Ultrasonic Vocalizations Calls Research Articles

A synergistic effect of herb and acupuncture on the methamphetamine

BackgroundHerbal medicine Ja-Geum-Jeong (JGJ) has been used for the treatment of detoxification in Eastern Asia. However, the mechanisms involved are not clearly defined. The purpose of the present study was to investigate if herb medication inhibits Methamphetamine (METH)’s reinforcing effect and also examined if a combination of herb medication and acupuncture produces a synergistic effect on METH. MethodsMale Sprague-Dawley rats were given acute METH intraperitoneally and the locomotor activity and ultrasonic vocalization (USV) calls were measured. Rats were administered JGJ orally and acupuncture was given at HT7 or SI5. Monosodium glutamate (MSG) and gamma-aminobutyric acid (GABA) agonists were injected into the Central amygdala (CeA) to investigate a possible neuroscientific mechanism. Tyrosine hydroxylase (TH) and fast scan cyclic voltammetry (FSCV) were measured to immunohistochemically and electrically confirm the behavioral data. ResultsLocomotor activity and USV calls were increased by METH (P<0.05) and these increases were inhibited by JGJ (P<0.05). Also, JGJ had no effect on the normal group given saline, and acupuncture at SI5 acupoint, but not at HT7 acupoint, produced a synergistic effect when combined with JGJ (P<0.05). The JGJ's inhibition was blocked by the inactivation of CeA (P<0.05), and MSG mimicked JGJ (P<0.05). TH and FSCV measures showed the same pattern with the behavioral data (P<0.05). ConclusionResults of the present study suggest that JGJ had inhibitory effects on the METH which was mediated through the activation of CeA and that combination of acupuncture and herb produced synergistic effect.

Neurodevelopmental consequences of gestational exposure to particulate matter 10: Ultrasonic vocalizations and gene expression analysis using a bayesian approach

Air pollution has been associated with a wide range of health issues, particularly regarding cardio-respiratory diseases. Increasing evidence suggests a potential link between gestational exposure to environmental pollutants and neurodevelopmental disorders such as autism spectrum disorder. The respiratory pathway is the most commonly used exposure model regarding PM due to valid and logical reasons. However, PM deposition on food (vegetables, fruits, cereals, etc.) and water has been previously described. Although this justifies the need of unforced, oral models of exposure, preclinical studies using oral exposure are uncommon. Specifically, air pollution can modify normal brain development at genetic, cellular, and structural levels. The present work aimed to investigate the effects of oral gestational exposure to particulate matter (PM) on ultrasonic vocalizations (USV). To this end, pregnant rats were exposed to particulate matter during gestation. The body weight of the pups was monitored until the day of recording the USVs. The results revealed that the exposed group emitted more USV calls when compared to the control group. Furthermore, the calls from the exposed group were longer in duration and started earlier than those from the non-exposed group. Gene expression analyses showed that PM exposure down-regulates the expression of Gabrg2 and Maoa genes in the brain, but no effect was detected on glutamate or other neurotransmission systems. These findings suggest that gestational exposure to PM10 may be related to social deficits or other phenomena that can be analyzed with USV. In addition, we were able to detect abnormalities in the expression of genes related to different neurotransmitter systems, such as the GABAergic and monoaminergic systems. Further research is needed to fully understand the possible effects of air pollutant exposure on neurodevelopmental disorders as well as the way in which these effects are linked to differences in neurotransmission systems.

Extended performance analysis of deep-learning algorithms for mice vocalization segmentation

