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The risk gene CACNA1C is strongly implicated in the etiology of all major psychiatric disorders, such as depressive disorder, bipolar disorder, autism spectrum disorder, and schizophrenia. These disorders feature high levels of comorbidity and share an overlap of symptoms; in particular, deficits in social functioning are common. Intriguingly, sex-dependent effects of CACNA1C single nucleotide polymorphisms on prevalence, health outcomes, and psychological traits have been reported, typically suggesting that women are more affected by CACNA1C mutations than men. In rodents, genetic modifications specifically targeting Cacna1c have repeatedly been linked to deficits in social behavior in male mice and rats but many studies neglect the sex-dependent effects observed in humans. Our study focused on the role of Cacna1c in regulating social behavior and communication in adult female rats. We compared social and non-social behavior together with concomitant emission of pro-social 50-kHz ultrasonic vocalizations (USV) associated with positive affect in constitutive heterozygous (Cacna1c+/-) rats to wildtype (Cacna1c+/+) littermate controls. Our results indicate that partial Cacna1c depletion leads to strongly reduced emission of 50-kHz USV and mild social deficits during female direct reciprocal social interaction. Detailed temporal analyses revealed most prominent reductions of 50-kHz USV during non-social behavior, suggesting that reduced positive affect occurs in a social context in Cacna1c+/- rats but is not specifically linked to social behavior. Finally, we observed increased self-grooming behavior in Cacna1c+/- rats, consistent with an autism-like phenotype. Our findings in rats thus support a role of Cacna1c in regulating behavioral phenotypes with relevance for several neuropsychiatric disorders.

Mania is characterized by elevated drive and mood but animal models of mania have often neglected elevated mood. Ultrasonic vocalizations (USV) of 50-kHz emitted by rats are thought to index the subject's positive affective state. Fifty-kHz USV emission is increased by amphetamine, an effect blocked by lithium administration. Sleep deprivation (SD) is an environmental model of mania and the present study evaluated SD effects on behavioral activity and USV emission, together with the impact of lithium treatment. Adult rats were submitted to 24h or 72h SD, and locomotor activity and USV emission were assessed. To test their sensitivity to a standard antimanic drug, these behavioral parameters were also evaluated after acute administration of lithium carbonate (25, 50 or 100 mg/kg, i.p.). Striatal monoamine content was measured post-mortem. SD (24h and 72h) led to increased locomotor activity, rearing behavior and 50-kHz USV emission, together with a change in the call profile characterized by an increase in the percentage of frequency-modulated 50-kHz USV, which may indicate the mania-like consequences of SD. Importantly, all SD effects were reverted by lithium administration. SD also led to a decrease in dopamine content in the ventral striatum, while increasing dopamine turnover. In conclusion, SD increased 50-kHz USV emission, an effect prevented by acute lithium administration. This suggests 50-kHz USV as a new marker for mania-like elevated mood, which shows construct validity (associated with increased dopaminergic tone), face validity (reflecting increased positive affect) and predictive validity (high sensitivity to lithium treatment).

Human genetics and genomics advances : HGG advances 3(2), 100093 (2022). doi:10.1016/j.xhgg.2022.100093, Published by Cell Press, Cambridge, Ma.

The CACNA1C gene is strongly implicated in the etiology of multiple major neuropsychiatric disorders, such as bipolar disorder, major depression, and schizophrenia, with cognitive deficits being a common feature. It is unclear, however, by which mechanisms CACNA1C variants advance the risk of developing neuropsychiatric disorders. This study set out to investigate cognitive functioning in a newly developed genetic Cacna1c rat model. Specifically, spatial and reversal learning, as well as object recognition memory were assessed in heterozygous Cacna1c +/− rats and compared to wildtype Cacna1c +/+ littermate controls in both sexes. Our results show that both Cacna1c +/+ and Cacna1c +/− animals were able to learn the rewarded arm configuration of a radial maze over the course of seven days. Both groups also showed reversal learning patterns indicative of intact abilities. In females, genotype differences were evident in the initial spatial learning phase, with Cacna1c +/− females showing hypo-activity and fewer mixed errors. In males, a difference was found during probe trials for both learning phases, with Cacna1c +/− rats displaying better distinction between previously baited and non-baited arms; and regarding cognitive flexibility in favor of the Cacna1c +/+ animals. All experimental groups proved to be sensitive to reward magnitude and fully able to distinguish between novel and familiar objects in the novel object recognition task. Taken together, these results indicate that Cacna1c haploinsufficiency has a minor, but positive impact on (spatial) memory functions in rats.

