EFFECTS OF PRENATAL DEXAMETHASONE ON HIPOPCAMPAL SEROTONIN 1A RECEPTORS IN ADULT MALE RATS

The main activation route for the stress response is the hypothalamo-pituitaryadrenal axis (HPA) and the sympatho-adrenomedullary system. The HPA axis is a neuroendocrine feedback loop mediated by an array of tissue specific hormones, receptors and neurotransmitters that regulate glucocorticoid (GC) release. GCs are steroidal hormones produced by the adrenal glands and are key players in a negativefeedback loop controlling HPA activity. They influence the HPA axis through glucocorticoid receptors in the hypothalamus and pituitary and through both glucocorticoid (GR) and mineralcorticoid receptors (MR) that are co-localized in the hippocampus. Repeated or chronic stress exerts a negative influence on these HPA axis regulatory sites and contributes to potentially pathological conditions, especially during early development. For example, chronic stress promotes increased maternal adrenal gland secretion of glucocortiocoid, leading to abnormally high concentrations of GC inthe fetal environment. The timing and maturation of the HPA axis relative to birth is highly species specific and is closely linked to landmarks in fetal development. In rats this development of the HPA axis takes place in utero and continues even shortly after birth. It is likely that the maternal endocrine environment will affect fetal development during this critical time point and may alter the overall set point for the expression ofgenes and their protein products that mediate fetal HPA axis function. Dexamethasone (DEX) is a synthetic glucocorticoid (sGC) and is a consensus treatment in preterm pregnancies used to expedite fetal lung development. However it has been shown that DEX causes long term physiological and behavioral disorders in prenatally-exposed laboratory animals. Previous studies have also shown that it alters the MR: GR receptor ratio in the hippocampus. Taking into consideration corticosteroid regulation of serotonin receptors, especially 5HT1A receptors and their putative interaction with glucocorticoid receptors in the hippocampus, we hypothesized that prenatal DEX exposure would lead to changes in the expression and function of 5HT1A receptors in the hippocampus. We administered DEX to rat dams during the last trimester of gestation and investigated the changes in these receptors in the adult rat offspring. Radioligand receptor binding assays were used to study hippocampal 5HT1A receptor binding affinity and number. Our results demonstrate that hippocampal 5HT1A receptors are increased in the DEX animalscompared with controls by 36%, with no change in binding affinity. The efficiency of ligand-induced receptor signal transduction via G-protein activation was also studied using [35S]GTPγS incorporation assay. Using this technique, we showed that there was no significant difference in the maximum ligand mediated stimulation (Emax) of 5HT1Areceptors between control and dex exposed animals. However, the intracellular signalling efficiency of hippocampal 5HT1A receptors was diminished, since a significant increase in EC50 values was obtained with the dex exposed group showing a value 51% higherEC50 than controls. Taken together these data illustrate a considerable change in the 5HT1A component of the serotonergic system following prenatal DEX exposure.

The Effect of Chronic Estrogen Administration on Same-Sex Social Behavior and Central Oxytocin Levels in Prairie Voles (Microtus ochrogaster)

The purpose of our study is to investigate the effects of chronic estrogen administration on same-sex interactions during exposure to a social stressor and on oxytocin (OT) levels in prairie voles (Microtus orchrogaster). Estrogen and OT are two hormones known to be involved with social behavior and stress. Estogen is involved in the transcription of OT and its receptor. Because of this, it is generally thought that estrogen upregulates OT, but evidence to support this assumption is weak. While estrogen has been shown to either increase or decrease stress, OT has been shown to have stress-dampening properties. The goal of our experiment is to determine how estrogen affects OT levels as well as behavior in a social stressor in the voles. In addition, estrogen is required for many opposite-sex interactions, but little is known about its influence on same-sex interactions. We hypothesized that prairie voles receiving chronic estrogen injections would show an increase in OT levels in the brain and alter behavior in response to a social stressor called the resident-intruder test. To test this hypothesis, 73 female prairie voles were ovariectomized and then administered daily injections of estrogen (0.05 ¿g in peanut oil, s.c.) or vehicle for 8 days. On the final day of injections, half of the voles were given the resident-intruder test, a stressful 5 min interaction with a same-sex stranger. Their behavior was video-recorded. These animals were then sacrificed either 10 minutes or 60 minutes after the conclusion of the test. Half of the animals (no stress group) were not given the resident-intruder test. After sacrifice, trunk blood and brains were collected from the animals. Videos of the resident-intruder tests were analyzed for pro-social and aggressive behavior. Density of OT-activated neurons in the brain was measured via pixel count using immunohistochemistry. No differences were found in pro-social behavior (focal sniffing, p = 0.242; focal initiated sniffing p = 0.142; focal initiated sniffing/focal sniffing, p = 0.884) or aggressive behavior (total time fighting, p= 0.763; number of fights, p= 0.148; number of strikes, p = 0.714). No differences were found in activation of OT neurons in the brain, neither in the anterior paraventricular nucleus (PVN) (pixel count p= 0.358; % area that contains pixelated neurons p = 0.443) nor in the medial PVN (pixel count p= 0.999; % area that contains pixelated neurons p = 0.916). These results suggest that estrogen most likely does not directly upregulate OT and that estrogen does not alter behavior in stressful social interactions with a same-sex stranger. Estrogen may prepare the animal to respond to OT, instead of increasing the production of the peptide itself, suggesting that we need to shift the framework in which we consider estrogen and OT interactions.

Social Cognition, Face Processing, and Oxytocin Receptor Single Nucleotide Polymorphisms in Typically Developing Children

Recent research has provided evidence of a link between behavioral measures of social cognition (SC) and neural and genetic correlates. Differences in face processing and variations in the oxytocin receptor (OXTR) gene have been associated with SC deficits and autism spectrum disorder (ASD) traits. Much work has examined the qualitative differences between those with ASD and typically developing (TD) individuals, but very little has been done to quantify the natural variation in ASD-like traits in the typical population. The present study examines this variation in TD children using a multidimensional perspective involving behavior assessment, neural electroencephalogram (EEG) testing, and OXTR genotyping. Children completed a series of neurocognitive assessments, provided saliva samples for sequencing, and completed a face processing task while connected to an EEG. No clear pattern emerged for EEG covariates or genotypes for individual OXTR single nucleotide polymorphisms (SNPs). However, SNPs rs2254298 and rs53576 consistently interacted such that the AG/GG allele combination of these SNPs was associated with poorer performance on neurocognitive measures. These results suggest that neither SNP in isolation is risk-conferring, but rather that the combination of rs2254298(A/G) and rs53576(G/G) confers a deleterious effect on SC across several neurocognitive measures. Copyright 2014. Published by Elsevier Ltd.