Wildtype peers rescue social play and 50-kHz ultrasonic vocalization deficits in juvenile female Cacna1c heterozygous rats

BackgroundHealthy brain development depends on early social practices and experiences. The risk gene CACNA1C is implicated in numerous neuropsychiatric disorders, in which key characteristics include deficits in social functioning and communication. Recently, we reported sex-dependent impairments in social behavior and ultrasonic vocalizations (USV) in juvenile heterozygous Cacna1c+/− (HET) rats. Specifically, HET females displayed increases in rough-and-tumble play that eliminated the typically observed sex difference between male and female rats. Interestingly, female wild-type Cacna1c+/+ (WT) pairs also showed a similar increase in social play when housed with HET females, suggesting their behavior may be influenced by HET cage mates. This indicates that the genetic makeup of the social environment related to Cacna1c can influence social play, yet systematic studies are lacking.MethodsIn the present study, we housed juvenile females in MIXED- or SAME-genotype cages and tested them in a social play paradigm with a same- and opposite-genotype partner.ResultsThe results show that the early social environment and the genotype of the play partner influence social play and 50-kHz USV emission. Experience with a WT play partner appears necessary for HET females to show comparable levels of play and 50-kHz USV emission. Same-genotype HET pairs played less and emitted fewer 50-kHz USV than same-genotype WT or opposite-genotype pairs; however, we found that the decrease in social play and 50-kHz USV in HET pairs can be rescued by playing with a WT partner. The effect was particularly prominent when the first play partner was WT, as we found it increased play and 50-kHz USV emission in all subsequent interactions with ensuing partners.ConclusionThese findings suggest that the genetic makeup related to the social environment and/or social peers influences social play in Cacna1c+/− haploinsufficient rats. Specifically, our results show that WT peers can rescue behavior and communication alterations in Cacna1c female rats. Our findings have important implications because they show that the genetic makeup of the social environment can divulge phenotypic changes in genetic rat models of neuropsychiatric disorders

Rethinking psychopharmacotherapy: The role of treatment context and brain plasticity in antidepressant and antipsychotic interventions

AbstractEmerging evidence indicates that treatment context profoundly affects psychopharmacological interventions. We review the evidence for the interaction between drug application and the context in which the drug is given both in human and animal research. We found evidence for this interaction in the placebo response in clinical trials, in our evolving knowledge of pharmacological and environmental effects on neural plasticity, and in animal studies analyzing environmental influences on psychotropic drug effects. Experimental placebo research has revealed neurobiological trajectories of mechanisms such as patients’ treatment expectations and prior treatment experiences. Animal research confirmed that “enriched environments” support positive drug effects, while unfavorable environments (low sensory stimulation, low rates of social contacts) can even reverse the intended treatment outcome. Finally we provide recommendations for context conditions under which psychotropic drugs should be applied. Drug action should be steered by positive expectations, physical activity, and helpful social and physical environmental stimulation. Future drug trials should focus on fully controlling and optimizing such drug×environment interactions to improve trial sensitivity and treatment outcome

Beta-decay half-lives and beta-delayed neutron emission probabilities of nuclei in the region below A=110, relevant for the r-process

Measurements of the beta-decay properties of r-process nuclei below A=110 have been completed at the National Superconducting Cyclotron Laboratory, at Michigan State University. Beta-decay half-lives for Y-105, Zr-106,107 and Mo-111, along with beta-delayed neutron emission probabilities of Y-104, Mo-109,110 and upper limits for Y-105, Zr-103,104,105,106,107 and Mo-108,111 have been measured for the first time. Studies on the basis of the quasi-random phase approximation are used to analyze the ground-state deformation of these nuclei.Comment: 21 pages, 10 figures, article accepted for publication in Physical Review

Audible pain squeaks can mediate emotional contagion across pre-exposed rats with a potential effect of auto-conditioning

Footshock self-experience enhances rodents' reactions to the distress of others. Here, we tested one potential mechanism supporting this phenomenon, namely that animals auto-condition to their own pain squeaks during shock pre-exposure. In Experiment 1, shock pre-exposure increased freezing and 22 kHz distress vocalizations while animals listened to the audible pain-squeaks of others. In Experiment 2 and 3, to test the auto-conditioning theory, we weakened the noxious pre-exposure stimulus not to trigger pain squeaks, and compared pre-exposure protocols in which we paired it with squeak playback against unpaired control conditions. Although all animals later showed fear responses to squeak playbacks, these were weaker than following typical pre-exposure (Experiment 1) and not stronger following paired than unpaired pre-exposure. Experiment 1 thus demonstrates the relevance of audible pain squeaks in the transmission of distress but Experiment 2 and 3 highlight the difficulty to test auto-conditioning: stimuli weak enough to decouple pain experience from hearing self-emitted squeaks are too weak to trigger the experience-dependent increase in fear transmission that we aimed to study. Although our results do not contradict the auto-conditioning hypothesis, they fail to disentangle it from sensitization effects. Future studies could temporarily deafen animals during pre-exposure to further test this hypothesis.</p

Structure of A=138 isobars above the 132Sn core and the N-N interaction in the neutron-rich environment