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders, characterized by early-onset deficits in social behavior and communication across multiple contexts, together with restricted, repetitive patterns of behavior, interests, or activities. ASD is among the most heritable neuropsychiatric conditions with heritability estimates higher than 80%, and while available evidence points to a complex set of genetic factors, the SHANK (also known as ProSAP) gene family has emerged as one of the most promising candidates. Several genetic Shank mouse models for ASD were generated, including Shank1 knockout mice. Behavioral studies focusing on the Shank1 knockout mouse model for ASD included assays for detecting ASD-relevant behavioral phenotypes in the following domains: (I) social behavior, (II) communication, and (III) repetitive and stereotyped patterns of behavior. In addition, assays for detecting behavioral phenotypes with relevance to comorbidities in ASD were performed, including but not limited to (IV) cognitive functioning. Here, we summarize and discuss behavioral and neuronal findings obtained in the Shank1 knockout mouse model for ASD. We identify open research questions by comparing such findings with the symptoms present in humans diagnosed with ASD and carrying SHANK1 deletions. We conclude by discussing the implications of the behavioral and neuronal phenotypes displayed by the Shank1 knockout mouse model for the development of future pharmacological interventions in ASD.

Parkinson’s disease is a chronic neurodegenerative disorder characterized by cardinal motor features, such as bradykinesia , but also vocal deficits (e.g. difficulties to articulate words and to keep the tone of voice) and depression. In the present study, rats with bilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta were evaluated for changes in the emission of 50-kHz ultrasonic vocalizations , gait impairment (catwalk test), and depressive-like behaviour (sucrose preference test). Furthermore, we evaluated the effect of repeated treatment (28 days) with ketamine (5, 10, and 15 mg/kg, ip, once per week) or imipramine (15 mg/kg, ip, daily). The lesion had prominent effects on the production of 50-kHz ultrasonic vocalizations (reduced call numbers, call durations, total calling time, and increased latency to start calling), led to gait impairment (increased run duration and stand of right forelimb) and induced anhedonia (reduced sucrose preference). Also, significant correlations between gait changes, sucrose preference, and ultrasonic calling were found, yet, except for run duration and sucrose preference, these correlations were low indicating that these associations are weak. Importantly, ketamine and imipramine reversed lesion-induced anhedonia and improved gait impairments, but neither drug improved ultrasonic calling. In conclusion, the substantia nigra lesion with 6-hydroxydopamine induced subtle motor and non-motor manifestations, reflecting key features of the wide clinical spectrum of early Parkinson’s disease. Furthermore, the present results suggest a potential efficacy of ketamine on depression and gait alterations in Parkinson’s disease.

Drug-induced hyperlocomotion in rodents is frequently used as a behavioral model for mania. However, the use of locomotor activity as the single parameter in these animal models of mania may pose some limitations for developing new pharmacological treatments. Thus, alternative behavioral markers are required. Fifty-kHz ultrasonic vocalizations (USV), which are thought to represent positive affect, are increased by the administration of the psychostimulant d-amphetamine, an effect that can be prevented by lithium treatment, the gold standard antimanic drug for treating bipolar disorder. The aim of this study was to evaluate 50-kHz USV in two other pharmacological-induced animal models of mania: ketamine (KET)- and lisdexamfetamine (LDX)-induced hyperlocomotion. After systemic injection of LDX (10mg/kg, ip), racemic-ketamine (25mg/kg, ip) or S-ketamine (25mg/kg, ip), locomotor activity and 50-kHz USV emission were evaluated in rats. Furthermore, the effects of an antimanic treatment, namely lithium carbonate (100mg/kg, ip), on LDX-induced 50-kHz USV and hyperlocomotion were tested. Rats treated with racemic KET and S-KET showed increased locomotor activity, but these drug treatments did not significantly affect 50-kHz USV emission rates. On the other hand, LDX administration increased both locomotor activity and 50-kHz USV with both effects being reversed by lithium administration. The present findings suggest that 50-kHz USV can differentiate between drug-induced models of mania, which may represent different types of manic episodes. Thus, measuring 50-kHz USV might serve as an additional valuable behavioral variable to assess mania-like phenotypes in rat models.

