Dopaminergic modulation of the circadian activity and sociability: Dissecting parental inheritance versus maternal styles as determinants of epigenetic influence.

In mammalians, social life and circadian rhythms find their neurobiological basis in a network that includes the dopaminergic system. The malfunctioning of dopamine pathways can lead to various disorders such as Attention-Deficit/Hyperactivity and Obsessive/compulsive disorders. A useful research approach is to exploit animal models that carry a functional silencing of SLC6A3 gene, encoding the dopamine transporter (DAT). Hyperactivity, working memory deficits, and asocial tendencies are core features in truncated-DAT rats, for example. We investigated how inheritance and maternal caring style influence circadian rhythms and social behaviours in DAT heterozygous (HET) rats, belonging to four groups: Mat-P, Mat-M, Mix-P, and Mix-M (Mat label stands for care from wild-type dam, Mix label stands for care by heterozygous dam; M label stands for maternal wild-DAT and P label stands for paternal wild-DAT). In Experiment 1, we monitored 24/7 the spontaneous locomotor activity of peri-adolescent subjects. Hyperactivity occurred only in P-asset subjects (with maternal-origin truncated-DAT allele) at specific bins of the day. In Experiment 2, we observed social interactions of the same rats. Mix-M subjects (raised by HET dams and/or inheriting the wild-DAT allele from mothers) tend to interact with all rats; Mat-P (cared by WT dams and/or inheriting the truncated-DAT allele from mothers) seem to be ignored, when acting as stimulus subjects. Overall, results confirm complex modulations for circadian cycle and social life: flexible DAT expression in HET subjects depends on epigenetic combinations of parental inheritance and early experiential factors. Once confirmed, these data could shed light on trans-generational contributions to dopaminergic-related disorders.

Altering the development of the dopaminergic system through social play in rats: Implications for anxiety, depression, hyperactivity, and compulsivity.

Dopamine is essential to many functions like reward, motivation, and attention; when its neural pathways do not function properly, various disorders (e.g., anxiety, depression, hyperactivity, compulsions) can arise. Truncated-DAT rats display persistent stereotypies and aggressiveness; hence they are a new valuable animal model to study the pathogenesis of these disorders. The focus of research is often on the individual epigenetic determinants and much less on the impact of social experiences. Here, we investigate the developmental impact of the social environment on adolescent wild type (WT) rats. We divided subjects at weaning into three groups: living with another adolescent (WT Peer), with a WT adult, or with a truncated-DAT one, and we observed homecage social behavior of these pairs (play, jump, victory, and "bullying") during whole adolescence. When adult, we observed the same subjects in plus maze, forced swim, and social preference tests to measure levels of anxiety, depression, and quality of social interactions. Compared to the other groups, WT rats that had spent their adolescence with a truncated-DAT adult as companion show more anxious, depressive, hyperactive, impulsive, and compulsive behaviours. Results confirm that social interactions and healthy play (i.e., when play has behavioural, social, and psychomotor rewards that support the cognitive, emotional and physical development of the individual) are essential to neurobehavioral maturation. Conversely, anomalous interactions like poor play and "bullying" in developing rats may impact onto their dopaminergic system. Consequently, an impoverished social play could be one of the factors contributing to the appearance of putative indexes of attention deficit hyperactivity disorder (ADHD) and\or obsessive-compulsive disorder (OCD).

"Himalayan Bridge": A New Unstable Suspended Bridge to Investigate Rodents' Venturesome Behavior.

While both risk-taking and avoidant behaviors are necessary for survival, their imbalanced expression can lead to impulse-control and anxiety disorders, respectively. In laboratory rodents, the conflict between risk proneness and anxiety can be studied by using their innate fear of heights. To explore this aspect in detail and investigate venturesome behavior, here we used a "Himalayan Bridge," a rat-adapted version of the suspended wire bridge protocol originally developed for mice. The apparatus is composed of two elevated scaffolds connected by bridges of different lengths and stability at 1 m above a foam rubber-covered floor. Rats were allowed to cross the bridge to reach food, and crossings, pawslips, turnabouts, and latencies to cross were measured. Given the link between risky behavior and adolescence, we used this apparatus to investigate the different responses elicited by a homecage mate on the adolescent development of risk-taking behavior. Thus, 24 wild-type (WT) subjects were divided into three different housing groups: WT rats grown up with WT adult rats; control WT adolescent rats (grown up with WT adolescents), which showed a proclivity to risk; and WT rats grown up with an adult rat harboring a truncated mutation for their dopamine transporter (DAT). This latter group exhibited risk-averse responses reminiscent of lower venturesomeness. Our results suggest that the Himalayan Bridge may be useful to investigate risk perception and seeking; thus, it should be included in the behavioral phenotyping of rat models of psychiatric disorders and cognitive dysfunctions.

Striatal dynamics as determinants of reduced gambling vulnerability in the NHE rat model of ADHD.

The Naples High-Excitability (NHE) is a validated rat strain to model for a mesocortical variant of Attention Deficit Hyperactivity Disorder (ADHD). NHE rats' brains have a tuned-down cortical and a potentiated limbic loop (Zoratto et al., 2017). ADHD and comorbid pathological gambling (PG) involve similar deficits of prefrontal-striatal dialogue. This work aimed to understand if NHE rats (compared to normal random-bred rats, NRB) can be a useful model for gambling vulnerability in ADHD. Experiment 1 evaluated gambling proneness in NHE rats, namely attraction/avoidance in nose-poking for a "Large & Luck-Linked" (LLL) reward (versus a "Small & Sure" one, SS), when the probability of LLL delivery was progressively reduced. Experiment 2 assessed (by phMRI) differential responsivity of ventral (vStr) versus dorsal (dStr) striatum following a methylphenidate (MPH, 4 mg/kg I.P.) challenge. In NHE rats, reduced attraction by secondary cues (associated with uncertain, rarefying LLL delivery) comes along with little or no activation of dStr and enhanced activation of vStr by MPH. Together, such evidences from NHE rats indicate distinctive roles of ventral (enhanced value given to actual primary reward) and dorsal (lower encoding of repeated stimulus-reward associations into a habit) striatum. In conclusion, the dynamics of reward systems could link an attention deficit with a decreased vulnerability to pathological gambling.