Abstract
Social interaction is essential for life but is impaired in many psychiatric disorders. We presently focus on rats with a truncated allele for dopamine transporter (DAT). Since heterozygous individuals possess only one non-mutant allele, epigenetic interactions may unmask latent genetic predispositions. Homogeneous “maternal” heterozygous offspring (termed MAT-HET) were born from dopamine-transporter knocked-out (DAT-KO) male rats and wild-type (WT) mothers; “mixed” heterozygous offspring (termed MIX-HET) were born from both DAT-heterozygous parents. Their social behavior was assessed by: partner-preference (PPT), social-preference (SPT) and elicited-preference (EPT) tests. During the PPT, focal MIX-HET and MAT-HET males had a choice between two WT females, one in estrous and the other not. In the SPT, they met as stimulus either a MIX-HET or a WT male. In the EPT, the preference of focal male WT rats towards either a MIX- or a MAT-HET stimulus was tested. MIX-HET focal males showed an abnormal behavior, seeming not interested in socializing either with a female in estrous or with another male if MIX-HET. Focal MAT-HET males, instead, were very attracted by the female in estrous, but totally ignored the MIX-HET male. We assessed the expression of noradrenaline transporter (NET) in prefrontal cortex, hippocampus and hypothalamus, finding differences between the two offspring. MIX-HETs’ hypothalamus and hippocampus showed less NET than MAT-HETs, while the latter, in turn, showed higher NET than WTs. These behavioral differences between heterozygous groups may be attributed to different maternal cares received. Results allow preclinical understanding of epigenetic factors involved in social-behavior abnormalities, typical of many psychiatric disorders.
Highlights
As already described in the introduction of this article, the heterozygous rats used in our study were obtained from two different sources of breeding: the first originated by classical breeding of both male and female dopamine transporter (DAT)-HET subjects, leading to “mixed” offspring with an inactivated allele being either of paternal or of maternal origin (MIX-HET); the second by breeding of KO male rats with WT female dams
The effect of epi-genotype was statistically significant in the CA1 region (F (2,15) = 7.619, p = 0.0052), where MIX-HET rats displayed a significant decrease with respect to MAT-HETs (q = 5.417, df = 15, p = 0.0044) (Figure 4N,O); in addition, we observed significant differences in the CA2 region (F (2,15) = 6.858, p = 0.0077) with a significant increase in MAT-HET epigenotype with respect to WT rats (q = 3.837, df = 15, p = 0.0401) and a significant decrease in MIX-HET rats with respect to MAT-HETs (q = 5.006, df = 15, p = 0.0079) (Figure 4P,Q)
MIX-HET male rats showed an altered social behavior: with the specifier of social apathy. This profile has been here associated to increased noradrenaline input to the hippocampal and hypothalamic regions
Summary
Social interaction is composed by complex behaviors, which are essential for life in many mammalian species. In humans, these interactions are impaired in several psychiatric disorders such as autism, schizophrenia, major depression and social anxiety disorder. Recent evidence highlighted how different neurotransmitters, including oxytocin, dopamine, noradrenaline, serotonine and β-endorphin, are recruited in social behavior and both dopaminergic and noradrenergic systems seem to be especially relevant to social drive [1]. A wide body of literature has demonstrated that external stimuli, such as stress, often result in significant changes in dopamine (DA) and noradrenaline (NE) concentrations
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