In two human predictive learning experiments, we investigated the impact of adding or removing context components on extinction performance toward a cue. In each experiment, participants initially received repeated pairings of a cue and an outcome in a context composed of two distinctive components (context AB). Initial training was followed by a series of trials in which the cue was no longer followed by the outcome. This extinction treatment was conducted in the presence of a different pair of distinctive context components (context CD). During a final test, we observed that changing the extinction context CD disrupted extinction performance toward the cue regardless of whether the context was changed by adding or removing context components. We discuss implications of our results for theories of associative learning.

Horses are kept in various housing systems, for example, with conspecifics in horse pens or singly in horseboxes, with or without pasturing. To provide appropriate living conditions for horses, it is necessary to know in which conditions they feel well or unwell. Here, a cognitive bias assessment provides information about an individual's affective state and its well-being. When a positive affective state prevails, animals tend to judge optimistically in ambiguous situations. When a negative affective state prevails, animals judge pessimistically in unclear situations. In the present study, we trained horses on a spatial discrimination task and evaluated their judgment of ambiguous locations when they had access to pastures and contact to conspecifics versus when they were kept singly in horseboxes. Ten days of pasturing and contact with conspecifics after being kept singly in horseboxes for 6 months induced a positive cognitive bias in the horses. We suggest that horses need to act out certain behaviors like exploration, social interaction, play, or grooming to fulfill their needs. After a time in which they were individually in horseboxes without pasturing and access to the herd, they seem to have a positive cognitive bias once they have access to pastures and conspecifics. This positive cognitive bias effect seems to disappear over time, as horses appear to adapt to the circumstances.

Although the involvement of the neuropeptide arginine vasopressin (AVP) in rodent social interaction is already extensively characterized, little is known about its role in social communication. Rats communicate in the ultrasonic range by means of ultrasonic vocalizations (USV). Depending on developmental stage and affective state, rats emit various distinct types of USV, with appetitive 50-kHz USV being induced by positive social interactions, like juvenile social play, probably serving an affiliative communicative function, namely to (re)establish or induce social proximity. In rats and mice selectively bred for low (LAB) and high (HAB) anxiety-related behavior, the emission of isolation-induced distress USV during maternal deprivation as pups correlates with innate high levels of hypothalamic AVP availability. Moreover, male LAB and HAB rats express deficits in social approach towards conspecifics, together with high and/or abnormal forms of aggression when confronted with harmless opponents, possibly due to a lack of social communication skills. The aim of this study was therefore (1) to investigate and characterize social play behavior and concomitant pro-social 50-kHz USV emission in male and female, juvenile LAB and HAB rats and to compare them to non-selected Wistar (NAB) rats; and (2) to link these findings pharmacologically to the central AVP system via applying an AVP 1a receptor (V1aR) antagonist (0.75 μg; Manning compound) or synthetic AVP (1 ng) into the lateral ventricle of male juvenile NAB rats. Our results show that reduced social play behavior in highly anxious male and female, juvenile HAB rats is accompanied by low amounts of pro-social 50-kHz USV, as compared to respective LAB and NAB rats, possibly reflecting a lack of positive affective states in expectation of or following social interactions in these individuals. Secondly, although synthetic AVP did not alter social play behavior and pro-social 50-kHz USV, we demonstrated for the first time that a blockade of the central AVP system not only reduces juvenile social play behavior, but at the same time pro-social 50-kHz USV emission rates, indicating an involvement of the social neuropeptide in regulating affiliative communication in rodents.

Rats emit vocalizations in the ultrasonic range (ultrasonic vocalizations; USVs), of which 50-kHz USVs could communicate positive affective states and induce approach behavior in conspecifics, whereas 22-kHz USVs might signal negative affective states and potential threats. Listening to 50-kHz USVs can be rewarding, but it is unknown which brain mechanisms are responsible for the assignment of reinforcing value to 50-kHz USVs. The behavioral responses induced by listening to 22-kHz USVs are heterogeneous and need further characterization. The amygdala is a region relevant for social perception, behavior and reward. Here, we tested the hypothesis that the basolateral amygdala (BLA) plays a causal role in motivating behavioral responses to 50-kHz and 22-kHz USVs. Rats with lesions of the BLA or sham lesions were repeatedly exposed to playback of either 50-kHz or 22-kHz USVs in a radial maze. Compared to sham rats, BLA-lesioned rats spent less time in the arms close to the USV speaker during playback of both 50-kHz or 22-kHz USVs. This difference in behavior was not due to impaired motor or general auditory abilities, indicating that BLA lesions selectively reduced the responsiveness to stimuli with social significance. This finding provides further support for the hypothesis that the BLA plays an important role in motivating approach behavior to social reinforcers.

