Paternal age affects offspring via an epigenetic mechanism involving REST/NRSF.

Advanced paternal age can have deleterious effects on various traits in the next generation. Here, we establish a paternal-aging model in mice to understand the molecular mechanisms of transgenerational epigenetics. Whole-genome target DNA methylome analyses of sperm from aged mice reveal more hypo-methylated genomic regions enriched in REST/NRSF binding motifs. Gene set enrichment analyses also reveal the upregulation of REST/NRSF target genes in the forebrain of embryos from aged fathers. Offspring derived from young mice administrated with a DNA de-methylation drug phenocopy the abnormal vocal communication of pups derived from aged fathers. In conclusion, hypo-methylation of sperm DNA can be a key molecular feature modulating neurodevelopmental programs in offspring by causing fluctuations in the expression of REST/NRSF target genes.

Chronic exposure to imipramine induces a switch from depression-like to mania-like behavior in female serotonin transporter knockout rats: Role of BDNF signaling in the infralimbic cortex.

BACKGROUND: Bipolar disorder (BD) is a highly burdensome psychiatric disorder characterized by alternating states of mania and depression. A major challenge in the clinic is the switch from depression to mania, which is often observed in female BD patients during antidepressant treatment such as imipramine. However, the underlying neural basis is unclear. METHODS: To investigate the potential neuronal pathways, serotonin transporter knockout (SERT KO) rats, an experimental model of female BD patients, were subjected to a battery of behavioral tests under chronic treatment of the antidepressant imipramine. In addition, the expression of brain-derived neurotrophic factor (BDNF) and its downstream signaling was examined in the prefrontal cortex. RESULTS: Chronic exposure to imipramine reduced anxiety and sociability and problem-solving capacity, and increased thigmotaxis and day/night activity in all animals, but specifically in female SERT KO rats, compared to female wild-type (WT) rats. Further, we found an activation of BDNF-TrkB-Akt pathway signaling in the infralimbic, but not prelimbic, cortex after chronic imipramine treatment in SERT KO, but not WT, rats. LIMITATIONS: Repeated testing behaviors could potentially affect the results. Additionally, the imipramine induced changes in behavior and in the BDNF system were measured in separate animals. CONCLUSIONS: Our study indicates that female SERT KO rats, which mirror the female BD patients with the 5-HTTLPR s-allele, are at higher risk of a switch to mania-like behaviors under imipramine treatment. Activation of the BDNF-TrkB-Akt pathway in the infralimbic cortex might contribute to this phenotype, but causal evidence remains to be provided.

Whole-brain mapping of neuronal activity evoked by maternal separation in neonatal mice: An association with ultrasound vocalization.

Neonatal mice emit ultrasonic vocalizations (USVs) when separated from their mothers. Since the USVs attract their mothers' attention and trigger maternal retrieval, they are considered to serve as social signals for communication. We have modeled paternal aging effects on the vocal communication of offspring in mice. However, little is known about the neural basis underlying neonatal USV production. To identify responsible brain regions driving the vocal behavior, we comprehensively mapped the neuronal activity associated with USV production in the entire brain of mice at postnatal day 6 (P6). Using an expression of immediate-early gene c-Fos as a neuronal activity marker, correlations between the numbers of USVs and c-Fos positive neurons were analyzed. We identified 23 candidate brain regions associated with USV production in the mice at P6. Our study would be a first step toward comprehensively understanding the neuronal mechanisms that regulate and develop vocal behaviors in neonatal mice.

Advanced paternal age diversifies individual trajectories of vocalization patterns in neonatal mice.

Infant crying is a communicative behavior impaired in neurodevelopmental disorders (NDDs). Because advanced paternal age is a risk factor for NDDs, we performed computational approaches to evaluate how paternal age affected vocal communication and body weight development in C57BL/6 mouse offspring from young and aged fathers. Analyses of ultrasonic vocalization (USV) consisting of syllables showed that advanced paternal age reduced the number and duration of syllables, altered the syllable composition, and caused lower body weight gain in pups. Pups born to young fathers had convergent vocal characteristics with a rich repertoire, whereas those born to aged fathers exhibited more divergent vocal patterns with limited repertoire. Additional analyses revealed that some pups from aged fathers displayed atypical USV trajectories. Thus, our study indicates that advanced paternal age has a significant effect on offspring's vocal development. Our computational analyses are effective in characterizing altered individual diversity.