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There is considerable interest in understanding what makes an individual vulnerable or resilient to the deleterious effects of stressful events. From candidate genes, dopamine (DA) and dopamine transporter (DAT) have been linked to anxiety, depression, and post-traumatic stress disorder. We investigated role of DAT using the new DAT heterozygous (DAT-HET) and homozygous mutant (DAT-KO) rat models of hyperdopaminergia. We studied the impact of two breeding conditions in spontaneous locomotor behavior of female rats. The classical colony, through mating DAT-HET males × DAT-HET females (breeding HET-HET), was used. A second WT colony was derived and maintained (breeding WT-WT). Additionally, a subgroup of rats was bred through mating DAT-KO males × WT females (atypical HET, breeding KO-WT). We studied the effects of genotype and its interaction with maternal care (depending by breeding condition). HET-HET breeding led to reduced activity in HET females compared to WT rats (from WT-WT breeding). However, HET females from KO-WT breeding did not differ so much from WT rats (WT-WT breeding). The maternal-care impact was then confirmed: HET mothers (breeding HET-HET) showed reduced liking/grooming of pups and increased digging away from nest, compared to WT mothers (breeding WT-WT). In their female offspring (HET, breeding HET-HET vs. WT, breeding WT-WT), isolation plus wet bedding induced higher and more persistent impact on activity of HET rats, even when the stressor was removed. Our results highlight the importance of epigenetic factors (e.g., maternal care) in responses to stress expressed by offspring at adulthood, quite independently of genotype. DAT hypofunction could determinate vulnerability to stressful agents via altered maternal care. K E Y W O R D S circadian rhythm, DAT heterozygous, maternal care, parent-of-origin effect, stress vulnerability How to cite this article: Mariano S, Pardo M, Buccheri C, et al. Own or dam's genotype? Classical colony breeding may bias spontaneous and stress-challenged activity in DAT mutant rats. Developmental Psychobiology. 2020;62:505-518.

Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder characterized by a developmentally inappropriate, pervasive and persistent pattern of severe inattention, hyperactivity and impulsivity. Despite onset in early childhood, ADHD may continue into adulthood with substantial impairment in social, academic and occupational functioning. A new animal model of this disorder was developed in rats with genetic deletion of the dopamine transporter (DAT) gene (dopamine transporter knockout rats; DAT-KO rats). We analyzed the behavior of DAT-KO rats for a deeper phenotypical characterization of this model. We first tested rats of the 3 genotypes at different ages (preadolescent, adolescent and adult), in a novelty-seeking test using a black/white box (Experiment 1). After that, we tested adult rats in a novelty-preference test using a 3-chamber apparatus with different shapes (Experiment 2). Experiment 1: as evidenced by analysis of time spent in the novel environment, adult DAT heterozygous (DAT-HET) rats show an increased curiosity-driven exploration compared with wild-type (WT) controls while DAT-KO rats did not recognize novelty. The locomotor activity data show a minimal difference between genotypes at adolescent age while the preadolescent and adult DAT-KO rats have significantly increased activity rate compared with WT and DAT-HET subjects. Experiment 2: in this case, due to more clearly evident spatial differences, time spent in novel environment was not significantly different among genotypes. During first 10 minutes, DAT-KO rats showed a decreased hyperactivity, apparently related to curiosity and attention to the new environments. In conclusion, DAT-KO rats may show some inattention while more novelty-seeking traits appear in DAT-HET rats.

Alterations in dopamine (DA) reuptake are involved in several psychiatric disorders whose symptoms can be investigated in knock out rats for the DA transporter (DAT‐KO). Recent studies evidenced the role of epigenetic DAT modulation in depressive‐like behavior. Accordingly, we used heterozygous (HET) rats born from both HET parents (termed MIX‐HET), compared to HET rats born from WT‐mother and KO‐father (MAT‐HET), implementing the role of maternal care on DAT modulation. We developed a “sudden fright” paradigm (based on dark‐light test) to study reaction to fearful inputs in the DAT‐KO, MAT‐HET, MIX‐HET, and WT groups. Rats could freely explore the whole 3‐chambers apparatus; then, they were gently confined in one room where they experienced the fright; finally, they could freely move again. As expected, after the fearful stimulus only MAT‐HET rats showed a different behavior consisting of avoidance towards the fear‐associated chamber, compared to WT rats. Furthermore, ex‐vivo immuno‐fluorescence reveals higher prefrontal DAT levels in MAT‐HET compared to MIX‐HET and WT rats. Immuno‐fluorescence shows also a different histone deacetylase (HDAC) enzymes concentration. Since HDAC concentration could modulate gene expression, within MAT‐HET fore brain, the enhanced expression of DAT could well impair the corticostriatal‐thalamic circuit, thus causing aberrant avoidance behavior (observed only in MAT‐HET rats). DAT expression seems to be linked to a simply different breeding condition, which points to a reduced care by HET dams for epigenetic regulation. This could imply significant prefronto‐cortical influences onto the emotional processes: hence an excessively frightful response, even to mild stressful agents, may draw developmental trajectories toward anxious and depressed‐like behavior.