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. Author manuscript; available in PMC: 2023 Mar 1.
Published in final edited form as: Dev Psychobiol. 2022 Mar;64(3):e22260. doi: 10.1002/dev.22260

Infant ultrasonic vocalizations predict adolescent social behavior in rats: Effects of early life adversity

Lauren E Granata 1, Alissa Valentine 1, Jason L Hirsch 1, Heather C Brenhouse 1
PMCID: PMC9340574  NIHMSID: NIHMS1825339  PMID: 35312059

Abstract

Early life adversity (ELA) increases risk for psychopathologies that often manifest during adolescence and involve disrupted social functioning. ELA affects development of the prefrontal cortex (PFC), which plays a role in social behavior. PFC oxytocin and vasopressin are important regulators of, first, mother–infant attachment, and, later, social behavior, and are implicated in psychiatric disorders. Here, we tested whether infant social communication is predictive of PFC development and adolescent social behavior. We used the limited bedding (LB) ELA model in rats during postnatal days (P)2–14, and measured isolation-induced ultrasonic vocalizations (USVs) at P10 to characterize differences in an early social response. Rats were tested for dyadic social interaction in adolescence (P34). Adolescent oxytocin receptor (Oxtr) and arginine-vasopressin receptor 1a mRNA were measured in the PFC. Relationships between infant USVs, adolescent behavior, and gene expression were assessed. LB-reared rats exhibited fewer USVs at P10. While social behaviors were not robustly affected by rearing, fewer total and complex-type infant USVs predicted fewer interactions in adolescence. LB increased Oxtr in both sexes but Oxtr was not directly predicted by USVs. Findings support the use of USVs as indicators of differential early life experience in rodents, toward further characterization of early factors associated with vulnerability.

Keywords: early life stress, limited bedding, play, prefrontal cortex, ultrasonic vocalization

1 |. INTRODUCTION

Early life experiences play an important role in shaping neurobehavioral development. Accumulating evidence has demonstrated that exposure to adverse experiences during childhood is associated with an increased risk for developmental disorders including autism spectrum disorder, schizophrenia, depression, and anxiety (Chapman et al., 2004; Sonuga-Barke et al., 2017). In several species, environmental insults have been shown to alter developmental trajectories and lead to long-lasting neural and behavioral deficits (Andersen, 2003; Romeo et al., 2009). Although early intervention in mental illness can reduce the likelihood that the illness will become debilitating, diagnosis most often occurs after progression of symptomology has disrupted daily living (Correll et al., 2018). There has been recent emphasis on identifying early life predictors of psychiatric progression, especially in vulnerable populations, to improve the ability to apply early interventions and improve later-life outcomes (Collin et al., 2020). Rodent models can begin to unravel the ways in which behavioral markers can predict the effects of early life adversity (ELA) on of later-life behavior.

Social dysfunction is a common indicator of several neuropsychiatric conditions and is often exhibited before full onset of the disorder occurs (Saris et al., 2017). The oxytocin (Oxt) and arginine-vasopressin (Avp) systems are associated with regulation of social behavior, including social recognition, pair bonding, mother–infant attachment, and aggression (Carter et al., 2008; Cataldo et al., 2018; Nelson & Panksepp, 1998). Oxt synthesized in the hypothalamus directly acts on the regions sensitive to ELA, such as the prefrontal cortex (PFC) (Gogtay et al., 2004; Ohta et al., 2020; Schubert et al., 2015), with Oxt receptors expressed in both GABAergic interneurons and glutamatergic pyramidal neurons (Raam, 2020; Tan et al., 2019; Wei et al., 2020). ELA in the forms of maternal separation or paternal separation reportedly yield reduced Oxt signaling in the PFC (Wei et al., 2020; Yuan et al., 2020), which is also seen in clinical manifestations of social dysfunction such as autism (Abramova et al., 2020; Cataldo et al., 2018; Mor et al., 2015). Taken together, early life experiences exert influence over the expression of Oxt, Avp, and their receptors, which may modulate the risk for developing psychopathologies following ELA (Ellis et al., 2021; Hostinar et al., 2014; Liu et al., 2015).

In rodents, ELA is often modeled by interfering with the mother–infant relationship (Brenhouse & Bath, 2019; Walker & McCormick, 2009). In the limited bedding (LB) paradigm, developed by Baram and colleagues (Ivy et al., 2008), rat or mouse litters are reared with reduced bedding and nesting material available to dams in the home cage to model an impoverished environment (Rice et al., 2008; Walker et al., 2017). To assess caregiving quality in rodents, investigators typically observe the amount of time the dam engages in high-quality maternal behaviors such as arch-backed nursing and licking and grooming (Gammie, 2005). Variations in maternal care produce differences in adult offspring (Caldji et al., 2000; Cameron et al., 2005; Champagne et al., 2001) and are therefore an important characteristic of the early environmental experience. In the LB model, increased stress from the lack of nesting material can cause the dam’s behavior to change (Molet et al., 2016). Therefore, LB-reared litters experience a resource-scarce environment and may receive atypical care compared with standard-reared pups.