Ultrasonic vocalizations (USVs) analysis represents a fundamental tool to study animal communication. It can be used to perform a behavioral investigation of mice for ethological studies and in the field of neuroscience and neuropharmacology. The USVs are usually recorded with a microphone sensitive to ultrasound frequencies and then processed by specific software, which help the operator to identify and characterize different families of calls. Recently, many automated systems have been proposed for automatically performing both the detection and the classification of the USVs. Of course, the USV segmentation represents the crucial step for the general framework, since the quality of the call processing strictly depends on how accurately the call itself has been previously detected. In this paper, we investigate the performance of three supervised deep learning methods for automated USV segmentation: an Auto-Encoder Neural Network (AE), a U-NET Neural Network (UNET) and a Recurrent Neural Network (RNN). The proposed models receive as input the spectrogram associated with the recorded audio track and return as output the regions in which the USV calls have been detected. To evaluate the performance of the models, we have built a dataset by recording several audio tracks and manually segmenting the corresponding USV spectrograms generated with the Avisoft software, producing in this way the ground-truth (GT) used for training. All three proposed architectures demonstrated precision and recall scores exceeding 90%, with UNET and AE achieving values above 95%, surpassing other state-of-the-art methods that were considered for comparison in this study. Additionally, the evaluation was extended to an external dataset, where UNET once again exhibited the highest performance. We suggest that our experimental results may represent a valuable benchmark for future works.

Stressed rats fail to exhibit avoidance reactions to innately aversive social calls.

Disruptions in amygdalar function, a brain area involved in encoding emotionally salient information, has been implicated in stress-related affective disorders. Earlier animal studies on the behavioral consequences of stress-induced abnormalities in the amygdala focused on learned behaviors using fear conditioning paradigms. If and how stress affects unconditioned, innate fear responses to ethologically natural aversive stimuli remains unexplored. Hence, we subjected rats to aversive ultrasonic vocalization calls emitted on one end of a linear track. Unstressed control rats exhibited a robust avoidance response by spending more time away from the source of the playback calls. Unexpectedly, prior exposure to chronic immobilization stress prevented this avoidance reaction, rather than enhancing it. Further, this stress-induced impairment extended to other innately aversive stimuli, such as white noise and electric shock in an inhibitory avoidance task. However, conditioned fear responses were enhanced by the same stress. Inactivation of the basolateral amygdala (BLA) in control rats prevented this avoidance reaction evoked by the playback. Consistent with this, analysis of the immediate early gene cFos revealed higher activity in the BLA of control, but not stressed rats, after exposure to the playback. Further, in vivo recordings in freely behaving control rats exposed to playback showed enhanced theta activity in the BLA, which also was absent in stressed rats. These findings offer a new framework for studying stress-induced alterations in amygdala-dependent maladaptive responses to more naturally threatening and emotionally relevant social stimuli. The divergent impact of stress on defensive responses--impaired avoidance responses together with increased conditioned fear--also has important implications for models of learned helplessness and depression.

Effects of β-Phenylethylamine on Psychomotor, Rewarding, and Reinforcing Behaviors and Affective State: The Role of Dopamine D1 Receptors.

Beta-phenylethylamine (β-PEA) is a well-known and widespread endogenous neuroactive trace amine found throughout the central nervous system in humans. In this study, we demonstrated the effects of β-PEA on psychomotor, rewarding, and reinforcing behaviors and affective state using the open-field test, conditioned place preference (CPP), self-administration, and ultrasonic vocalizations (USVs) paradigms. We also investigated the role of the dopamine (DA) D1 receptor in the behavioral effects of β-PEA in rodents. Using enzyme-linked immunosorbent assay (ELISA) and Western immunoblotting, we also determined the DA concentration and the DA-related protein levels in the dorsal striatum of mice administered with acute β-PEA. The results showed that acute β-PEA increased stereotypic behaviors such as circling and head-twitching responses in mice. In the CPP experiment, β-PEA increased place preference in mice. In the self-administration test, β-PEA significantly enhanced self-administration during a 2 h session under fixed ratio (FR) schedules (FR1 and FR3) and produced a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement in rats. In addition, acute β-PEA increased 50-kHz USV calls in rats. Furthermore, acute β-PEA administration increased DA concentration and p-DAT and TH expression in the dorsal striatum of mice. Finally, pretreatment with SCH23390, a DA D1 receptor antagonist, attenuated β-PEA-induced circling behavior and β-PEA-taking behavior in rodents. Taken together, these findings suggest that β-PEA has rewarding and reinforcing effects and psychoactive properties, which induce psychomotor behaviors and a positive affective state by activating the DA D1 receptor in the dorsal striatum.

