Avpr1a variant associated with preschoolers' lower altruistic behavior

10.1371/journal.pone.0025274PLoS ONE69

Gestational Valproate Alters BOLD Activation in Response to Complex Social and Primary Sensory Stimuli

Valproic acid (VPA) has been used clinically as an anticonvulsant medication during pregnancy; however, it poses a neurodevelopmental risk due to its high teratogenicity. We hypothesized that midgestational (GD) exposure to VPA will lead to lasting deficits in social behavior and the processing of social stimuli. To test this, animals were given a single IP injection of 600 mg/kg of VPA on GD 12.5. Starting on postnatal day 2 (PND2), animals were examined for physical and behavior abnormalities. Functional MRI studies were carried out after PND60. VPA and control animals were given vehicle or a central infusion of a V1a antagonist 90 minutes before imaging. During imaging sessions, rats were presented with a juvenile test male followed by a primary visual stimulus (2 Hz pulsed light) to examine the effects of prenatal VPA on neural processing. VPA rats showed greater increases in BOLD signal response to the social stimulus compared to controls in the temporal cortex, thalamus, midbrain and the hypothalamus. Blocking the V1a receptor reduced the BOLD response in VPA animals only. Neural responses to the visual stimulus, however, were lower in VPA animals. Blockade with the V1a antagonist did not revert this latter effect. Our data suggest that prenatal VPA affects the processing of social stimuli and perhaps social memory, partly through a mechanism that may involve vasopressin V1a neurotransmission

Does the oxytocin receptor polymorphism (rs2254298) confer 'vulnerability' for psychopathology or 'differential susceptibility'? insights from evolution

The diathesis-stress model of psychiatric conditions has recently been challenged by the view that it might be more accurate to speak of 'differential susceptibility' or 'plasticity' genes, rather than one-sidedly focusing on individual vulnerability. That is, the same allelic variation that predisposes to a psychiatric disorder if associated with (developmentally early) environmental adversity may lead to a better-than-average functional outcome in the same domain under thriving (or favourable) environmental conditions. Studies of polymorphic variations of the serotonin transporter gene, the monoamino-oxidase-inhibitor A coding gene or the dopamine D4 receptor gene indicate that the early environment plays a crucial role in the development of favourable versus unfavourable outcomes. Current evidence is limited, however, to establishing a link between genetic variation and behavioural phenotypes. In contrast, little is known about how plasticity may be expressed at the neuroanatomical level as a 'hard-wired' correlate of observable behaviour. The present review article seeks to further strengthen the argument in favour of the differential susceptibility theory by incorporating findings from behavioural and neuroanatomical studies in relation to genetic variation of the oxytocin receptor gene. It is suggested that polymorphic variation at the oxytocin receptor gene (rs2254298) is associated with sociability, amygdala volume and differential risk for psychiatric conditions including autism, depression and anxiety disorder, depending on the quality of early environmental experiences. Seeing genetic variation at the core of developmental plasticity can explain, in contrast to the diathesis-stress perspective, why evolution by natural selection has maintained such 'risk' alleles in the gene pool of a population

Pharmacokinetic and pharmacodynamic effects of high-dose monoclonal antibody therapy in a rat model of immune thrombocytopenia

Intravenous administration of pooled, polyvalent human immunoglobulin (IVIG) has been used for over 20 years as a therapy for immune thrombocytopenia (ITP). IVIG is available in limited quantities, and clinical preparations have been associated with the transfer of human pathogens. We have proposed that high-dose monoclonal antibody may be used in lieu of IVIG to achieve beneficial effects in the treatment of ITP. The current study investigates the effects of high-dose monoclonal antibody therapy in a rat model of ITP. Hybridoma cells secreting a murine monoclonal antiplatelet antibody (7E3) and murine monoclonal anti-methotrexate IgG (AMI) were grown in serum-free media. Next, 7E3, 8 mg kg−1, was administered intravenously to rats following pretreatment with saline or AMI (1 g kg−1 IV). AMI and 7E3 plasma concentrations were determined via enzyme-linked immunosorbent assay, and platelet count was determined with a Cell-Dyne hematology analyzer. Severe, transient thrombocytopenia was induced by 7E3. Platelet counts dropped to ≈8% of initial values within 1 hour after 7E3 administration. AMI pretreatment dramatically affected 7E3-induced thrombocytopenia, significantly altering the time course of throm-bocytopenia (P<.05) and significantly decreasing the severity of 7E3-induced thrombocytopenia (ie, following AMI pretreatment, nadir platelet count was greater than 8-fold that of the control group,P<.05). In addition, AMI pretreatment induced a 57% increase in 7E3 clearance (1.13±0.13 mL h−1 kg−1 vs 0.72±0.08 mL h−1 kg−1,P<.05). Consequently, high-dose monoclonal antibody therapy attenuated thrombocytopenia and produced a moderate increase in the clearance of antiplatelet antibodies in a rat model of ITP

Oxytocin and Vasopressin Receptor Gene Variation as a Proximate Base for Inter- and Intraspecific Behavioral Differences in Bonobos and Chimpanzees

<div><p>Recent literature has revealed the importance of variation in neuropeptide receptor gene sequences in the regulation of behavioral phenotypic variation. Here we focus on polymorphisms in the oxytocin receptor gene (<i>OXTR</i>) and vasopressin receptor gene 1a (<i>Avpr1a</i>) in chimpanzees and bonobos. In humans, a single nucleotide polymorphism (SNP) in the third intron of <i>OXTR</i> (rs53576 SNP (A/G)) is linked with social behavior, with the risk allele (A) carriers showing reduced levels of empathy and prosociality. Bonobos and chimpanzees differ in these same traits, therefore we hypothesized that these differences might be reflected in variation at the rs53576 position. We sequenced a 320 bp region surrounding rs53576 but found no indications of this SNP in the genus <i>Pan</i>. However, we identified previously unreported SNP variation in the chimpanzee <i>OXTR</i> sequence that differs from both humans and bonobos. Humans and bonobos have previously been shown to have a more similar 5′ promoter region of <i>Avpr1a</i> when compared to chimpanzees, who are polymorphic for the deletion of ∼360 bp in this region (+/− DupB) which includes a microsatellite (RS3). RS3 has been linked with variation in levels of social bonding, potentially explaining part of the interspecies behavioral differences found in bonobos, chimpanzees and humans. To date, results for bonobos have been based on small sample sizes. Our results confirmed that there is no DupB deletion in bonobos with a sample size comprising approximately 90% of the captive founder population, whereas in chimpanzees the deletion of DupB had the highest frequency. Because of the higher frequency of DupB alleles in our bonobo population, we suggest that the presence of this microsatellite may partly reflect documented differences in levels of sociability found in bonobos and chimpanzees.</p></div