Background Autism spectrum disorder (ASD) is characterized by persistent deficits in social behavior and communication, together with restricted and repetitive patterns of behavior. Several ASD candidate genes have been identified, including the SHANK gene family with its three family members SHANK1 , SHANK2 , and SHANK3 . Methods Typically, repetitive behavior in mouse models for ASD is assessed by measuring self-grooming behavior. The first aim of the current study was to assess repetitive behaviors in Shank1 −/− null mutant, Shank1 +/− heterozygous, and Shank1 +/+ wildtype littermate control mice by means of a comprehensive approach, including the assessment of self-grooming, digging behavior, and marble burying. The second aim was to establish a test paradigm that allows for assessing the effects of social context on the occurrence of repetitive behaviors in a genotype-dependent manner. To this aim, repetitive behaviors were repeatedly tested on three consecutive days in distinct social contexts, namely in presence or absence of social odors. Results Shank1 +/− heterozygous and to a lesser extent Shank1 −/− null mutant mice displayed slightly elevated levels of self-grooming behavior as adults, but not as juveniles, with genotype differences being most prominent in the social context. In contrast to elevated self-grooming behavior, marble burying was strongly reduced in adult Shank1 +/− heterozygous and Shank1 −/− null mutant mice across social contexts, as compared to adult Shank1 +/+ wildtype littermate controls. Conclusion The opposite effects of the Shank1 deletion on the two types of repetitive behaviors are in line with a number of studies on repetitive behaviors in other genetic Shank models.

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

Maternal exposure to infection during pregnancy greatly increases the risk of psychopathology in the offspring. In support of clinical findings, rodent models of maternal immune activation (MIA) show that prenatal exposure to pathogens can induce phenotypic changes in the offspring associated with schizophrenia, autism, depression and anxiety. In the current study, we investigated the effects of MIA via polyinosinic:polycytidylic acid (poly I:C) on emotional behavior and communication in rats. Pregnant rats were administered poly I:C or saline on gestation day 15 and male offspring were tested in an auditory fear conditioning paradigm in early adulthood. We found that prenatal poly I:C exposure significantly altered affective signaling, namely, the production of aversive 22-kHz ultrasonic vocalizations (USVs), in terms of call number, structure and temporal patterning. MIA led to an increase in aversive 22-kHz USVs to 300% of saline controls. Offspring exposed to MIA not only emitted more 22-kHz USVs, but also emitted calls that were shorter in duration and occurred in bouts containing more calls. The production of appetitive 50-kHz USVs and audible calls was not affected. Intriguingly, alterations in aversive 22-kHz USV emission were observed despite no obvious changes in overt defensive behavior, which highlights the importance of assessing USVs as an additional measure of fear. Aversive 22-kHz USVs are a prominent part of the rat's defensive behavioral repertoire and serve important communicative functions, most notably as alarm calls. The observed changes in aversive 22-kHz USVs show that MIA has long-term effects on emotional behavior and communication in exposed rat offspring.

The neutron long counter NERO was built at the National Superconducting Cyclotron Laboratory (NSCL), Michigan State University, for measuring β -delayed neutron-emission probabilities. The detector was designed to work in conjunction with a β -delay implantation station, so that β decays and β -delayed neutrons emitted from implanted nuclei can be measured simultaneously. The high efficiency of about 40%, for the range of energies of interest, along with the small background, are crucial for measuring β -delayed neutron emission branchings for neutron-rich r-process nuclei produced as low intensity fragmentation beams in in-flight separator facilities.

Rats, Rattus norvegicus, produce 22 kHz ultrasonic vocalizations in aversive situations such as during exposure to cats or fear conditioning. These calls are considered to be part of the animal's defensive repertoire and might serve as alarm signals for conspecifics. The aim of the present study was to test whether the production of 22 kHz calls is affected by the social context during fear conditioning. Animals were tested in one of three experimental conditions: either alone, with an anaesthetized conspecific, or with an active conspecific. In line with the hypothesized alarming function of 22 kHz calls, we expected the presence of a conspecific to potentiate the production of 22 kHz calls. The results, however, show that the production of 22 kHz calls during fear conditioning is clearly not potentiated by the presence of a conspecific; if at all, its presence had a mild attenuating effect on call rate. Also, call characteristics were similar in all three experimental conditions. Therefore, our findings do not support the hypothesis that the sender actively produces 22 kHz calls to warn conspecifics about danger.