Behaviors displayed during separation from the mother can provide information about the affective state of the infant or the motivation to solicit maternal care and have been proposed as predictive of later-life behavior in both humans and nonhuman animal models (Schwartz et al., 1999; Zimmerberg et al., 2005). In rodents, isolation-induced ultrasonic vocalizations (USVs) have been interpreted as a sign of separation distress in infants (Branchi et al., 2001; Brudzynski, 2021) as well as solicitation of maternal care (Harmon-Jones & Richardson, 2021; Wöhr & Schwarting, 2008); when isolated from the dam, infant rats emit USVs in the 40 kHz range, which serve as a signal to the dam to initiate maternal behavior (Brouette-Lahlou et al., 1992; Ehret & Haack, 1981). Both higher-than-typical and lower-than-typical USV emission during isolation have been associated with temperaments that predict anxiety-like and social behaviors later in life (Brunelli et al., 2006). For example, more frequent emissions of isolation-induced USV in postnatal day (P)8–10 infants are reportedly associated with a phenotype that predicts heightened fear learning in adulthood (Harmon-Jones et al., 2020), while mice lines selectively bred to emit abnormally low or high numbers of USVs show reduced social play behaviors compared with those that have not been selectively bred (Brunelli et al., 2006). Therefore, isolation-induced USVs may be a valuable way to assess a pup’s experience of the early-life environment.

Rat pups exposed to repeated maternal separation ELA reportedly emit more isolation-induced USVs at postnatal day (P)12, but these vocalizations are qualitatively different (higher-pitch and shorter) than those emitted by control-reared pups (Kaidbey et al., 2019). In contrast, when assessed at P10, LB-exposed pups were observed to emit fewer isolation-induced USVs, also with different qualitative characteristics compared with control USVs (Granata et al., 2021). Importantly, isolation-induced USVs follow a developmental trajectory with age-related changes in number and quality (Granata et al., 2021), and ELA paradigms may yield increases or decreases depending on age; here, we concentrated on P10 due to the reported relationships between ELA and USV at this age. Moreover, the effects of LB on more intricate acoustic properties of USVs and types of calls have not been characterized. These qualities may be more informative of attempts to solicit maternal care, since specific spectral properties, such as frequency, amplitude, and duration, are thought to be functional in guiding maternal behavior throughout rearing (Brudzynski et al., 1999). For example, the occurrence of complex calls, characterized by recurrent frequency modulation, increases over development and comprises more than 50% of all call types by P21. Complex calls could thereby signify a more mature vocal repertoire. Notably, reductions in complex calls have been observed in mice prenatally exposed to valproic acid, an animal model with outcomes associated with autism spectrum disorder (Tsuji et al., 2020). Additionally, high-frequency calls that are short in duration in infancy are proposed to be associated with distress, compared with longer low-frequency calls, and driven by low maternal care (Kaidbey et al., 2019). Therefore, sonographic structure of isolation-induced USVs may provide information about individual pup’s experiences of its environment.

Early experience impacts the development of social behaviors as the rat enters adolescence, when social interactions have a critical impact on later brain development (Lundberg et al., 2017). ELA exposure leads to less exhibition of play behavior (Cuarenta et al., 2021) and affects underlying neural systems, including Oxt and Avp (Lukas et al., 2010; Oreland et al., 2010; Shi et al., 2021; Wei et al., 2020; Yuan et al., 2020). In rats, social play is a normal part of development necessary for proper maturation of anxiety-related circuits (Pellis & Pellis, 2009) and are modulated by Oxt, Avp, and antagonists to their receptors. Social play is thus an informative measure of behavioral functioning that may be predictable from early life indicators.

Social play in rats follows a well-defined pattern of behaviors (Himmler et al., 2013; Pellis et al., 2006; S. M. Pellis et al., 1992). A play bout begins with a pounce from the initiating rat, to which the receiving rat can respond by turning onto their dorsal side to facilitate a bout of “rough-and-tumble” play. This sequence can also be followed by a bout of chasing if the receiving rat runs away, or the rats may remain upright and initiate a bout of “boxing.” The medial PFC is necessary for engaging in typical social play fighting patterns, such as appropriate defensive strategies (Bell et al., 2009). Increased (Veenema & Neumann, 2009) or decreased engagement in adolescent play–behavior interactions is indicative of social deficit (Diaz et al., 2016). Some previous studies have shown that males are more susceptible to the effects of ELA on play behavior than females (Lundberg et al., 2017; Walker et al., 2017; effects on social behavior in general reviewed by White & Kaffman, 2019), but sex differences in the effects of the LB paradigm have not been widely explored (White & Kaffman, 2019). Additionally, there are sex differences in Oxt and Avp systems that are present as early as juvenility that may guide sexually dimorphic behavioral profiles (Bredewold et al., 2014). For example, males have more Avp-expressing cells in limbic brain regions such as the lateral septum, bed nucleus of the stria terminalis, and the medial amygdala and more Oxt receptor expression density in forebrain regions (De Vries & Panzica, 2006; Dumais et al., 2013; Sharma et al., 2019). Thus, sex-specific investigation of Oxt and Avp regarding the development and modulation of social behavior is crucial.

The present study investigated the effects of LB on neonatal isolation-induced USVs in male and female rats. Subjects were then tested in adolescence to determine changes in their social behavior by measuring their play and nonplay social behavior in a dyadic social interaction test. Gene expression levels of the Oxt receptor (Oxtr) and Avp receptor 1a (Avpr1a) in the PFC were also assessed in adolescence. We hypothesized that (1) LB would yield fewer isolation-induced USVs at P10, which would predict fewer play-based interactions in adolescence; (2) LB would yield reduced adolescent expression of Oxtr in the PFC, which would also be predicted by fewer USVs at P10; and (3) that these associations would be mediated by sex and rearing. Our investigation of how different call-types were related to adolescent measures was exploratory given the novelty of these measurements. We also aimed to determine whether USVs, an early-life social signal, were predictors of adolescent outcomes regardless of rearing experience.

