Chronic maternal hyperglycemia induced during mid-pregnancy in rats increases RAGE expression, augments hippocampal excitability, and alters behavior of the offspring

Chandna, Andrew R.; Kuhlmann, Naila; Bryce, Courtney A.; Greba, Quentin; Campanucci, Verónica A.; Howland, John G.

doi:10.1016/j.neuroscience.2015.06.063

Cited by 51 publications

(33 citation statements)

References 65 publications

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“…It should be noted that increased anxiety‐like behaviour is not a phenotype shared by other rat strains with absence seizures (van Luijtelaar, ) and the behaviour of the NEC strain as a ‘control’ has been drawn into question (Marques‐Carneiro et al ., ). In the present experiments, NEC rats generally performed similarly to Long Evans rats in these tests (Hannesson et al ., ; Chandna et al ., ). An exception is the relatively short time spent in the open arms of the elevated plus maze by the NEC male rats on P56 compared with the Long Evans male rats tested in Chandna et al .…”

Section: Discussionmentioning

confidence: 97%

The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans

Marks

Cavanagh

Greba

et al. 2015

Eur J of Neuroscience

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Behavioural, neurological, and genetic similarities exist in epilepsies, their psychiatric comorbidities, and various psychiatric illnesses, suggesting common aetiological factors. Rodent models of epilepsy are used to characterize the comorbid symptoms apparent in epilepsy and their neurobiological mechanisms. The present study was designed to assess Pavlovian fear conditioning and latent inhibition in a polygenetic rat model of absence epilepsy, i.e. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the non-epileptic control (NEC) strain. Electrophysiological recordings confirmed the presence of spike-wave discharges in young adult GAERS but not NEC rats. A series of behavioural tests designed to assess anxiety-like behaviour (elevated plus maze, open field, acoustic startle response) and cognition (Pavlovian conditioning and latent inhibition) was subsequently conducted on male and female offspring. Results showed that GAERS exhibited significantly higher anxiety-like behaviour, a characteristic reported previously. In addition, using two protocols that differed in shock intensity, we found that both sexes of GAERS displayed exaggerated cued and contextual Pavlovian fear conditioning and impaired fear extinction. Fear reinstatement to the conditioned stimuli following unsignalled footshocks did not differ between the strains. Male GAERS also showed impaired latent inhibition in a paradigm using Pavlovian fear conditioning, suggesting that they may have altered attention, particularly related to previously irrelevant stimuli in the environment. Neither the female GAERS nor NEC rats showed evidence of latent inhibition in our paradigm. Together, the results suggest that GAERS may be a particularly useful model for assessing therapeutics designed to improve the emotional and cognitive disturbances associated with absence epilepsy.

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Section: Discussionmentioning

confidence: 97%

The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans

Marks

Cavanagh

Greba

et al. 2015

Eur J of Neuroscience

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“…Epigenetics may be another potential mechanism (33). An animal study showed that chronic maternal hyperglycemia during pregnancy increased hippocampal excitement and altered behavior in offspring, and the effect appeared to be mediated by increased activation of the receptor for advanced glycation end products (RAGE)d a major source of inflammatory signaling in diabetes (34). The potential role of maternal hypoglycemia, which has been linked to altered brain function in adults (35), is unclear.…”

Section: Discussionmentioning

confidence: 99%

Maternal Gestational Diabetes Mellitus, Type 1 Diabetes, and Type 2 Diabetes During Pregnancy and Risk of ADHD in Offspring

