DNA methylation at the DAT promoter and risk for psychopathology. Intergenerational transmission between school-age youths and their parents in a community sample

Background: The effect of gene polymorphisms and promoter methylation, associated with maladaptive developmental outcomes, vary depending on environmental factors (e.g., parental psychopathology). Most studies have focused on 0- to 5-year-old children, adolescents, or adults, whereas there is dearth of research on school-age youths and pre-adolescents. Methods: In a sample of 21 families recruited at schools, we addressed parents' psychopathological symptoms (through SCL-90-R); offspring emotional-behavioral functioning (through CBCL-6-18); dopamine transporter gene (DAT1) for epigenetic status of the 5'-untranslated region (UTR) and for genotype, i.e., variable number of tandem repeats polymorphism at the 3'-UTR. Possible associations were explored between bio-genetic and psychological characteristics within the same individual and between triplets of children, mothers, and fathers. Results: DAT methylation of CpG at positions M1, M6, and M7 in mothers was correlated with maternal (phobic) anxiety, whereas in fathers' position M6 was related to paternal depression, anxiety, hostility, psychoticism, and higher Global Severity Index (GSI). No significant correlations were found between maternal and offspring DAT methylation. Significant correlations were found between fathers' methylation at CpG M1 and children's methylation at CpG M6. Linear regressions showed that mothers and fathers' GSI predicted children's methylation at CpG sites M2, M3, and M6, whereas fathers' GSI predicted children's methylation at CpG sites, particularly M1, M2, and M6. Moreover, offspring methylation of DAT at CpG M2 predicted somatic complaint, internalizing and attention problems; methylation of DAT at CpG M6 predicted withdraw. Conclusion: This study may have important clinical implication for the prevention and treatment of emotional-behavioral difficulties in children, as it adds to previous knowledge about the role of genetic and environmental factors in predicting psychopathological symptoms within non-clinical population

Dopamine transporter and transmission of psychopathological risk. A review of gene-environment interplay

Research underlines that intergenerational transmission of psychopathological risk results from a complex interplay of genetic and environmental risk factors which predispose child to develop emotionalbehavioral problems. Mechanisms of transmission are poorly understood, but few studies have focused on the role played by dopamine transporter (DAT) gene. This review aims to examine mediating mechanism of DAT genotype-environmental interaction (GxE), DAT genotype-environmental correlation (rGE), and methylation status involved in transmission of psychopathological risk. The review of literature was made through researches in university libraries on paper material, and telematics systems research. Studies have evidenced that DAT is implicated in intergenerational transmission of psychopathological risk. Results are mixed regarding its genetic variants, but mechanisms through which this gene can affect both quality of parenting and child development are partially established. Only few studies have examined methylation mechanisms that can be implicated. Findings suggest to involve an improved focus on DAT genotypes, methylation status associated, and their relationship with environment to better understanding child’s vulnerability and resilience following exposure to contextual risk factors associated with parental psychopathological symptoms

Behavioral Phenotyping of Dopamine Transporter Knockout Rats: Compulsive Traits, Motor Stereotypies, and Anhedonia

Alterations in dopamine neurotransmission are generally associated with diseases such as attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Such diseases typically feature poor decision making and lack of control on executive functions and have been studied through the years using many animal models. Dopamine transporter (DAT) knockout (KO) and heterozygous (HET) mice, in particular, have been widely used to study ADHD. Recently, a strain of DAT KO rats has been developed (1). Here, we provide a phenotypic characterization of reward sensitivity and compulsive choice by adult rats born from DAT-HET dams bred with DAT-HET males, in order to further validate DAT KO rats as an animal model for preclinical research. We first tested DAT KO rats' sensitivity to rewarding stimuli, provided by highly appetitive food or sweet water; then, we tested their choice behavior with an Intolerance-to-Delay Task (IDT). During these tests, DAT KO rats appeared less sensitive to rewarding stimuli than wild-type (WT) and HET rats: they also showed a prominent hyperactive behavior with a rigid choice pattern and a wide number of compulsive stereotypies. Moreover, during the IDT, we tested the effects of amphetamine (AMPH) and RO-5203648, a trace amine-associated receptor 1 (TAAR1) partial agonist. AMPH accentuated impulsive behaviors in WT and HET rats, while it had no effect in DAT KO rats. Finally, we measured the levels of tyrosine hydroxylase, dopamine receptor 2 (D2), serotonin transporter, and TAAR1 mRNA transcripts in samples of ventral striatum, finding no significant differences between WT and KO genotypes. Throughout this study, DAT KO rats showed alterations in decision-making processes and in motivational states, as well as prominent motor and oral stereotypies: more studies are warranted to fully characterize and efficiently use them in preclinical research