2 |. METHODS

2.1 |. Subjects

All experiments were performed in accordance with the 1996 Guide for the Care and Use of Laboratory Animals (NIH) with approval from the Institutional Animal Care and Use Committee at Northeastern University. Male and female Sprague–Dawley rats originally obtained from Charles River Laboratories (Wilmington, MA) were used to breed subjects for this study. One male and one female were caged together until pregnancy was confirmed, a maximum of 4 days. All females were primiparous, and pregnant dams were housed singly. Parturition was checked daily, and the day of birth was denoted as P0. On P1, litters were culled to 10 pups, five males and five females when possible. Whole litters were randomly assigned to be reared under control (Con) or LB rearing. To limit litter effects, a maximum of two males and two females from each litter were analyzed (n = 10–11/group; seven Con litters and six LB litters used). Dams and pups were housed under standard laboratory conditions in polycarbonate wire-top caged with pine shave bedding and food and water available ad libitum. The facility was kept on a 12-h light/dark cycle (light period between 0700 and 1900) with regulated temperature (22–23°C) and humidity (37−53%). Con pups were left undisturbed except to be weighed on P9 and P20, and USV recording days (timeline in Figure 1(a)).

FIGURE 1.

FIGURE 1

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Limited bedding impacts on ultrasonic vocalizations. (a) Experimental timeline. (b) Examples of different types of ultrasonic vocalizations used for automatic classification. (c) and (d) Total number of USVs emitted. Colors represent the arcsine transformed proportions of each type of call defined by sonographic structure (c) or duration and bandwidth (d). (e) Arcsine transformed proportion of complex USVs. (f) Arcsine transformed proportion of fragmented USVs. Data are expressed as mean ± SEM. n = 9–11/group. *p < .05; **p < .01

2.2 |. Limited bedding

LB took place between P2 and P14, adapted from (Brunson et al., 2005). The P2–P14 timeframe, also used in Lapp et al. (2020), was chosen to target critical HPA axis maturation and development of the Oxt system that occurs during the first 2 weeks of life. On P2, dams and litters were transferred to a wire-lid cage with a wire grid (0.25″ × 0.25″ grid size) resting 0.5″ above the cage floor with a thin layer of pine shaving bedding underneath and a small handful of pine shaving bedding and half of a C-fold paper towel placed on top of the wire mesh (Molet et al., 2014; Walker et al., 2017). On P7, the cage was changed and the bedding and C-fold were replaced. LB housing took place until P14, when pups and dams were returned to standard housing conditions as described above.

2.3 |. USV recording and analysis

USVs were recorded for each pup on P10. The dam was removed from the home cage in order transport the test pup to the recording area. Each pup was recorded in an individual plastic cup with pine shavings from their home cage. Because decreased body temperature can induce USVs, the pup and recording cup were placed in a circulating water bath at 37°C to maintain their body temperature. An ultrasonic microphone (Avisoft Bioacoustics, model CM16/CMPA) positioned 10 cm above the cage was used to record the pups for a 5-min recording period. Following the recording, the pup was returned to the home cage. When more than one pup was recorded from a single litter, the sex of the first pup recorded was counterbalanced.

Audio files were uploaded and analyzed using Deepsqueak (Coffey et al., 2019), a Matlab program for USV analysis. USVs were visualized by converting each file to spectrograms using Fast Fourier Transformation. Each call detected by Deepsqueak was manually confirmed or rejected by a trained experimenter. The duration, maximum frequency, minimum frequency, and peak frequency of each call were determined. Bandwidth was calculated by the difference between maximum and minimum frequency. For each pup, the duration, bandwidth, and peak frequency were averaged across all vocalizations.

Call types were determined by two methods. First, all calls were classified depending on their duration and bandwidth, which categorized calls as either short, flat, or frequency modulated (FM). Short calls were any call less than 0.01 s in length, flat calls were longer than .01 s with a bandwidth less than 8 kHz, and FM calls were longer than 0.01 s with a bandwidth greater than 8 kHz. USVs were also classified by sonographic structure using a previous dataset of 12,227 USVs from 75 subjects to train a supervised classifier in Deepsqueak. USV types were developed based on pup calls identified by Brudzynski et al. (1999). The types identified in manual classification of the training dataset were complex, constant, downsweep, fragmented, inverted-U or upright-U, upsweep, and trill (representative images in Figure 1(b)). In the supervised classification, trills and complex calls were combined into one category due to high confusion matrix correlations between the two types. Inverted-Us and upright-Us were also combined for the same reason. The proportion of each call type out of the total number of vocalizations emitted was calculated for each subject, and this proportion was used to perform an arcsine transformation to reduce the skew of values of 0.0 and 1.0.

2.4 |. Maternal behavior

In order to probe important changes to environmental stimuli associated with LB rearing, maternal behavior was recorded and measured at three timepoints on P8–9. Full methods for maternal behavior assessments can be found in the Supporting Information, and results in Table S1.