Linking of NMDA receptors and mGluR5 in the nucleus accumbens core to repeated cocaine-induced 50-kHz ultrasonic vocalization in rats.

Rats express a positive emotional state by emitting 50-kHz ultrasonic vocalization (USV) calls in response to drug exposure. This study demonstrated the linking of glutamate receptors in the nucleus accumbens (NAc) to vocal expression of 50-kHz USV calls after repeated cocaine administration in freely moving rats. Repeated systemic injections of cocaine (20 mg/kg/day, i.p.) for seven consecutive days increased the number of 50-kHz USV calls. Intra-NAc core infusion of the broad-glutamate receptor antagonist, γDGG (50 nmol/side), decreased the repeated cocaine-induced increase in the number of 50-kHz USV calls. Intra-NAc core infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist, MK801 (2nmol/side), but not α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kainic acid receptor antagonist, CNQX disodium salt (2nmol/side), decreased the number of 50-kHz USV calls that had been elevated by repeated exposure to cocaine. Intra-NAc core infusion of the group I metabotropic glutamate receptor subtype 5 (mGluR5), MPEP (0.5nmol/side), MTEP (15 nmol/side) and inositol-1,4,5-trisphosphate receptor blocker, xestospongin C (0.004 nmol/side) decreased the cocaine-induced increase in the number of USV calls. These data suggest that the NMDA receptor- and mGluR5-dependent increase in intracellular Ca2+ concentrations in the NAc core is linked to a positive emotional state after repeated exposure to cocaine in rats.

Ontogenetic Oxycodone Exposure Affects Early Life Communicative Behaviors, Sensorimotor Reflexes, and Weight Trajectory in Mice.

Nationwide, opioid misuse among pregnant women has risen four-fold from 1999 to 2014, with commensurate increase in neonates hospitalized for neonatal abstinence syndrome (NAS). NAS occurs when a fetus exposed to opioids in utero goes into rapid withdrawal after birth. NAS treatment via continued post-natal opioid exposure has been suggested to worsen neurodevelopmental outcomes. We developed a novel model to characterize the impact of in utero and prolonged post-natal oxycodone (Oxy) exposure on early behavior and development. Via subcutaneous pump implanted before breeding, C57BL/6J dams were infused with Oxy at 10 mg/kg/day from conception through pup-weaning. At birth, in utero oxy-exposed pups were either cross-fostered (paired with non-Oxy exposed dams) to model opioid abstinence (in utero Oxy) or reared by their biological dams still receiving Oxy to model continued post-natal opioid exposure (prolonged Oxy). Offspring from vehicle-exposed dams served as cross-fostered (in utero Veh) or biologically reared (prolonged Veh) controls. In utero Oxy exposure resulted in sex-dependent weight reductions and altered spectrotemporal features of isolation-induced ultrasonic vocalization (USV). Meanwhile, prolonged Oxy pups exhibited reduced weight and sex-differential delays in righting reflex. Specifically, prolonged Oxy female offspring exhibited increased latency to righting. Prolonged Oxy pups also showed decreases in number of USV calls and changes to spectrotemporal USV features. Overall, ontogenetic Oxy exposure was associated with impaired attainment of gross and sensorimotor milestones, as well as alterations in communication and affective behaviors, indicating a need for therapeutic interventions. The model developed here will enable studies of withdrawal physiology and opioid-mediated mechanisms underlying these neurodevelopmental deficits.

Lactobacillus reuteri effects on maternal separation stress in newborn mice.

