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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 atypically exploratory and inattentive behavior and impairs recognition memory in offspring. Behavioral test analysis of 14- to 15-week-old rats. a, b Open field heat map demonstrates that GDM offspring on postnatal HFS diet stayed more in the center of the field. #p < 0.05, compared to lean LF cohorts, n = 8–10. c–e GDM offspring also showed reduced rearing, but their moving activity was not different from the lean offspring cohorts. f, g In NOR, GDM offspring failed to differentiate the familiar object from the novel object presented to them a day after the training, while lean offspring spent significantly more time exploring the novel object on test day.*p < 0.05, n = 6–10
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Fig1: Gestational diabetes mellitus induces atypically exploratory and inattentive behavior and impairs recognition memory in offspring. Behavioral test analysis of 14- to 15-week-old rats. a, b Open field heat map demonstrates that GDM offspring on postnatal HFS diet stayed more in the center of the field. #p < 0.05, compared to lean LF cohorts, n = 8–10. c–e GDM offspring also showed reduced rearing, but their moving activity was not different from the lean offspring cohorts. f, g In NOR, GDM offspring failed to differentiate the familiar object from the novel object presented to them a day after the training, while lean offspring spent significantly more time exploring the novel object on test day.*p < 0.05, n = 6–10

Mentions: Offspring of GDM dams were analyzed at 14–15 weeks of age, which is equivalent to the young adult stage in humans. At this age, the GDM offspring are overweight (Table 2) and insulin resistant [25]. General and locomotor activity, as assessed by the OF test, was similar between all groups of offspring (Fig. 1a, c, d). However, significantly fewer rearing were observed by the GDM offspring compared to the lean offspring (Fig. 1e). GDM offspring fed a LF diet (GDM-LF) tended (p = 0.054) to spend more time in the center than lean-LF and lean-HFS offspring, while GDM offspring fed a HFS diet (GDM-HFS) spend significantly more (p < 0.05) time in the center of the field (Fig. 1b), indicating differences in the exploration habits of the GDM offspring. Rodents typically avoid being exposed to open space but prefer to remain close to the walls as a thigmotactic response [38] and actively observe their surroundings by rearing, suggesting that the GDM-HFS offspring show reduced anxiety level and inattentive behavior as they explore the center of the OF while not actively surveying their surroundings as indicated by their reduced rearing. The NOR test demonstrated that offspring of GDM dams also had impaired recognition memory because they spent equal time exploring both the familiar and novel object, while lean offspring preferred to examine the novel object displaying healthy recognition memory (Fig. 1f, g).Fig. 1


Exposure to gestational diabetes mellitus induces neuroinflammation, derangement of hippocampal neurons, and cognitive changes in rat offspring
Gestational diabetes mellitus induces atypically exploratory and inattentive behavior and impairs recognition memory in offspring. Behavioral test analysis of 14- to 15-week-old rats. a, b Open field heat map demonstrates that GDM offspring on postnatal HFS diet stayed more in the center of the field. #p < 0.05, compared to lean LF cohorts, n = 8–10. c–e GDM offspring also showed reduced rearing, but their moving activity was not different from the lean offspring cohorts. f, g In NOR, GDM offspring failed to differentiate the familiar object from the novel object presented to them a day after the training, while lean offspring spent significantly more time exploring the novel object on test day.*p < 0.05, n = 6–10
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5384149&req=5

Fig1: Gestational diabetes mellitus induces atypically exploratory and inattentive behavior and impairs recognition memory in offspring. Behavioral test analysis of 14- to 15-week-old rats. a, b Open field heat map demonstrates that GDM offspring on postnatal HFS diet stayed more in the center of the field. #p < 0.05, compared to lean LF cohorts, n = 8–10. c–e GDM offspring also showed reduced rearing, but their moving activity was not different from the lean offspring cohorts. f, g In NOR, GDM offspring failed to differentiate the familiar object from the novel object presented to them a day after the training, while lean offspring spent significantly more time exploring the novel object on test day.*p < 0.05, n = 6–10
Mentions: Offspring of GDM dams were analyzed at 14–15 weeks of age, which is equivalent to the young adult stage in humans. At this age, the GDM offspring are overweight (Table 2) and insulin resistant [25]. General and locomotor activity, as assessed by the OF test, was similar between all groups of offspring (Fig. 1a, c, d). However, significantly fewer rearing were observed by the GDM offspring compared to the lean offspring (Fig. 1e). GDM offspring fed a LF diet (GDM-LF) tended (p = 0.054) to spend more time in the center than lean-LF and lean-HFS offspring, while GDM offspring fed a HFS diet (GDM-HFS) spend significantly more (p < 0.05) time in the center of the field (Fig. 1b), indicating differences in the exploration habits of the GDM offspring. Rodents typically avoid being exposed to open space but prefer to remain close to the walls as a thigmotactic response [38] and actively observe their surroundings by rearing, suggesting that the GDM-HFS offspring show reduced anxiety level and inattentive behavior as they explore the center of the OF while not actively surveying their surroundings as indicated by their reduced rearing. The NOR test demonstrated that offspring of GDM dams also had impaired recognition memory because they spent equal time exploring both the familiar and novel object, while lean offspring preferred to examine the novel object displaying healthy recognition memory (Fig. 1f, g).Fig. 1

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