2.5 |. Social interaction

On P34, animals underwent a 10-min dyadic social interaction test with a novel age- and sex-matched conspecific as previously described (Holland et al., 2014). On the day of testing, rats were transported to the testing room and left to habituate for 10 min. Testing took place in a 100 cm × 100 cm Plexiglass open field arena in dim lighting. To begin testing, the test rat was placed in the arena for 10 min to habituate, then moved to a holding cage. Then, the arena was cleaned with 60% ethanol, and the conspecific partner was placed in the arena for 10 min. To start the trial, the test rat was placed in the arena on the opposite side as the conspecific facing the opposite direction. The test rat and conspecific were left to interact for 10 min. The interaction was video recorded for later scoring. Videos were scored by an experimenter blind to experimental condition. The number of pounces and pins and the number and duration of sniffing or licking, crawling, chasing, boxing, and wrestling were tracked. Pouncing was defined as attempting to rub or nose the nape of the conspecific’s neck. Pinning was defined as the conspecific fully rotating onto its dorsal side with the test rat standing over it. Chasing was counted when the test rat was running after or following the conspecific. Boxing was upright pushing, pawing, or grabbing of the other rat. Wrestling was continuous rough and tumble play following one rat being pinned. Sniffing or licking was counted when the test rat’s nose was in close contact with the conspecific’s body. Crawling or climbing was counted when the test rat was walking over the conspecific’s body, but not soliciting play with a pounce. Only the behaviors of the test rat acting on the conspecific were counted. Pouncing, pinning, chasing, boxing, and wrestling were considered playful interactions, whereas sniffing and licking or crawling over the conspecific were considered nonplayful exploratory interactions.

2.6 |. mRNA quantification with qPCR

Taq-man reverse transcriptase polymerase chain reaction (qPCR) was performed on single hemisphere PFC chunks. Animals were sacrificed 24 h after the social interaction test, on P35. Animals were briefly anesthetized with 4% isoflurane before decapitation and brain extraction. The left and right PFC were obtained from a 1 mm coronal slice and immediately frozen on dry ice and stored at −80°C until processing. Left and right hemispheres were counterbalanced across subjects in qPCR. Total RNA was isolated using the RNAqeuous-4PCR Total RNA Isolation Kit (Applied Biosystems, Foster City, CA, USA) and processed per the manufacturer’s instructions. Then, cDNA was synthesized with the High-Capacity cDNA Reverse Transcriptase Kit (Applied Biosystems), and concentration of total cDNA was quantified with the Nanodrop Spectrophotometer (Thermo Fisher Scientific). Samples were then diluted to 200 μg/μl. Gene-specific primers (details in Table S8) from Thermo Fisher Scientific for Oxtr and Avpr1a were used for Taq-Man Gene Expression Assays on a StepOnePlus Real-Time PCR System (Applied Biosystems) using standard cycling conditions. Each reaction contained 4 μl of diluted cDNA and 16 μl of master mix with 1× dilution of either the Oxtr (Rn.6841) or Avpr1a (Rn.32282) primer, and all reactions were performed in triplicate. Reactions were carried out with a holding stage at 50°C for 2 min, followed by 95°C for 10 min, followed by 40 cycles of 15 s at 95°C and 1 min at 60°C. The relative standard curve analysis method was performed using the threshold cycle (CT) and the 2−ΔΔC(t) method to determine the relative gene expression with the house-keeping control gene, β-actin (Rn.94978). Data are expressed as mean fold change relative to control males.

2.7 |. Statistical analysis

Before analysis, data were assessed for outliers using Grubbs’ Test. Statistical analyses were performed in RStudio with the rstatix, lsr, and emmeans packages to calculate analysis of variance, effect sizes, and posthoc comparisons. To test for differences in USVs, first, two-way analysis of covariance tests was performed with rearing condition and sex as predictor variables, controlling for P9 weight to determine whether variation in USVs could be attributable to differences in weight. When there was a significant effect of rearing, Tukey’s posthoc contrasts within males and females were performed to determine whether there was an effect of rearing specific to either sex. For measures from the social interaction test and mRNA expression, two-way ANOVAs and posthoc contrasts were performed in the same fashion. To evaluate whether properties of USVs at P10 were predictive of adolescent social behavior and gene expression, multiple regression analyses were performed with rearing, sex, and individual USV measures as predictors and social behavior or relative gene expression as outcome variables. Each regression was tested for homogeneity of regression slopes to ensure no interaction between USV outcome and rearing was present. Normality of residuals was tested with Shapir–-Wilk tests and homogeneity of variances was tested with Levene’s test. Models are reported with adjusted R2 values and the p value and η2p effect size for the effect of USVs on the outcome measure.

3 |. RESULTS

3.1 |. Effects of LB on total USVs and acoustic properties

The total number of USVs emitted and their acoustic properties were assessed for sex and rearing effects by two-way ANCOVA controlling for P9 weight to ensure that USV differences were not due to individual differences in weight. One statistical outlier was removed for the analysis of total USVs (n = 9–11/group). Additionally, we ran Pearson’s correlation analyses between all USV measures, and a correlation matrix is shown in Table S7.

There was no effect of sex (F1,37 = 0.050, p = .825, hp2 = .0013), LB (F1,37 = 2.997, p = .091, hp2 = .0.73) or interaction effect (F1,37 = 0.0023, p = .962, hp2 < .0001) on the pups’ weight on P9. ANCOVAs revealed no relationships between P9 weight and total USVs (F1,36 = 0.108, p = .844, hp2 = .003), average principle frequency (F1,36 = .603, p = .442, hp2 = .016), duration (F1,36 = 0.051, p = .824, hp2 = .001), or bandwidth (F1,36 = .234, p = .632, hp2 = .006). However, P9 weight significantly adjusted the average power of USVs (F1,36 = 5.694, p = .022, hp2 = .133), with greater weight associating with less power (Figure 2(b)), but there were no effects of sex (F1,36 = 0.034, p = .855, hp2 = .001), rearing (F1,36 = 0.3371, p = .565, hp2 = .009), or interaction (F1,36 = 0.5252, p = .4732, hp2 = .0140) on the average power (Figure 2(a)). In a follow-up simple linear regression, there was a negative correlation between P9 weight and USV power (R2adj = .4281, p = .04) (Figure 2(b)).

