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.

Acoustic Communication in Rats: Effects of Social Experiences on Ultrasonic Vocalizations as Socio-affective Signals.

Ultrasonic vocalizations (USV) serve important communicative functions as socio-affective signals in rats. In aversive situations, such as inter-male aggression and predator exposure, 22-kHz USV are emitted. They likely function as appeasement signals during fighting and/or as alarm calls to warn conspecifics. In appetitive situations, 50-kHz USV are uttered, most notably during social interactions, such as rough-and-tumble play and mating. It is believed that they fulfill an affiliative function as social contact calls. Social experiences or their lack, such as social isolation, can have profound impact on the emission of 22- and 50-kHz USV by the sender in later life, albeit direction and strength of observed effects vary, with time point of occurrence and duration being critical determinants. Little, however, is known about how social experiences affect the behavioral responses evoked by 22- and 50-kHz USV in the recipient. By means of our 50-kHz USV radial maze playback paradigm, we recently showed that the behavioral response elicited in the recipient is affected by post-weaning social isolation. Rats exposed to four weeks of isolation during the rough-and-tumble play period did not display social approach behavior toward 50-kHz USV but some signs of social avoidance. We further found that physical environmental enrichment providing minimal opportunities for social interactions has similar detrimental effects. Together, this indicates that social experiences can affect socio-affective communication in rodents, both at the level of sender and recipient. Deficits seen following post-weaning social isolation or physical environmental enrichment might be useful to model aspects of neurodevelopmental disorders characterized by social and communication deficits, such as autism and schizophrenia.

Studying Socio-Affective Communication in Rats through Playback of Ultrasonic Vocalizations.

Rats are able to produce ultrasonic vocalizations (USVs). Such USVs are an important component of the rat social behavior repertoire and serve distinct communicative functions as socio-affective signals. Depending on the emotional valence of the situation, juvenile and adult rats utter (1) aversive 22-kHz USVs conveying an appeasing and/or alarming function; or (2) appetitive 50-kHz USVs, which act as social contact calls, amongst others. A 50-kHz USV radial maze playback paradigm that allows assessment of the behavioral responses displayed by the recipients in a highly standardized manner has been developed. In this newly developed paradigm, a rat is exposed individually to playback of natural 50-kHz USVs and appropriate acoustic control stimuli using an acoustic presentation system for ultrasound. By this means, it has been consistently shown that 50-kHz USVs lead to social approach behavior in the recipient, supporting the notion that they serve an affiliative function as social contact calls.

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.

A coding-independent function of an alternative Ube3a transcript during neuronal development.

The E3 ubiquitin ligase Ube3a is an important regulator of activity-dependent synapse development and plasticity. Ube3a mutations cause Angelman syndrome and have been associated with autism spectrum disorders (ASD). However, the biological significance of alternative Ube3a transcripts generated in mammalian neurons remains unknown. We report here that Ube3a1 RNA, a transcript that encodes a truncated Ube3a protein lacking catalytic activity, prevents exuberant dendrite growth and promotes spine maturation in rat hippocampal neurons. Surprisingly, Ube3a1 RNA function was independent of its coding sequence but instead required a unique 3' untranslated region and an intact microRNA pathway. Ube3a1 RNA knockdown increased activity of the plasticity-regulating miR-134, suggesting that Ube3a1 RNA acts as a dendritic competing endogenous RNA. Accordingly, the dendrite-growth-promoting effect of Ube3a1 RNA knockdown in vivo is abolished in mice lacking miR-134. Taken together, our results define a noncoding function of an alternative Ube3a transcript in dendritic protein synthesis, with potential implications for Angelman syndrome and ASD.

Pro-social ultrasonic communication in rats: insights from playback studies.

Rodent ultrasonic vocalizations (USV) serve as situation-dependent affective signals and convey important communicative functions. In the rat, three major USV types exist: (I) 40-kHz USV, which are emitted by pups during social isolation; (II) 22-kHz USV, which are produced by juvenile and adult rats in aversive situations, including social defeat; and (III) 50-kHz USV, which are uttered by juvenile and adult rats in appetitive situations, including rough-and-tumble play. Here, evidence for a communicative function of 50-kHz USV is reviewed, focusing on findings obtained in the recently developed 50-kHz USV radial maze playback paradigm. Up to now, the following five acoustic stimuli were tested in this paradigm: (A) natural 50-kHz USV, (B) natural 22-kHz USV, (C) artificial 50-kHz sine wave tones, (D) artificial time- and amplitude-matched white noise, and (E) background noise. All studies using the 50-kHz USV radial maze playback paradigm indicate that 50-kHz USV serve a pro-social affiliative function as social contact calls. While playback of the different kinds of acoustic stimuli used so far elicited distinct behavioral response patterns, 50-kHz USV consistently led to social approach behavior in the recipient, indicating that pro-social ultrasonic communication can be studied in a reliable and highly standardized manner by means of the 50-kHz USV radial maze playback paradigm. This appears to be particularly relevant for rodent models of neurodevelopmental disorders, as there is a tremendous need for reliable behavioral assays with face validity to social communication deficits seen in autism and schizophrenia in order to study underlying genetic and neurobiological alterations.

Rodent ultrasonic communication: Male prosocial 50-kHz ultrasonic vocalizations elicit social approach behavior in female rats (Rattus norvegicus).

Rats emit distinct types of ultrasonic vocalizations (USV), which serve as situation-dependent affective signals with important communicative functions. Low-frequency 22-kHz USV typically occur in aversive situations, such as social defeat, whereas high-frequency 50-kHz USV can be observed in appetitive situations, like rough-and-tumble-play in juveniles or mating in adults. The 2 main USV types serve distinct communicative functions and induce call-specific behavioral responses in the receiver. While 22-kHz USV probably serve as alarm calls, 50-kHz USV appear to serve a prosocial communicative function in the sexual and the nonsexual context. In the sexual context, however, this view has recently been challenged by playback studies where only very limited behavioral changes were observed in response to prosocial 50-kHz USV. The aim of the present study was therefore to test whether female rats display social approach behavior in response to male prosocial 50-kHz USV by means of our established playback paradigm. To this aim, we exposed female rats to playback of the following 2 acoustic stimuli: (a) natural male 50-kHz USV and (b) time- and amplitude-matched white noise, with the latter serving as acoustic control for novelty-induced changes in behavior not linked to the communicative function of male prosocial 50-kHz USV. Our present findings show that female rats display high levels of social approach behavior in response to male prosocial 50-kHz USV, but not time- and amplitude-matched white noise, supporting the conclusion that male prosocial 50-kHz USV are likely to play an important role in establishing social proximity and possibly regulate mating behavior.