et al. 2018

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OBJECTIVETo examine the relative importance of maternal preexisting type 1 diabetes (T1D), preexisting type 2 diabetes (T2D), and gestational diabetes mellitus (GDM) on risk of attention deficit/hyperactivity disorder (ADHD) in offspring. RESEARCH DESIGN AND METHODSThis retrospective birth cohort study included 333,182 singletons born in 1995-2012 within Kaiser Permanente Southern California hospitals. Children were prospectively followed through electronic medical records from age 4 years. Relative risks of ADHD associated with diabetes exposures in utero were estimated by hazard ratios (HRs) using Cox regression with adjustment for potential confounders. For GDM, timing of exposure was evaluated by gestational age at diagnosis and severity was assessed by the need for antidiabetes medication treatment during pregnancy. RESULTSA total of 37,878 (11.4%) children were exposed to diabetes (522 exposed to T1D, 7,822 T2D, and 29,534 GDM). During a median of 4.9 years (interquartile range 2.2, 9.6) of follow-up after age 4 years, 17,415 (5.2%) children were diagnosed with ADHD. ADHD risk was not associated with GDM taken as a whole (P = 0.50) or with gestational age at GDM diagnosis (P = 0.16). However, the risk was significantly greater for the GDM requiring versus not requiring antidiabetes medications (P < 0.001). Compared with children unexposed to diabetes, the adjusted HRs for ADHD in children were 1.57 (95% CI 1.09-2.25) for exposure to T1D, 1.43 (1.29-1.60) for T2D, 1.26 (1.14-1.41) for GDM requiring antidiabetes medications, and 0.93 (0.86-1.01) for GDM not requiring medications. CONCLUSIONSThe hierarchy of risks suggests that severity of maternal diabetes (T1D vs. T2D vs. GDM requiring antidiabetes medications) influences the risk of ADHD in offspring of mothers with diabetes.

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“…A decreased number of neurons was found in the pyramidal layers of CA1 and CA3 hippocampal regions at postnatal days 7 and 21, in the offspring of STZ-treated rats (Golalipour et al 2012). Chandna et al (2015) reported that hippocampal neurons in newborn pups from STZ-treated females showed altered action potential kinetics along with a more hyperpolarized resting membrane potential. Despite these changes in neonatal hippocampal excitability, animals in this study showed normal memory acquisition as adults.…”

Section: Memory and Brain Insulin Signalingmentioning

confidence: 99%

“…Studies which directly investigated whether intra-uterine exposure to hyperglycemia and hyperinsulinemia were associated to altered anxiety levels showed confounding results. While some of them report no differences in anxiety levels among rats born from GD dams when diabetes was induced before pregnancy (Kinney et al 2003, Ramanathan et al 2000, one study reported decreased anxiety levels in the offspring when STZ was administered during mid pregnancy (Chandna et al 2015), a condition which more closely resembles the time course of GD development in humans.…”

Section: Mood Disordersmentioning

confidence: 99%

“…Clinical evidence suggest that the offspring of GD mothers have increased risk of developing schizophrenia (Van Lieshout andVoruganti 2008, Boksa 2004) and autism (Gardener et al 2009, Xiang et al 2015 during adolescence and adulthood. Interestingly, a schizophrenic-like phenotype was successfully reproduced in male rats born from STZ-treated dams, as these animals showed disruption of prepulse inhibition response in their young adulthood (Chandna et al 2015). This behavior persisted even when euglycemia was ensured by insulin treatment during pregnancy, but authors did not further evaluate the mechanisms underlying this interesting behavioral finding.…”

Section: Neuropsychiatric Disordersmentioning

confidence: 99%

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Consequences of gestational diabetes to the brain and behavior of the offspring

Sousa

Torres

Figueiredo

et al. 2018

An. Acad. Bras. Ciênc.

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Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during the second/third trimesters of pregnancy in previously normoglycemic women. It is currently estimated that 10% of all pregnancies in the United States show this condition. For many years, the transient nature of GD has led researchers and physicians to assume that long-term consequences were absent. However, GD diagnosis leads to a six-fold increase in the risk of developing type 2 diabetes (T2D) in women and incidence of obesity and T2D is also higher among their infants. Recent and concerning evidences point to detrimental effects of GD on the behavior and cognition of the offspring, which often persist until adolescence or adulthood. Considering that the perinatal period is critical for determination of adult behavior, it is expected that the intra-uterine exposure to hyperglycemia, hyperinsulinemia and pro-inflammatory mediators, hallmark features of GD, might affect brain development. Here, we review early clinical and experimental evidence linking GD to consequences on the behavior of the offspring, focusing on memory and mood disorders. We also discuss initial evidence suggesting that downregulation of insulin signaling cascades are seen in the brains of GD offspring and could contribute to the consequences on their behavior.

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Chronic maternal hyperglycemia induced during mid-pregnancy in rats increases RAGE expression, augments hippocampal excitability, and alters behavior of the offspring

Cited by 51 publications

References 65 publications

The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans

The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans

Maternal Gestational Diabetes Mellitus, Type 1 Diabetes, and Type 2 Diabetes During Pregnancy and Risk of ADHD in Offspring

Consequences of gestational diabetes to the brain and behavior of the offspring

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