FIGURE 2.

FIGURE 2

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Acoustic properties of ultrasonic vocalizations. (a) Average power (dB). (b) Pup weight at P9 (g) was negatively correlated with average USV power (dB). (c) Average bandwidth (kHz). (d) Average principle frequency. (e) Average duration. Each data point is the average of all calls emitted by a subject. Data are expressed as mean ± SEM. n = 9–11/group

There was no main effect of sex on total USVs emitted (F1,37 = 0.0771, p = .7829, hp2 = .0021). There was a main effect of rearing on total USVs, where LB decreased total USVs emitted (F1,37 = 11.51, p = .002, hp2 = .237), and there was no significant interaction (F1,37 = .0816, p = .7768, hp2 = .0023) (Figures 1(b) and 1(c)). Average bandwidth was not affected by sex (F1,37 = 0.128, p = .265, hp2 = .0033), rearing (F1,37 = .199, p = .658, hp2 = .005), or their interaction (F1,37 = 0.069, p = .794, hp2 = .002) (Figure 2(c)). Average principle frequency was not affected by sex (F1,37 = 0.923, p = .343, hp2 = .024), rearing (F1, 37 = 1.893, p = .177, hp2 = .047) or their interaction (F1,37 = 2.136, p = .152, hp2 = .053) (Figure 2(d)). Average duration of USVs was not affected by sex (F1,37 = .938, p = .339, hp2 = .024), rearing (F1,37 = 2.123, p = .153, hp2 = .053), or their interaction (F1,37 = 2.018, p = .164, hp2 = .050) (Figure 2(e)).

3.2 |. USV call types: sex differences and effects of LB

Two statistical outliers were removed from call type analysis of complex calls (n = 9–11/group). Statistics for all call types can be found in Table S2. There was no main effect of sex on complex calls (F1,38 = 1.043, p = .314, hp2 = .018), but there was a main effect of rearing (F1,36 = 7.032, p = .012, hp2 = .163), with LB pups emitting a lesser proportion of complex calls than Con (Figure 1(d)), and there was no interaction (F1,38 = 0.161, p = .121, hp2 = .066). Overall, females emitted a lesser proportion of fragmented calls compared with males (F1,38 = 4.673, p = .037, hp2 = .1003), but there was no effect of rearing (F1,38 = 1.99, p = .167, hp2 = .05) or interaction (F1,38 = 1.003, p = .323, hp2 = .026) (Figure 1(e)).

3.3 |. Social interaction

Subject weights were taken on the day of the social interaction test, and there was no effect of sex (F1,37 = 3.240, p = .099, hp2 = .228), rearing (F1,37 = 1.959, p = .189, hp2 = .151), or interaction (F1,37 = .054, p = .820, hp2 = .005) on weight. Results for all behaviors measured in the social interaction test can be found in Table S3. The following sex differences were observed in the social interaction test. Play frequency (F1,37 = 4.514, p = .0404, hp2 = .109) (Figure 3(a)) and play duration (F1,37 = 4.813, p = .035, hp2 = .115) (Figure 3(b)) was higher in females, and exploration duration (F1,37 = 9.131, p = .005, hp2 = .198) (Figure 3(d)) was lower in females (Figure 3(d)), but there was no effect on exploration frequency (Figure 3(c)). Within play behaviors, females more frequently engaged in boxing bouts (F1,37 = 6.892, p = .013, hp2 = .161) than males (Figure S4(a)). Within exploratory social behaviors, females spent less time sniffing and/or licking the conspecific (F1,37 = 6.613, p = .0143, hp2 = .152) (Figure S3(b)) and less time crawling over them (F1,37 = 4.253, p = .046, hp2 = .103) (Figure S3(f)), but the number of sniffing/licking (Figure S3(a)) or crawling (Figure S3(e)) bouts did not differ.

FIGURE 3.

FIGURE 3

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Adolescent social behavior. (a) Frequency and (b) duration (s) of play behaviors (pouncing, pinning, chasing, boxing, and wrestling). (c) Frequency and (d) duration (s) of nonplay social exploration behaviors (sniffing, licking, and crawling). Data are expressed as mean ± SEM. n = 9–11/group. *p < .05

There was a main effect of rearing on the duration engaged in nose-to-tail interaction (experimental animal exploring the conspecific’s tail) (F1,37 = 7.73, p = .0086, hp2 = .1768) (Figure S3(c)). There was also a main effect of rearing on chasing frequency (F1,37 = 5.706, p = .022, hp2 = .134) and chasing duration (F1,37 = 9.957, p = .003, hp2 = .221), with LB animals chasing more than Con (Figures S4(c) and S4(d)).

3.4 |. Oxtr and Avpr1a mRNA expression in the PFC

In the PFC at P35, there was no main effect of sex (F1,34 = .099, p = .755, hp2 = .003) on Oxtr mRNA expression, but LB increased Oxtr mRNA (F1,34 = 12.31, p = .001, hp2 = .266). There was no interaction (F1,34 = .005, p = .943, hp2 = .001) (Figure 6(a)). Avpr1a mRNA was unaffected by sex (F1,36 = .011, p = .919, hp2 = .001), LB (F1,36 = 1.006, p = .323, hp2 = .027), and their interaction (F1,36 = 0.654, p = .424, hp2 = .018) (Figure 6(b)).

FIGURE 6.