Probiotic Lactobacillus reuteri DSM 17938 (LR 17938) is beneficial to infants with colic. To understand its mechanism of action, we assessed ultrasonic vocalizations (USV) and brain pain/stress genes in newborn mice exposed to maternal separation stress. Pups were exposed to unpredictable maternal separation (MSU or SEP) or MSU combined with unpredictable maternal stress (MSU + MSUS or S + S), from postnatal days 5 to 14. USV calls and pain/stress/neuroinflammation-related genes in the brain were analyzed. We defined 10 different neonatal call patterns, none of which increased after MSU. Stress reduced overall USV calls. Orally feeding LR 17938 also did not change USV calls after MSU. However, LR 17938 markedly increased vocalizations in mice allowed to stay with their dams. Even though LR 17938 did not change MSU-related calls, LR 17938 modulated brain genes related to stress and pain. Up-regulatedgenes following LR 17938 treatment were opioid peptides, kappa-opioid receptor 1 genes, and CD200, important in anti-inflammatory signaling. LR 17938 down-regulated CCR2 transcripts, a chemokine receptor, in the stressed neonatal brain. USV calls in newborn mice are interpreted as "physiological calls" instead of "cries." Feeding LR 17938 after MSU did not change USV calls but modulated cerebral genes favoring pain and stress reduction and anti-inflammatory signaling. We defined mouse ultrasonic vocalization (USV) call patterns in this study, which will be important in guiding future studies in other mouse strains. Newborn mice with maternal separation stress have reduced USVs, compared to newborn mice without stress, indicating USV calls may represent "physiological calling" instead of "crying." Oral feeding of probiotic Lactobacillus reuteri DSM 17938 raised the number of calls when newborn mice continued to suckle on their dams, but not when mice were under stress. The probiotic bacteria had a dampening effect on monocyte activation and on epinephrine and glutamate-related stress gene expression in the mouse brain.

Selection on ultrasonic call rate in neonatal rats affects low frequency, but not ultrasonic, vocalizations in adults

AbstractIn this experiment, we studied a rodent model selected over 57 generations for high or low rates of ultrasonic vocalizations (USVs) during maternal separation as pups. We investigated the influence of this breeding on the adult animals’ subsequent vocal output, comparing acoustic variables across developmental stages. We hypothesized that selection on pup USV rate would impact adult USV production without affecting lower frequency calls. Contrary to this hypothesis, we found neither number of USV calls or other acoustic variables to differ among selected adult lines. Instead, we found that pup USV selection mainly affected adults’ low‐frequency (human‐audible) calls. Furthermore, low‐frequency vocalizations did not fully fit a predicted correlation between body weight and fundamental frequency: high line males, although the heaviest on average, did not produce the lowest fundamental frequencies. Our findings suggest that selection for early ultrasonic vocal behaviour pleiotropically results in changes in anatomical production mechanisms and/or neural control affecting low‐frequency calls.

Rapid development of mature vocal patterns of ultrasonic calls in a fast-growing rodent, the yellow steppe lemming (Eolagurus luteus).

Ultrasonic vocalizations (USV) of laboratory rodents may serve as age-dependent indicators of emotional arousal and anxiety. Fast-growing Arvicolinae rodent species might be advantageous wild-type animal models for behavioural and medical research related to USV ontogeny. For the yellow steppe lemming Eolagurus luteus, only audible calls of adults were previously described. This study provides categorization and spectrographic analyses of 1176 USV calls emitted by 120 individual yellow steppe lemmings at 12 age classes, from birth to breeding adults over 90 days (d) of age, 10 individuals per age class, up to 10 USV calls per individual. The USV calls emerged since 1st day of pup life and occurred at all 12 age classes and in both sexes. The unified 2-min isolation procedure on an unfamiliar territory was equally applicable for inducing USV calls at all age classes. Rapid physical growth (1 g body weight gain per day from birth to 40 d of age) and the early (9–12 d) eyes opening correlated with the early (9–12 d) emergence of mature vocal patterns of USV calls. The mature vocal patterns included a prominent shift in percentages of chevron and upward contours of fundamental frequency (f0) and the changes in the acoustic variables of USV calls. Call duration was the longest at 1–4 d, significantly shorter at 9–12 d and did not between 9-12-d and older age classes. The maximum fundamental frequency (f0max) decreased with increase of age class, from about 50 kHz in neonates to about 40 kHz in adults. These ontogenetic pathways of USV duration and f0max (towards shorter and lower-frequency USV calls) were reminiscent of those in laboratory mice Mus musculus.

