elevated from the anti-inflammatory cytokines (IL-4, IL-10, IL-13). *p ≤ 0.05 compared to lean, n = 6
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5384149&req=5

Fig3: Gestational diabetes mellitus induces neuroinflammation in the offspring brain (at 20E). Micrographs of immunostaining with Iba1 and GFAP demonstrate elevated neuroinflammation status throughout the rat embryo brain. a, b Iba1 allows visualization of microglial morphology. The microglia of embryos from GDM dams have more activated, amoeboid morphology compared to embryos from dams with healthy pregnancy of which majority possess resting, ramified microglial morphology. d Increase in GFAP expression seen in embryos of GDM dams reflects on astroglial activation and chronic inflammation. Quantitative analysis of hippocampal Iba1-positive cells (c) and GFAP staining (e) confirms the elevated neuroinflammation in GDM offspring. f Cytokine analysis demonstrates increase in pro-inflammatory cytokines (IFNγ, TNFα, IL-1, MCP-1), while only IL-4 was elevated from the anti-inflammatory cytokines (IL-4, IL-10, IL-13). *p ≤ 0.05 compared to lean, n = 6
Mentions: Since GDM can promote a pro-inflammatory environment [14], we evaluated activation of microglia, the resident immune cells of the brain. Iba1 immunohistochemical analysis of the hippocampi from neonates revealed microglial morphological activation, as judged by the reduced proportion of ramified microglia (lean 65 ± 11% vs GDM 19 ± 6%), and an increased proportion of microglia exhibiting amoeboid morphology (lean 8 ± 2% vs GDM 46 ± 8%) (Fig. 3a–c). Increased GFAP expression (Fig. 3d, e) in the GDM neonates indicated elevated hippocampal astogliosis. Increased levels of pro-inflammatory cytokines IFNγ, IL-1α, IL-4, MCP-1, and TNFα were also observed in the brain of the neonatal offspring of GDM dams (Fig. 3f). Overall, our findings show that GDM increased neuroinflammation status in the neonatal offspring.Fig. 3

View Article: PubMed Central - PubMed

ABSTRACT

Background: Birth cohort studies link gestational diabetes mellitus (GDM) with impaired cognitive performance in the offspring. However, the mechanisms involved are unknown. We tested the hypothesis that obesity-associated GDM induces chronic neuroinflammation and disturbs the development of neuronal circuitry resulting in impaired cognitive abilities in the offspring.

Methods: In rats, GDM was induced by feeding dams a diet high in sucrose and fatty acids. Brains of neonatal (E20) and young adult (15-week-old) offspring of GDM and lean dams were analyzed by immunohistochemistry, cytokine assay, and western blotting. Young adult offspring of GDM and lean dams went also through cognitive assessment. Cultured microglial responses to elevated glucose and/or fatty acids levels were analyzed.

Results: In rats, impaired recognition memory was observed in the offspring of GDM dams. GDM exposure combined with a postnatal high-fat and sucrose diet resulted in atypical inattentive behavior in the offspring. These cognitive changes correlated with reduced density and derangement of Cornu Ammonis 1 pyramidal neuronal layer, decreased hippocampal synaptic integrity, increased neuroinflammatory status, and reduced expression of CX3CR1, the microglial fractalkine receptor regulating microglial pro-inflammatory responses and synaptic pruning. Primary microglial cultures that were exposed to high concentrations of glucose and/or palmitate were transformed into an activated, amoeboid morphology with increased nitric oxide and superoxide production, and altered their cytokine release profile.

Conclusions: These findings demonstrate that GDM stimulates microglial activation and chronic inflammatory responses in the brain of the offspring that persist into young adulthood. Reactive gliosis correlates positively with hippocampal synaptic decline and cognitive impairments. The elevated pro-inflammatory cytokine expression at the critical period of hippocampal synaptic maturation suggests that neuroinflammation might drive the synaptic and cognitive decline in the offspring of GDM dams. The importance of microglia in this process is supported by the reduced Cx3CR1 expression as an indication of the loss of microglial control of inflammatory responses and phagocytosis and synaptic pruning in GDM offspring.

No MeSH data available.


Related in: MedlinePlus