Large basis untruncated shell model calculations have been done for the A=138 neutron -rich nuclei in the pi(gdsh) X nu(hfpi) valence space above the 132Sn core. Two (1+2) -body nuclear Hamiltonians, viz., realistic CWG and empirical SMPN in this model space have been used. Calculated ground state binding energies, level spectra and other spectroscopic properties have been compared with the available experimental data. Importance of untruncated shell model calculations in this model space has been pointed out. Shell model results for the very neutron rich Sn isotope (138Sn, N/Z=1.76) of astrophysical interest for which no spectroscopic information except beta -decay half life is available, have been presented. Shell structure and evolution of collectivity in the even-even A=138 isobars have been studied as a function of valence neutron and /or proton numbers. Calculations done for the first time, reproduce remarkably well the collective vibrational states in 138Te and 138Xe. Comparison of some of the important two-body matrix elements of the empirical SMPN, CW5082 and the realistic CWG interactions has been done. These matrix elements are important for ground state binding energies and low-lying spectra of nuclei in this region. Consideration of the predictability of the two interactions seems to suggest that, in order to incorporate the special features of the N-N interaction in such exotic n-rich environment above the 132Sn core, the use of local spectroscopic information from the region might be essential.Comment: 22 pages, 14 figure

Direct neutron capture of 48Ca at kT = 52 keV

The neutron capture cross section of 48Ca was measured relative to the known gold cross section at kT = 52 keV using the fast cyclic activation technique. The experiment was performed at the Van-de-Graaff accelerator, Universitaet Tuebingen. The new experimental result is in good agreement with a calculation using the direct capture model. The 1/v behaviour of the capture cross section at thermonuclear energies is confirmed, and the adopted reaction rate which is based on several previous experimental investigations remains unchanged.Comment: 9 pages (uses Revtex), 2 postscript figures, accepted for publication as Brief Report in Phys. Rev.

Selective laser ionization of N ≥\geq 82 indium isotopes: the new r-process nuclide 135^{135}In

Production yields and beta-decay half-lives of very neutron-rich indium isotopes were determined at CERN/ISOLDE using isobaric selectivity of a resonance-ionization laser ion-source. Beta-delayed neutron multiscaling measurements have yielded improved half-lives for 206(6)~ms $^{132}$In, 165(3)~ms $^{133}$In and 141(5)~ms $^{134}$In. With 92(10)~ms $^{135}$In, a new r-process nuclide has been identified which acts as an important `waiting-point' in the In isotopic chain for neutron densities in the range n$_n \simeq 10^{24}$--10$^{26}$ n/cm$^3$, where the r-matter flow has already passed the ${\rm A} \simeq 130$ abundance-peak region

Half Life of the Doubly-magic r-Process Nucleus 78Ni

Nuclei with magic numbers serve as important benchmarks in nuclear theory. In addition, neutron-rich nuclei play an important role in the astrophysical rapid neutron-capture process (r-process). 78Ni is the only doubly-magic nucleus that is also an important waiting point in the r-process, and serves as a major bottleneck in the synthesis of heavier elements. The half-life of 78Ni has been experimentally deduced for the first time at the Coupled Cyclotron Facility of the National Superconducting Cyclotron Laboratory at Michigan State University, and was found to be 110 (+100 -60) ms. In the same experiment, a first half-life was deduced for 77Ni of 128 (+27 -33) ms, and more precise half-lives were deduced for 75Ni and 76Ni of 344 (+20 -24) ms and 238 (+15 -18) ms respectively.Comment: 4 pages, 3 figure

Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome.

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am-/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3am+/p- paternal transmission cohort. We also discovered Ube3am-/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3am-/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3am+/p- did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS

Reduced Efficacy of d-Amphetamine and 3,4-Methylenedioxymethamphetamine in Inducing Hyperactivity in Mice Lacking the Postsynaptic Scaffolding Protein SHANK1

Genetic defects in the three SH3 and multiple ankyrin repeat domains (SHANK) genes (SHANK1, SHANK2, and SHANK3) are associated with multiple major neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BPD). Psychostimulant-induced hyperactivity is a commonly applied paradigm to assess behavioral phenotypes related to BPD and considered to be the gold standard for modeling mania-like elevated drive in mouse models. Therefore, the goal of our present study was to test whether Shank1 plays a role in the behavioral effects of psychostimulants and whether this is associated with genotype-dependent neurochemical alterations. To this aim, male and female null mutant Shank1-/- mice were treated with d-amphetamine (AMPH; 2.5 mg/kg) and 3,4-methylenedioxymethamphetamine (MDMA, commonly known as ecstasy; 20 mg/kg), and psychostimulant-induced hyperactivity was compared to heterozygous Shank1+/- and wildtype Shank1+/+ littermate controls. Results show that Shank1-/- mice display reduced psychostimulant-induced hyperactivity, although psychostimulants robustly stimulated locomotor activity in littermate controls. Shank1 deletion effects emerged throughout development, were particularly prominent in adulthood, and seen in response to both psychostimulants, i.e., AMPH and MDMA. Specifically, while AMPH-induced hyperactivity was reduced but still detectable in Shank1-/- mice, MDMA-induced hyperactivity was robustly blocked and completely absent in Shank1-/- mice. Reduced efficacy of psychostimulants to stimulate hyperactivity in Shank1-/- mice might be associated with alterations in the neurochemical architecture in prefrontal cortex, nucleus accumbens, and hypothalamus. Our observation that psychostimulant-induced hyperactivity is reduced rather than enhanced in Shank1-/- mice clearly speaks against a behavioral phenotype with relevance to BPD. Lack of BPD-like phenotype is consistent with currently available human data linking mutations in SHANK2 and SHANK3 but not SHANK1 to BPD