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25Autism Spectrum Disorder (ASD) is one of the neurodevelopmental disorders and 26 characterized with persistent impairments in social communication (including verbal 27 and nonverbal communication) and repetitive behavior together with various 28 comorbid symptoms. Epidemiological studies suggest a significant association 29 between advanced paternal age and incidence of ASD in offspring, which has been 30 modeled in rodents. However, how paternal aging makes an impact on the offspring's 31 early communicative behavior, especially at the individual level, has not been 32 addressed. Here we systematically analyzed postnatal development of vocal 33 communication of pups by measuring ultrasonic vocalization (USV) induced by 34 maternal separation that is considered to correspond to baby's cry, an earliest verbal 35 communication in human. Maternal separation-induced USV of each offspring 36 derived from young (3 months) or aged (>12 months) father was individually 37 measured for 5 minutes at postnatal day 3 (P3), P6, P9, and P12. We classified USV 38 syllables into twelve types according to Scattoni's classification with minor 39 modifications, and analyzed duration, maximum frequency, maximum amplitude and 40 interval of each syllable. Compared between the two groups, the offspring derived 41 from aged fathers emitted the syllables with less number, shorter duration, different 42 syllable components and less diversity. From an individual perspective, offspring 43 derived from young father showed a developmental convergence in vocal 44 communication, while those from aged fathers exhibited atypical developmental 45 patterns. Taken together, we showed for the first time a significant influence of 46 paternal aging on early vocal development with qualitative and quantitative aspects in 47 50 Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by 51 two core symptoms; i.e., social interaction impairment (including verbal and 52 nonverbal communication deficits) and repetitive behavior [1][2][3] . In most cases, the 53 exact etiology of ASD remains unclear, although researchers believe that genetic, 54 environmental and epigenetic factors are involved in the neuropathology of ASD [4][5][6] . 55In recent years, epidemiological studies repeatedly suggest a significant association 56 between paternal aging and a risk of ASD in offspring. Compared with the children of 57 young fathers, the children were more likely to be diagnosed ASD if their fathers 58 were older [7][8][9][10] . Thus, paternal aging can be worth to be focused as one of the 59 non-genetic mechanisms leading to ASD. 60 61In the new criteria of DSM-5, the communication and social interaction parts are 62 combined into one, i.e., "Social/Communication Deficits". This modification 63 emphasizes the importance of the social communication domain in ASD in early 64 infancy. Human infant crying is an innate social communication [11, 12] , which has a 65 natural peak in frequency of approximately 2.5 hours of crying per day at aroun...

When a rodent pup is separated from its mother and littermates, it emits ultrasonic vocalizations (USVs), which can trigger maternal approach and retrieval behavior. 1,2 Therefore, the maternal separationinduced USVs are a type of vocal communication that is crucial for maternal care behaviors preserving the social bonds between mother and pups. [3][4][5][6][7][8] In recent decades, maternal separation-induced USVs have served as a valuable tool in understanding the communicative behavioral phenotype of rodent models of neurodevelopmental disorders (NDDs). 9,10 Previous studies have observed that USVs produced by NDD genetic models such as Tbx1 heterozygous mouse pups or nongenetic models such as aged father-derived mouse pups exhibited NDD-like impairments. [11][12][13] In contrast to the substantial significance of USVs as behavioral phenotypes in mouse NDDs models, the mechanisms of neuronal activity underlying the fundamental process of USVs, including responsible brain regions, remain largely unknown.Brain activity associated with maternal separation-induced USV production is intricate. Extensive studies have identified the hypothalamus 14 and cerebellum 15 as relevant brain regions. However, multiple brain regions related to anxiety and sociability may also modulate USV production. Thus, we tried comprehensive brainwide mapping of neuronal activity evoked by maternal separation