Cross-correlations between motifs in the 5′-UTR of DAT1 gene. Findings from Parkinson’s disease

Parkinson’s disease (PD) is a neuro-degenerative disorder affecting the striatal motor system, caused by the loss of neuronal cells in the mid-brain, where reduced amounts of dopamine do cause involuntary movements and others symptoms. Alterations of methylome have been reported in PD epigenomic studies, and also human dopamine transporter gene (DAT1, SLC6A3) is considered as a candidate risk factor for PD. Since the DNA methylation on DAT promoter may well have a role in the development of this disease, we aimed to further assess the epigenetic control, by focusing on specific CpG sites located in the 5′ -untranslated region (5′ -UTR) of the DAT1 gene. Significant changes in DAT 5′ -UTR methylation were already found in peripheral blood mononuclear cells (PBMCs) of PD subjects (Rubino et al., 2020). Of note, methylation values at the CpG 5 were increased. We run on same data a novel statistical approach: crosscorrelation between pairs of loci. CpG 5 was the only always-differing variable but, alternatively, CpGs 2 and 6 or CpGs 1 and 3 were also significantly correlated with CpG 5. Interestingly, this picture emerged for those patients whose M2xM6 index was above-median; loci were rather independent for below-median patients. Present data may shed light into dynamics occurring at 5′ -UTR of DAT1, a gene involved in PD but also in many psycho-physiological pathologies

Micro-Vesicles of Moringa oleifera Seeds in Heterozygous Rats for DAT Gene: Effects of Oral Intake on Behavioral Profile and Hematological Parameters

Previous studies have shown multiple biological properties of Moringa oleifera, a plant native to Africa and Asia. In the present study, potential physiological properties of microvesicles extracted from Moringa oleifera seeds were assessed. For this purpose, we investigated behavioral profile and hematological parameters in a recent rat model characterized by dysregulation in dopamine transporter, a key regulator of dopaminergic system. Experimental design consisted of male Wistar-DAT rats aged between two and four months: wild-type (WT) (n = 5) and heterozygous (DATHET) (n = 4) control groups, which drank tap water; WT (n = 5) and DATHET (n = 6) groups which drank a solution of Moringa microvesicles and water (2: 68 mL per day), which was orally administered for two months. Rats were monitored for spontaneous locomotor activity on a 24/7 basis. In the early lit hours, treated DATHET subjects showed higher locomotor activity, proposing a sleep-delay effect of Moringa. In forced swimming test, WT subjects who took Moringa exhibited more depressive behavior. In DATHET rats, Moringa seemed to potentiate the struggle to find a way out, counteracting an initial panic. Hemoglobin and hematocrit underwent opposite changes in either genotype, supporting the opposite effects on behavioral phenotype observed. Future work is clearly needed to further explore these preliminary profiles

Social Interactions of Dat-Het Epi-Genotypes Differing for Maternal Origins: The Development of a New Preclinical Model of Socio-Sexual Apathy

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

Prior activation of 5-HT7 receptors modulates the conditioned place preference with methylphenidate

