ABSTRACT
Maternal ethanol consumption during pregnancy can produce a range of teratogenic outcomes in offspring. The mechanism of ethanol teratogenicity is multi-faceted, but may involve alterations in insulin and insulin-like growth factor (IGF) signaling pathways. These pathways are not only important for metabolism, but are also critically involved in neuronal survival and plasticity, and they can be altered by chronic prenatal ethanol exposure (CPEE). The objective of this study was to test the hypothesis that CPEE alters expression of insulin and IGF signaling molecules in the prefrontal cortex and liver of adult guinea pig offspring. Pregnant Dunkin-Hartley-strain guinea pigs received ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding (nutritional control) throughout gestation. Fasting blood glucose concentration was measured in male and female offspring at postnatal day 150-200, followed by euthanasia, collection of prefrontal cortex and liver, and RNA extraction. IGF-1, IGF-1 receptor (IGF-1R), IGF-2, IGF-2 receptor (IGF-2R), insulin receptor substrate (IRS)-1, IRS-2, and insulin receptor (INSR) mRNA expression levels were measured in tissues using quantitative real-time PCR. The mean maternal blood ethanol concentration was 281 ± 15 mg/dL at 1 h after the second divided dose of ethanol on GD 57. CPEE resulted in increased liver weight in adult offspring, but produced no difference in fasting blood glucose concentration compared with nutritional control. In the liver, CPEE decreased mRNA expression of IGF-1, IGF-1R, and IGF-2, and increased IRS-2 mRNA expression in male offspring only compared with nutritional control. Female CPEE offspring had decreased INSR hepatic mRNA expression compared with male CPEE offspring. In the prefrontal cortex, IRS-2 mRNA expression was increased in CPEE offspring compared with nutritional control. The data demonstrate that CPEE alters both central and peripheral expression of insulin and IGF signaling molecules at the mRNA level, which may be related to metabolic dysregulation in adult offspring. Furthermore, altered insulin and IGF signaling may be a mechanism of ethanol neurobehavioral teratogenicity.
Subject(s)
Ethanol/adverse effects , Insulin-Like Growth Factor II/analysis , Insulin-Like Growth Factor I/analysis , Prenatal Exposure Delayed Effects/physiopathology , Receptor, IGF Type 1/analysis , Receptor, IGF Type 2/analysis , Receptor, Insulin/analysis , Animals , Animals, Newborn , Blood Glucose/analysis , Female , Guinea Pigs , Liver/chemistry , Male , Prefrontal Cortex/chemistry , Pregnancy , Real-Time Polymerase Chain ReactionABSTRACT
Naked mole-rats are eusocial rodents that live in large subterranean colonies with a strict reproductive and social hierarchy. The breeding female (referred to as the queen) and 1 to 3 breeding males are the only reproductive members of the colony. Breeders are socially dominant and all other colony members are non-reproductive subordinates. The effects of manipulating the serotonergic neurotransmitter system on aggression and dominance behaviors are well studied in many species, but not in eusocial rodents like the naked mole-rat. The current study investigated how the serotonergic system influences aggressive/dominant behaviors in this species. To do this, two separate but related experiments were conducted: the effects of fluoxetine hydrochloride (FLX) on status-specific behaviors of subordinates (Experiment 1) and dominant queens (Experiment 2) were evaluated both in-colony and in a social-pairing paradigm. In accordance with our main hypothesis, chronic treatment of FLX attenuated the frequency and duration of aggression in queens, but not subordinates, when paired with an unfamiliar conspecific. Further exploration of pharmacological manipulation on status-specific behaviors of this eusocial species may elucidate the neurobiological mechanisms underlying their unique and rigid social hierarchy.
Subject(s)
Behavior, Animal/drug effects , Dominance-Subordination , Fluoxetine/pharmacology , Hierarchy, Social , Selective Serotonin Reuptake Inhibitors/pharmacology , Animals , Female , Male , Mole Rats , Sexual Behavior, Animal/drug effectsABSTRACT
Ethanol consumption during pregnancy can produce a variety of teratogenic effects in offspring, termed Fetal Alcohol Spectrum Disorders (FASD). The most debilitating and permanent consequence of chronic prenatal ethanol exposure (CPEE) is neurobehavioral teratogenicity, which often manifests as cognitive and behavioral impairments, including deficits in spatial learning and memory. This study tested the hypothesis that a modified dry-land version of the multi-choice Biel-maze task is more sensitive than the rewarded-alternation Y-maze task for the determination of spatial learning and memory deficits of ethanol teratogenicity. Pregnant guinea pigs received ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding (control) for 5days/week throughout gestation. CPEE resulted in ethanol neurobehavioral teratogenicity in offspring, as demonstrated by increased spontaneous locomotor activity at postnatal day (PD) 10 and decreased brain weight at euthanasia (PD 150-200). On PD 21, offspring were randomly assigned to one of two tasks to assess spatial learning and memory performance: a dry-land version of the Biel maze or a rewarded-alternation Y-maze. Animals were habituated to the environment of their assigned task and performance of each CPEE or control offspring was measured. In the modified Biel maze, CPEE and control offspring were not different for percent completed trials or time to complete a trial. However, CPEE offspring made more errors (reversals and entering dead ends) in the Biel maze, demonstrating impaired spatial learning and memory. In contrast, CPEE offspring did not have impaired performance of the rewarded-alternation Y-maze task. Therefore, the modified dry-land version of the Biel-maze task, which measures cognitive performance using a complex multi-choice design, is more sensitive in demonstrating CPEE-induced spatial learning and memory deficits compared with a simple, rewarded-alternation Y-maze task.