Longitudinal analysis of ultrasonic vocalizations in mice from infancy to adolescence: Insights into the vocal repertoire of three wild-type strains in two different social contexts.

Ultrasonic vocalizations (USV) are emitted by mice under certain developmental, social and behavioral conditions. The analysis of USV can be used as a reliable measure of the general affective state, for testing the efficacy of pharmacological compounds and for investigating communication in mutant mice with predicted social or communication deficits. Social and communication studies in mice have focused mainly on the investigation of USV emitted by neonatal pups after separation from the dam and during social interaction between adult males and females. Longitudinal USV analysis among the different developmental states remained uninvestigated. In our study, we first recorded USV from three inbred mouse strains C57BL/6N, DBA/2 and FVB/N during the neonatal stages after separation from the littermates and then during a reunion with one littermate. Our results revealed significant strain-specific differences in the numbers and categories of USV calls. In addition, the USV profiles seemed to be sensitive to small developmental progress during infancy. By following these mice to the adolescent stage and measuring USV in the three-chamber social test, we found that USV profiles still showed significant differences between these strains in the different trials of the test. To study the effects of social context on USV characteristics, we measured USV emitted by another cohort of adolescent mice during the direct social interaction test. To this end, this study provides a strategy for evaluating novel mouse mutants in behavioral questions relevant to disorders with deficits in communication and sociability and emphasizes the important contribution of genetics and experimental contexts on the behavioral outcome.

Ultrasonic vocalization of pup and adult fat-tailed gerbils (Pachyuromys duprasi).

Ultrasonic vocalizations (USVs) of laboratory rodents indicate animal emotional arousal and may serve as models of human disorders. We analysed spectrographically USV calls of pup and adult fat-tailed gerbils Pachyuromys duprasi during 420-s tests, including isolation, touch and handling. Based on combination of six different USV syllable contour shapes and six different note compositions, we classified 782 USV syllables of 24 pups aged 5–10 days to 18 types and 232 syllables of 7 adults to 24 types. Pups and adults shared 16 of these 26 USV types. Percentages of USV syllables with certain contour shapes differed between pups and adults. The contour shape and note composition significantly affected most acoustic variables of USV syllables in either pups or adults. The 1-note USV syllables were most common in either pups or adults. Pup USV syllables were overall longer and higher-frequency than adult ones, reminiscent of the USV ontogenetic pathway of bats and distinctive to rats and mice. We discuss that the USV syllable types of fat-tailed gerbils were generally similar in contour shapes and note compositions with USV syllable types of mice and rats, what means that software developed for automated classifying of mice ultrasound might be easily adapted or re-tuned to gerbil USV calls. However, using fat-tailed gerbils as model for biomedical research including control of USV vocalization is only possible since 6th day of pup life, because of the delayed emergence of USV calls in ontogeny of this species.

New Insights from 22-kHz Ultrasonic Vocalizations to Characterize Fear Responses: Relationship with Respiration and Brain Oscillatory Dynamics.

Fear behavior depends on interactions between the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA), and the expression of fear involves synchronized activity in θ and γ oscillatory activities. In addition, freezing, the most classical measure of fear response in rodents, temporally coincides with the development of sustained 4-Hz oscillations in prefrontal-amygdala circuits. Interestingly, these oscillations were recently shown to depend on the animal's respiratory rhythm, supporting the growing body of evidence pinpointing the influence of nasal breathing on brain rhythms. During fearful states, rats also emit 22-kHz ultrasonic vocalizations (USVs) which drastically affect respiratory rhythm. However, the relationship between 22-kHz USV, respiration, and brain oscillatory activities is still unknown. Yet such information is crucial for a comprehensive understanding of how the different components of fear response collectively modulate rat's brain neural dynamics. Here, we trained male rats in an odor fear conditioning task, while recording simultaneously local field potentials (LFPs) in BLA, mPFC, and olfactory piriform cortex (PIR), together with USV calls and respiration. We show that USV calls coincide with an increase in delta and gamma power and a decrease in theta power. In addition, during USV emission in contrast to silent freezing, there is no coupling between respiratory rate and delta frequency, and the modulation of fast oscillations amplitude relative to the phase of respiration is modified. We propose that sequences of USV calls could result in a differential gating of information within the network of structures sustaining fear behavior, thus potentially modulating fear expression/memory.