FIGURE 6

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(a) Oxtr and (b) Avpr1a mRNA expressed by the fold change relative to male controls. Relationship between the arcsine transformed proportion of complex USVs at and (c) P35 Oxtr mRNA and (d) total interactions in the adolescent social interaction test. Males are represented by black circles, females are represented by gray circles, controls are solid circles, and LB are open circles. n = 9–11/group. Estimates of β coefficients for the USV predictor are displayed and bolded when p < .05

3.5 |. Relationship between P10 USVs, adolescent social interaction, and Oxtr mRNA expression

To evaluate whether properties of USVs at P10 were predictive of adolescent social behavior and gene expression, we carried out linear regression analyses with rearing, sex, and individual USV measures as predictor variables and social interaction behaviors or gene expression as outcome measures. All results are shown in Tables S4 and S5. Regressions were also run with rearing, sex, and social interaction measures as predictors of Oxtr and Avpr1a expression (Table S6).

Social behaviors were split into either playful (pouncing, pinning, boxing, wrestling, or chasing) or exploratory interactions (sniffing, licking, or crawling). Pups that emitted more total USVs at P10 engaged in more total interactions (play and exploratory combined) (Figure 4(c)), specifically more exploratory social interactions (Figure 4(b)), but not playful interactions (Figure 4(a)). USV principle frequency was negatively associated with the total number of interactions (Figure 4(f)), specifically exploratory interactions (Figure 4(e)) and not playful interactions (Figure 4(d)).

FIGURE 4.

FIGURE 4

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Relationship between P10 USVs and adolescent social interaction. Graphs depict linear regressions between total USVs and number of playful interactions (a), number of exploratory interactions (b), and total interactions (c), and USV principle frequency (kHz) and number of playful interactions (d), number of exploratory interactions (e), and total interactions (f). Males are represented by black circles, females are represented by gray circles, control are solid circles and LB are open circles. n = 9–11/group. Estimates of β coefficients for the USV predictor are displayed and bolded when p < .05

Relationships were then assessed between social interactions and USV types determined by their duration and bandwidth, which categorized USV as either short, flat, or FM. All statistics for these analyses can be found in Table S4. The proportion of short USVs was negatively associated with the total number of interactions, whereas flat USVs were positively associated with the total number of interactions, and FM USVs were not associated with total interactions. Specifically, short USVs were associated with fewer playful interactions (Figure 5(c)), flat USVs were associated with more playful interactions (Figure 5(b)), and FM USVs were not associated with playful interactions (Figure 5(a)). Short USVs were associated with more time spent in exploratory interactions, but flat USVs and FM USVs were not associated with exploratory interactions.

FIGURE 5.

FIGURE 5

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Relationship between frequency-modulated (FM), flat, short USV types. Correlations between the arcsine transformed proportion of FM (a), flat (b), and short (c) USVs and the number of play interactions (pounces, pins, chasing, boxing, and wrestling). Males are represented by black circles, females are represented by gray circles, controls are solid circles, and LB are open circles. n = 9–11/group. Estimates of β coefficients for the USV predictor are displayed and bolded when p < .05

In another analysis of call types, the same USVs were classified into six different call types based on their sonographic structure with machine learning in DeepSqueak. The arcsin transformed proportion of complex calls was positively associated with the total number of interactions in adolescence (b = 50.361, p = .021, hp2 = .1470) (Figure 6(d)). With the linear regression analysis, there was a moderate, but not significant relationship between complex calls and Oxtr mRNA expression (b = −0.436, p = .064, hp2 = .106). This analysis was followed up with a simple linear regression to assess the overall relationship between complex calls and Oxtr mRNA expression, which showed that complex calls were negatively associated with Oxtr in adolescence (R2 = .2022, p = .0059) (Figure 6(c)). Although there was a correlative relationship between complex USVs and Oxtr expression, since LB affected complex calls as well as Oxtr expression, as reported above in the ANOVAs, complex calls may not be a unique predictor of Oxtr mRNA.

4 |. DISCUSSION

The aim of this study was to determine how ELA affects infant isolation-induced USVs and to establish relationships between early life USVs, adolescent social behaviors, and PFC gene expression. We characterized the quantity, acoustic properties, and call types of isolation-induced USVs in control and LB-reared rat pups. These measures were then correlated with adolescent social behavior and Oxtr and Avpr1a gene expression in the PFC. We hypothesized that LB would impact infant USVs and that the measures affected by LB would be predictive of subsequent behavior and gene expression in adolescents. This study focused on social play because these interactions are crucial to normative adolescent development, and atypical social behavior is often indicative of behavioral dysfunction in other domains like cognition and anxiety. Because USVs have a functional social component, we tested the hypothesis that variations in neonatal vocalizations would be indicative of later social behavior differences. We found that LB affected both the quantity of USVs and the proportion of specific call types as distinguished by their acoustic properties and sonographic structure. Some of these call types were predictive of social behavior in adolescence, and fewer complex USVs were correlated with higher Oxtr mRNA expression.