The serotonin receptor subtype 7 (5-HT7R) is clearly involved in behavioral functions such as learning/memory, mood regulation and circadian rhythm. Recent discoveries proposed modulatory physiological roles for serotonergic systems in reward-guided behavior. However, the interplay between serotonin (5-HT) and dopamine (DA) in reward-related behavioral adaptations needs to be further assessed. TP-22 is a recently developed arylpiperazine-based 5-HT7R agonist, which is also showing high affinity and selectivity towards D1 receptors. Here, we report that TP-22 displays D1 receptor antagonist activity. Moreover, we describe the first in vivo tests with TP-22: first, a pilot experiment (assessing dosage and timing of action) identified the 0.25 mg/kg i.v. dosage for locomotor stimulation of rats. Then, a conditioned place preference (CPP) test with the DA-releasing psychostimulant drug, methylphenidate (MPH), involved three rat groups: prior i.v. administration of TP-22 (0.25 mg/kg), or vehicle (VEH), 90 min before MPH (5 mg/kg), was intended for modulation of conditioning to the white chamber (saline associated to the black chamber); control group (SAL) was conditioned with saline in both chambers. Prior TP-22 further increased the stimulant effect of MPH on locomotor activity. During the place-conditioning test, drug-free activity of TP-22+MPH subjects remained steadily elevated, while VEH+MPH subjects showed a decline. Finally, after a priming injection of TP-22 in MPH-free conditions, rats showed a high preference for the MPH-associated white chamber, which conversely had vanished in VEH-primed MPH-conditioned subjects. Overall, the interaction between MPH and pre-treatment with TP-22 seems to improve both locomotor stimulation and the conditioning of motivational drives to environmental cues. Together with recent studies, a main modulatory role of 5-HT7R for the processing of rewards can be suggested. In the present study, TP-22 proved to be a useful psychoactive tool to better elucidate the role of 5-HT7R and its interplay with DA in reward-related behavior

The Radio Continuum-Star Formation Rate Relation in WSRT SINGS Galaxies

This is an author-created, un-copyedited version of an article accepted for published in The Astronomical Journal. IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from it. The Version of Record is available online at https://doi.org/10.1088/0004-6256/147/5/103.We present a study of the spatially resolved radio continuum–star formation rate (RC–SFR) relation using stateof-the-art star formation tracers in a sample of 17 THINGS galaxies. We use SFR surface density (ΣSFR) maps created by a linear combination of GALEX far-UV (FUV) and Spitzer 24μm maps. We use RC maps at λλ22 and 18 cm from the WSRT SINGS survey and Hα emission maps to correct for thermal RC emission. We compare azimuthally averaged radial profiles of the RC and FUV/mid-IR (MIR) based ΣSFR maps and study pixel-by-pixel correlations at fixed linear scales of 1.2 and 0.7 kpc. The ratio of the integrated SFRs from the RC emission to that of the FUV/MIR-based SF tracers is Rint = 0.78 ± 0.38, consistent with the relation by Condon. We find a tight correlation between the radial profiles of the radio and FUV/MIR-based ΣSFR for the entire extent of the disk. The ratio R of the azimuthally averaged radio to FUV/MIR-based ΣSFR agrees with the integrated ratio and has only quasi-random fluctuations with galactocentric radius that are relatively small (25%). Pixel-by-pixel plots show a tight correlation in log-log diagrams of radio to FUV/MIR-based ΣSFR, with a typical standard deviation of a factor of two. Averaged over our sample we find (ΣSFR)RC ∝ (ΣSFR) 0.63±0.25 hyb , implying that data points with high ΣSFR are relatively radio dim, whereas the reverse is true for low ΣSFR. We interpret this as a result of spectral aging of cosmic-ray electrons (CREs), which are diffusing away from the star formation sites where they are injected into the interstellar medium. This is supported by our finding that the radio spectral index is a second parameter in pixel-by-pixel plots: those data points dominated by young CREs are relatively radio dim, while those dominated by old CREs are slightly more RC bright than what would be expected from a linear extrapolation. We studied the ratio R of radio to FUV/MIR-based integrated SFR as a function of global galaxy parameters and found no clear correlation. This suggests that we can use RC emission as a universal star formation tracer for galaxies with a similar degree of accuracy as other tracers, if we restrict ourselves to global or azimuthally averaged measurements. We can reconcile our finding of an almost linear RC–SFR relation and sub-linear resolved (on 1 kpc scale) RC–ΣSFR relation by proposing a non-linear magnetic field–SFR relation, B ∝ SFR0.30±0.02 hyb , which holds both globally and locally.Peer reviewe