Functional clustering of mouse ultrasonic vocalization data.

Mouse ultrasonic vocalizations (USVs) are studied in many fields of science. However, various noise and varied USV patterns in observed signals make complete automatic analysis difficult. We improve several methods to reduce noise, detect USV calls and automatically cluster USV calls. After reduction of noise and detection of USV calls, we consider USV calls as functional data and characterize them as USV functions with B-spline basis functions. For discontinuous USV calls, breakpoints in the USV functions are defined using multiple knots in the construction of the B-spline basis functions, and a hierarchical method is used to cluster the USV functions by shape. We finally show the performance of the proposed methods with USV data recorded for laboratory mice.

Diazepam blocks 50kHz ultrasonic vocalizations and stereotypies but not the increase in locomotor activity induced in rats by amphetamine.

We have recently shown that the benzodiazepine diazepam inhibits dopamine release in the NAc and blocks the increased release of dopamine induced by DL-amphetamine. Rewarding stimuli and many drugs of abuse can induce dopamine release in the nucleus accumbens as well as 50-kHz ultrasonic vocalizations (USVs) in rats. In the present study, we tested the hypothesis that diazepam can also block the increase in locomotor activity and USVs elicited by amphetamine. Fifty-kilohertz USVs, stereotypy, and locomotor behavior were scored in adult male Wistar rats treated with i.p. injections of saline, 3mg/kg DL-amphetamine, 2mg/kg diazepam, 0.2mg/kg haloperidol, or a combination of these drugs. In agreement with previous studies, amphetamine caused significant increases in the number of USV calls, stereotypies, and locomotor activity. The D2 dopamine receptor antagonist haloperidol blocked the effects of amphetamine on USVs, stereotypy, and locomotor activity. Diazepam blocked the effect of amphetamine on USV and stereotypy, but not on horizontal locomotion. These results suggest that diazepam blocks the rewarding effect of amphetamine. This finding is promising for basic research regarding treatments of substance use disorders and evaluation of the impact of benzodiazepines on motivation.

Genetic tagging of active neurons in auditory cortex reveals maternal plasticity of coding ultrasonic vocalizations

Cortical neurons are often functionally heterogeneous even for molecularly defined subtypes. In sensory cortices, physiological responses to natural stimuli can be sparse and vary widely even for neighboring neurons. It is thus difficult to parse out circuits that encode specific stimuli for further experimentation. Here, we report the development of a Cre-reporter mouse that allows recombination for cellular labeling and genetic manipulation, and use it with an activity-dependent Fos-CreERT2 driver to identify functionally active circuits in the auditory cortex. In vivo targeted patch recordings validate our method for neurons responding to physiologically relevant natural sounds such as pup wriggling calls and ultrasonic vocalizations (USVs). Using this system to investigate cortical responses in postpartum mothers, we find a transient recruitment of neurons highly responsive to USVs. This subpopulation of neurons has distinct physiological properties that improve the coding efficiency for pup USV calls, implicating it as a unique signature in parental plasticity.

The function of ultrasonic vocalizations during territorial defence by pair-bonded male and female California mice

