Advanced paternal age as a risk factor for neurodevelopmental disorders: a translational study.

Advanced paternal age (APA) is a risk factor for several neurodevelopmental disorders, including autism and schizophrenia. The potential mechanisms conferring this risk are poorly understood. Here, we show that the personality traits schizotypy and neuroticism correlated with paternal age in healthy subjects (N = 677). Paternal age was further positively associated with gray matter volume (VBM, N = 342) in the right prefrontal and the right medial temporal cortex. The integrity of fiber tracts (DTI, N = 222) connecting these two areas correlated positively with paternal age. Genome-wide methylation analysis in humans showed differential methylation in APA individuals, linking APA to epigenetic mechanisms. A corresponding phenotype was obtained in our rat model. APA rats displayed social-communication deficits and emitted fewer pro-social ultrasonic vocalizations compared to controls. They further showed repetitive and stereotyped patterns of behavior, together with higher anxiety during early development. At the neurobiological level, microRNAs miR-132 and miR-134 were both differentially regulated in rats and humans depending on APA. This study demonstrates associations between APA and social behaviors across species. They might be driven by changes in the expression of microRNAs and/or epigenetic changes regulating neuronal plasticity, leading to brain morphological changes and fronto-hippocampal connectivity, a network which has been implicated in social interaction.

Environmental and Pharmacological Modulation of Amphetamine- Induced 50-kHz Ultrasonic Vocalizations in Rats.

Rats emit high-frequency 50-kHz ultrasonic vocalizations (USV) in appetitive situations like social interactions. Drugs of abuse are probably the most potent non-social elicitors of 50-kHz USV, possibly reflecting their euphorigenic properties. Psychostimulants induce the strongest elevation in 50-kHz USV emission, particularly amphetamine (AMPH), either when applied systemically or locally into the nucleus accumbens (Nacc). Emission of AMPH-induced 50-kHz USV depends on test context, such as the presence of conspecifics, and can be manipulated pharmacologically by targeting major neurotransmitter systems, including dopamine (DA), noradrenaline (NA), and serotonin (5-HT), but also protein kinase C (PKC) signaling. Several D1 and D2 receptor antagonists, as well as typical and atypical antipsychotics block the AMPH-induced elevation in 50-kHz USV. Inhibiting D1 and D2 receptors in the Nacc abolishes AMPH-induced 50-kHz USV, indicating a key role for this brain area. NA neurotransmission also regulates AMPH-induced 50-kHz USV emission given that α 1 receptor antagonists and α 2 receptor agonists exert attenuating effects. Supporting the involvement of the 5-HT system, AMPH-induced 50-kHz USV are attenuated by 5-HT2C receptor activation, whereas 5-HT2C receptor antagonism leads to the opposite effect. Finally, treatment with lithium, tamoxifen, and myricitrin was all found to result in a complete abolishment of the AMPH-induced increase in 50-kHz USV, suggesting the involvement of PKC signaling. Neurotransmitter systems involved in AMPH-induced 50-kHz USV emission only partially overlap with other AMPH-induced behaviors like hyperlocomotion. The validity of AMPHinduced 50-kHz USV as a preclinical model for neuropsychiatric disorders is discussed, particularly with relevance to altered drive and mood seen in bipolar disorder.

Pro-social 50-kHz ultrasonic communication in rats: post-weaning but not post-adolescent social isolation leads to social impairments-phenotypic rescue by re-socialization.

Rats are highly social animals and social play during adolescence has an important role for social development, hence post-weaning social isolation is widely used to study the adverse effects of juvenile social deprivation and to induce behavioral phenotypes relevant to neuropsychiatric disorders, like schizophrenia. Communication is an important component of the rat's social behavior repertoire, with ultrasonic vocalizations (USV) serving as situation-dependent affective signals. High-frequency 50-kHz USV occur in appetitive situations and induce approach behavior, supporting the notion that they serve as social contact calls; however, post-weaning isolation effects on the behavioral changes displayed by the receiver in response to USV have yet to be studied. We therefore investigated the impact of post-weaning isolation on socio-affective information processing as assessed by means of our established 50-kHz USV radial maze playback paradigm. We showed that post-weaning social isolation specifically affected the behavioral response to playback of pro-social 50-kHz but not alarm 22-kHz USV. While group-housed rats showed the expected preference, i.e., approach, toward 50-kHz USV, the response was even stronger in short-term isolated rats (i.e., 1 day), possibly due to a higher level of social motivation. In contrast, no approach was observed in long-term isolated rats (i.e., 4 weeks). Importantly, deficits in approach were reversed by peer-mediated re-socialization and could not be observed after post-adolescent social isolation, indicating a critical period for social development during adolescence. Together, these results highlight the importance of social experience for affiliative behavior, suggesting a critical involvement of play behavior on socio-affective information processing in rats.

Critical involvement of 5-HT2C receptor function in amphetamine-induced 50-kHz ultrasonic vocalizations in rats.

RATIONALE: Rats emit various distinct types of ultrasonic vocalizations (USV), with high-frequency 50-kHz USV typically occurring in appetitive situations being elicited by administering drugs of abuse, most notably amphetamine (AMPH), possibly reflecting drug wanting/craving and/or liking. OBJECTIVES: Because 50-kHz USV emission is, at least in part, dopamine (DA) dependent and 5-HT2C agonists inhibit DA neurotransmission, we hypothesized that AMPH-induced 50-kHz USV can be attenuated by pretreatment with a 5-HT2C agonist. METHODS: In experiments I and II, a dose-response curve for AMPH-induced 50-kHz USV was established, and the partial dependency of AMPH-induced 50-kHz USV on DA neurotransmission was validated by pretreatment with the D2-antagonist eticlopride. In experiment III, rats were pretreated with the 5-HT2C agonist CP 809,101 (0.0, 0.3, 1.0, 3.0, and 10 mg/kg), while in experiment IV, CP 809,101 (3.0 mg/kg), the 5-HT2C antagonist SB 242084 (1.0 mg/kg), or the combination of the two, was applied before AMPH administration (2.0 mg/kg). Finally, in experiment V, rats were treated with SB 242084 (0.0, 0.1, 0.3, and 1.0 mg/kg) only, i.e., in absence of AMPH. RESULTS: The 5-HT2C agonist CP 809,101 dose-dependently blocked AMPH-induced 50-kHz USV, most notably trills, a call subtype that is considered to exclusively reflect a positive affective state, while the 5-HT2C antagonist SB 242084 induced opposite effects. Moreover, SB 242084 induced 50-kHz USV by its own. CONCLUSIONS: 5-HT2C receptors are critically involved in AMPH-induced 50-kHz USV, with 5-HT2C antagonism resulting in a stimulant-like effect. Attenuation of drug wanting/craving and/or liking by coadministration of a 5-HT2C agonist could be a translational pharmacodynamic biomarker.