4.1 |. LB suppressed USVs, and call types were affected

At P10, isolation-induced USVs were suppressed in LB-exposed pups, and complex calls, in particular, were decreased. Here, we recorded USVs at P10 because at this age, rat pups emit USVs in isolation without the need for adding another potentially stressful stimulus such as a predator odor, decreased temperature, or a novel environment (Brudzynski et al., 1999). Our observation of decreased USV emissions after ELA is consistent with other types of adversity, like maternal separation and an acute immune challenge (Kentner et al., 2018; Zimmerberg et al., 2003), although these findings conflict with the increased USVs found in Kaidbey et al. (2019) after maternal separation. Another study found that isolation USVs were not affected by LB in Wistar, Wistar–Kyoto, Flanders Sensitive Line, or Sprague–Dawley strains, although that study did not specify whether males and females were combined in the analyses (Braw et al., 2008). Separating analyses based on sex is critical, since our laboratory and others have found sex-dependent effects of ELA on USV emission rates and call types (Granata et al., 2021; Kentner et al., 2018), although these sex differences have been reported by some to be minor (Stark et al., 2020). Additionally, the context in which USVs are recorded can produce different effects. For example, when recorded with the dam present, as opposed to in isolation, pups reared under the scarcity-adversity paradigm produced more USVs than control pups (Perry et al., 2019). Further experiments testing the USV response to maternal presence should be conducted to assess how LB affects USVs outside of the context of isolation.

Although no significant sex × rearing interactions were found for the effects on infant USV, we did note a moderate effect size for a sex × rearing interaction on isolation-induced complex calls (hp2 = 0.066). We decided to run a posthoc analysis on this data set and observed that LB-exposed females (Sidak’s post hoc 0.01) but not males (0.704) emitted fewer complex calls than controls. This female-specific effects of LB on USV emissions could be associated with sex differences found in neural and behavioral development after LB rearing (Bath, 2020). For example, females, but not males, were found to exhibit more depressive-like behaviors after LB rearing (Goodwill et al., 2019), whereas only males exhibited long-term deficits in object location learning after LB (Bath et al., 2017). These sex differences could be related to differences in maternal behavior exhibited toward male and female offspring. Although the reasons for differential maternal treatment are not fully understood, the dam’s preference for retrieving male pups was found to be driven by sexually dimorphic USV patterns (Bowers et al., 2013). In a maltreatment paradigm, stressed dams were found to direct more abusive-like behavior toward female pups (Keller et al., 2019). We did not measure maternal behavior directed at male and female pups specifically, but future research should investigate how USVs and LB affect maternal behavior directed to each sex to further explore how sex-dependent vulnerabilities may arise after adverse rearing.

4.2 |. Adolescent females engaged in more play behavior, and LB had subtle effects on social behavior

Sex differences in the quantity and quality of play and exploratory social behaviors are reportedly complex (Vanderschuren et al., 1997). Although some studies suggest that male rats engage in more play behavior than females (Meaney & Stewart, 1981; Vanderschuren et al., 1997), here we found that females spent more time playing and less time in exploratory social behavior than males, which is consistent with other findings from dyadic interactions with no previous social isolation (Northcutt & Nwankwo, 2018). We hypothesized that LB would reduce play-based interactions in adolescence, as ELA is generally thought to induce a social deficit by decreasing play motivation and hindering social preference. Specifically, LB has been shown to decrease social approach and play behavior in juveniles and adolescents (Raineki et al., 2012; Rincón-Cortés & Sullivan, 2016). Here, we found that chasing and nose-to-tail contact time were enhanced by LB, but the total time spent interacting with the conspecific was not affected. Chasing is a behavior often preceding rough-and-tumble behaviors like pouncing and pinning, and increased chasing could indicate that more investigation of the partner rat was necessary before continuing with the archetypical rough-and-tumble sequence (Vanderschuren et al., 1995).

4.3 |. Properties of infant isolation-induced USV predicted adolescent social exploration and play behavior

We found that the total number of USVs emitted, certain acoustic properties, and call types correlated with the frequency to engage in social interactions in adolescence. Particularly, more USVs in infants predicted greater exploratory interactions, such as sniffing, licking, and crawling in the adolescent interaction test. Lower principle frequency of their USVs also predicted more exploratory interactions. Playful interactions, on the other hand, were correlated with specific types of USVs, which were identified by their frequency modulation and duration. Pups producing a greater proportion of flat USVs and fewer short duration USVs initiated more playful interactions in adolescence. Finally, adolescents who had produced more complex USVs in infancy engaged in more total interactions, but this relationship was not specific to play or exploratory behavior. Both types of interactions, playful and exploratory, have been used to interpret deficits after adversity or chronic stress, but each may be controlled by distinct neural circuits (van Kerkhof et al., 2013). The relationships between infant USVs and playful versus exploratory behaviors demonstrated here could point to the possible function of USVs, although further experimentation will be needed to support this hypothesis. For example, more total USV emissions of any type predicting more social interactions could mean that the propensity to vocalize in infancy is related to eventual differences in social drive. Short and flat USVs, which predicted fewer and greater play behaviors, respectively, may support their role in shaping the characteristic social play structure demonstrated by adolescent rats (Pellis et al., 2006).

Acoustic features of USVs affect their directionality and their propensity to degrade over distance as they perpetuate through the environment (Allin & Banks, 1972). Therefore, different types of calls may be adaptively relevant for facilitating the maternal response, but specific experiments will need to be carried out to determine how frequency modulation and duration affect these relationships. Although associations between 50 kHz USVs and specific behaviors have been outlined in adolescent rats (Burgdorf et al., 2008), neonatal USVs are their own class of spectrographically and functionally distinct vocalizations (Brudzynski et al., 1999). Thus, we consider the predictive nature of flat, short, and complex neonatal USVs independently from the role that USVs play in shaping behaviors during the social interaction itself.

4.4 |. Oxtr mRNA expression was increased by LB and correlated with neonatal complex USV

We assessed the effects of LB on PFC Oxtr and Avpr1a expression to address a potential mechanism underlying altered social behavior. Oxt and Avp are present in the brain by gestational day 18, but these systems undergo further development during the postnatal period, making them potentially vulnerable to altered trajectories after ELA (Jurek & Neumann, 2018). In rodents, Oxtr and Avpr1a are distributed throughout brain regions important for social behavior like the PFC, hippocampus, nucleus accumbens, and more variably in the amygdala and basal ganglia (Stoop, 2012). Despite the role of the PFC in regulating social behavior and its relatively protracted development, few studies have investigated how ELA affects Oxt and Avp systems in the PFC specifically, and to our knowledge ours is the first assessment of Oxt receptor levels in ELA-exposed adolescents. Predictable maternal separation ELA (which caused stress resilience) was observed to increase Oxt receptors in the PFC of adults (Shi et al., 2021), whereas unpredictable maternal separation and other ELA paradigms leading to anxiety-like behavior yielded reduced Oxt receptor expression (Wei et al., 2020; Yuan et al., 2020). Since studies in rodents and humans have corroborated a link between ELA and reduced PFC Oxt signaling alongside social behavioral dysfunction, our findings were contrary to our hypothesis of reduced Oxtr expression in PFC. The only other study specifically investigating LB effects on Oxt revealed that LB increased Oxtr in the paraventricular nucleus on P15 (Lapp et al., 2020), with no previous reports of LB effects on Oxt in the PFC. Our finding of increased PFC Oxtr does, however, align with a report from a postmortem study in humans that patients with major depressive disorder and bipolar disorder—two illnesses more prevalent following ELA (Nemeroff, 2016; Weder et al., 2014)—displayed increased dorsolateral PFC Oxtr mRNA (Lee et al., 2018). Studies in rodents have shown that Oxt administration decreases offensive behaviors while increasing social exploration (Calcagnoli et al., 2013) and can prevent ELA-induced anxiety-like behavior (Mansouri et al., 2020). In humans, it has been shown that the effects of Oxt administration on prosocial behavior are moderated by individual differences in attachment anxiety and avoidance (Bartz et al., 2011). By evaluating the impact of individual differences in USVs on social development in rodent models, we can begin to uncover the factors that lead to increased vulnerability and affect clinical outcomes.

We observed that a lesser proportion of complex USVs in infancy correlated with higher Oxtr expression in adolescence, however the correlation may be due to effects of LB on both measures, rather than a direct relationship between the two regardless of rearing. Complex USVs, characterized by repeated fluctuations in frequency, have been postulated to be evolutionarily advantageous for guiding maternal behaviors due to their ambulatory nature, which helps dams orient toward pups (Brudzynski et al., 1999; Brunelli et al., 1994). Fewer complex USVs may, then, be indicative of a deficit in the adaptive response to separation from a caregiver. Indeed, this disruption by LB exposure was associated with increased Oxtr expression, which reportedly contributes to stress resilience (Shi et al., 2021) and can alleviate autism-like behaviors following ELA (Wei et al., 2020). It is not clear from our data, however, whether preweanling USVs are directly linked to developmental programming of the Oxt system. That said, although we did not measure Oxt peptide levels, increased receptor expression after LB could be a compensatory mechanism due to a state of reduced Oxt. Quantifying Oxt in the PFC will be necessary to verify how LB affects oxytocinergic system development into adolescence.

4.5 |. Limitations and future directions

The findings presented should be considered alongside the limitations of this study. First, the LB model typically produces a fragmented behavioral profile in dams, as defined by increased nest entries and shorter nursing bouts (Molet et al., 2016). Importantly, the present findings show that LB dams had fewer nest entries and exits and longer bouts of passive nursing. This could be due to the shorter 30-min observation period we used for each time point, compared with other studies that used 1-h observation periods. The second limitation is that USVs were recorded at P10, but USVs can change over development, and changes due to LB may be different at different ages (Stark et al., 2020). Additionally, recording pups in the circulating water bath was meant to reduce stress as much as possible, but the environment used for recording was still somewhat novel for both experimental groups. This study did not test the effects of ELA on adolescent USVs during the social interaction, but other studies have found that adolescent rats preferentially emit certain types of vocalizations while performing specific behaviors (Burke et al., 2018). In the future, it will be informative to conduct similar analyses of USVs as they coincide with specific play and nonplay behaviors. Whether these vocalization–behavioral pairings are impacted by ELA will be an important line of research, as this could be another indicator of altered social functioning.

4.6 |. Conclusions

Here, we found that the LB paradigm of ELA, which induces atypical patterns of maternal behavior, decreased infant USV emissions and increased adolescent Oxtr expression. The total number of USVs positively correlated with exploratory social behavior, and principle frequency negatively correlated with exploratory behavior. Playful interactions positively correlated with flat USVs and negatively correlated with short USVs. These findings provide a basis that isolation-induced USVs are an early life indicator of later behavior. This will be useful for characterizing rodent models of early experience to determine the impacts of environment on individual pups and how early social communication modulates later social behavior. Social behavior is a central aspect of development necessary for neurobehavioral development, and identifying early indicators of changes in social functioning will lead to better targeted testing of intervention strategies in vulnerable individuals.

Supplementary Material

Supplemental Material

ACKNOWLEDGMENT

This work was funded in part by NIMH R01MH107556.

Funding information

National Institute of Mental Health, Grant/Award Number: R01MH107556

Footnotes

CONFLICT OF INTEREST

The authors declare no conflict of interest.

SUPPORTING INFORMATION

Additional supporting information may be found in the online version of the article at the publisher’s website.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Supplemental Material
NIHMS1825339-supplement-Supplemental_Material.docx (424.8KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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