Observed neutron-capture elemental abundances in metal-poor stars, along with ongoing analysis of the extremely metal-poor Eu-enriched sub-class provide new guidance for astrophysical models aimed at finding the r-process sites. The present paper emphasizes the importance of nuclear physics parameters entering in these models, particularly β -decay properties of neutron-rich nuclei. In this context, several r-process motivated β -decay experiments performed at the National Superconducting Cyclotron Laboratory (NSCL) are presented, including a summary of results and impact on model calculations.

Rodent ultrasonic vocalizations, which serve as sensitive measures in a number of relevant individual and social behaviours, have become increasingly interesting for biopsychological studies on emotion and motivation. Of these, high frequency (50-kHz) ultrasonic vocalizations can index a positive emotional state, and induce approach, whereas low frequency (22-kHz) ultrasonic vocalizations can induce avoidance and may index anxiety, since they are emitted during various unconditioned and conditioned aversive situations. While cholinergic and dopaminergic systems have been implicated, specific neural substrates that sub-serve these vocalization-dependent states remain to be elucidated. Using c-fos immunocytochemistry, we revealed neural activity in brain areas of naïve male Wistar rats in response to playback of 22-kHz and flat and frequency-modulated 50-kHz ultrasonic vocalizations. Presentation of background noise or no acoustic stimulus at all constituted the controls. Playback of 50-kHz ultrasonic vocalizations led to approach behaviour. Acoustically stimulated animals demonstrated differential activation in auditory areas, with a frequency-dependent activation in the auditory cortex. Specific forebrain, thalamic, hypothalamic and brainstem areas were also activated differentially. While 50-kHz playback induced sparse fos-like immunoreactivity in frontal association cortex, nucleus accumbens, thalamic parafascicular and paraventricular nuclei, 22-kHz playback elicited c-fos expression in the perirhinal cortex, amygdalar nuclei and the periaqueductal gray. This study unveils neural substrates that are activated during ultrasonic playback perception, which could sub-serve the affective states elicited by these vocalizations.

Rats can emit ultrasonic 50-kHz vocalizations which are generally assumed to reflect the animals' positive emotional state. However, some aspects question the reliability of 50-kHz calls as indicators of positive affective states. Firstly, rats also emit them in novel environments containing scents of other rats, or even while being victims of intra-species aggression. Secondly, huge inter-individual variability in call production can be observed. The present two studies were conducted to further determine factors other than reward, which may influence or even induce calling. Experiment A showed that 50-kHz calls were emitted in relatively high numbers during short isolation in test cages, and, to a lesser extent, also during testing in an open field and an elevated plus maze. Despite inter-individual variability, calling behavior was individually stable over days and occurred irrespective of whether rats were tested in a cage with or without familiar rat scents. These data indicate that 50-kHz calling is not necessarily a response to the presence of pleasurable or social stimuli. Additionally, it was observed that call emission during isolation is strongly affected by prior experience. Rats that had been trained repeatedly in an appetitive discrimination task emitted only few calls during short isolation in test cages, whereas naïve rats emitted high numbers of 50-kHz calls which decreased over time. The most likely explanation is that rats call in response to separation from the cage mate, as the first group was trained before the recordings, while the naïve rats were recorded immediately after separation. This explanation was supported by Experiment B, which showed that the rats that remained alone in the home cage also called at 50 kHz after separation from the cage mates. In both experiments, most of the 50-kHz calls were not frequency modulated, which lend support for the suggestion that this subtype has a social-coordinating function. The present findings urge sophisticated spectrographic analysis of ultrasonic vocalizations and caution when interpreting 50-kHz vocalizations, since specific subtypes of these calls can occur in contexts that are not necessarily pleasurable to rats, and are affected by prior experience and huge individual differences.

We studied the low spin structure of 208Bi via γ – γ coincidence measurements using a sub-Coulomb 208Pb(p, n)208Bi reaction. This nucleus has one neutron hole and one proton particle relative to the doubly magic 208Pb and therefore its spectrum directly depends on the particle–hole interaction. The available data on 208Bi is re-evaluated using the data obtained in this measurement. Comparison of the measured energy levels with a shell model calculation with a realistic interaction is presented.