Acoustic communication is vital to complex social behaviours such as territorial defence. The use of ultrasonic vocalizations, particularly in territorial defence by monogamous species and females, remains understudied. We studied ultrasonic vocalization production and associated aggression in the monogamous, biparental and territorial California mouse, Peromyscus californicus, in which both males and females were found to display similar levels of physical aggression against same-sex intruders. We identified specific ultrasonic vocalization calls that are modulated based on social context: (1) sustained vocalizations, which are long, low-bandwidth calls ranging from 22 to 25 kHz, and (2) barks, which are short, high-intensity calls beginning and ending in the audible range. Despite similarities in physical aggression, sex differences emerged in vocal communication. Only resident males, and not females, produced sustained vocalizations prior to the onset of physical aggression, and were found to shorten the duration of individual sustained vocalization calls over both the course of the pre-encounter phase and from the pre-encounter to encounter phase. In addition, the degree of sustained vocalization shortening in males predicted offensive aggression of the resident. Males exhibited shorter sustained vocalization calls during encounters than females. Barks occurred more frequently during female–female physical aggression than in male–male encounters, and correlated highly with defensive aggression by intruders. Finally, a newly identified highly complex call, sweep phrases, was recorded in a subset of both sexes in the pre- and post-encounter phases. The overall results indicate that ultrasonic vocalizations may play an important role in territorial defence during both territorial advertisement and aggression in a monogamous rodent. Overall, this monogamous species showed sex similarities in physical aggression but sex differences in vocal communication and a more sophisticated function for sustained vocalizations than previously recognized.

Altered ultrasonic vocalization in neonatal SAPAP3-deficient mice.

Ultrasonic vocalizations (USVs) in neonatal mice provide a means of modeling communication deficits in neurodevelopmental disorders. Mature mice deficient in SAP90/PSD95-associated protein 3 (SAPAP3) display compulsive grooming and anxiety-like behavior, conditions that are often associated with neurodevelopmental disorders. To date, however, aspects of neurodevelopment have not been investigated in SAPAP3-deficient mice. Here, we examined whether neonatal SAPAP3-deficient mice display altered USVs. We recorded USVs from 5-day-old sapap3 and sapap3 mice, and also monitored developmental reflexes in these mice during the early postnatal period. Sapap3 mice display an increase in the number and duration of USV calls relative to sapap3 littermates, despite otherwise similar developmental profiles. Thus, SAPAP3, previously well-characterized for its role in compulsive grooming, also plays a heretofore unidentified role in neonatal communication. Aberrant social communication and compulsive behavior are core symptoms of autism spectrum disorders, and these results show that SAPAP3-deficient mice may serve to model some aspects of these conditions.

The effects of long-term estradiol treatment on social behavior and gene expression in adult female rats

This study tested the effects of long-term estradiol (E2) replacement on social behavior and gene expression in brain nuclei involved in the regulation of these social behaviors in adult female rats. We developed an ultrasonic vocalization (USV) test and a sociability test to examine communications, social interactions, and social preference, using young adult female cagemates. All rats were ovariectomized (OVX) and implanted with a Silastic capsule containing E2 or vehicle, and housed in same-treatment pairs for a 3-month period. Then, rats were behaviorally tested, euthanized, and 5 nuclei in the brain's social decision-making circuit were selected for neuromolecular profiling by a multiplex qPCR method. Our novel USV test proved to be a robust tool to measure numbers and types of calls emitted by cagemates that had been reintroduced after a 1-week separation. Results also showed that E2-treated OVX rats had profoundly decreased numbers of USV calls compared to vehicle-treated OVX rats. In a test of sociability, in which a female was allowed to choose between her cagemate or a same-treatment novel rat, we found few effects of E2 compared to vehicle, although interestingly, rats chose the cagemate over an unfamiliar conspecific. Gene expression results revealed that the supraoptic nucleus had the greatest number of gene changes caused by E2: Oxt, Oxtr and Avp were increased, and Drd2, Htr1a, Grin2b, and Gabbr1 were decreased, by E2. No genes were affected in the prefrontal cortex, and 1–4 genes were changed in paraventricular nucleus (Pgr), bed nucleus of the stria terminalis (Oxtr, Esr2, Dnmt3a), and medial amygdala (Oxtr, Ar, Foxp1, Tac3). Thus, E2 changes communicative interactions between adult female rats, together with selected expression of genes in the brain, especially in the supraoptic nucleus.

Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia.

Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of Akt1-deficiency and Nrg1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male Akt1+/−, Nrg1+/−, and double mutant mice were bred and compared with their wild-type (WT) littermate controls. In Experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In Experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating function. However, both Nrg1+/− and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between Akt1 and Nrg1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and Nrg1+/− mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of Akt1 and Nrg1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition.