Selective oxytocin receptor activation prevents prefrontal circuit dysfunction and social behavioral alterations in response to chronic prefrontal cortex activation in male rats

IntroductionSocial behavioral changes are a hallmark of several neurodevelopmental and neuropsychiatric conditions, nevertheless the underlying neural substrates of such dysfunction remain poorly understood. Building evidence points to the prefrontal cortex (PFC) as one of the key brain regions that orchestrates social behavior. We used this concept with the aim to develop a translational rat model of social-circuit dysfunction, the chronic PFC activation model (CPA).MethodsChemogenetic designer receptor hM3Dq was used to induce chronic activation of the PFC over 10 days, and the behavioral and electrophysiological signatures of prolonged PFC hyperactivity were evaluated. To test the sensitivity of this model to pharmacological interventions on longer timescales, and validate its translational potential, the rats were treated with our novel highly selective oxytocin receptor (OXTR) agonist RO6958375, which is not activating the related vasopressin V1a receptor.ResultsCPA rats showed reduced sociability in the three-chamber sociability test, and a concomitant decrease in neuronal excitability and synaptic transmission within the PFC as measured by electrophysiological recordings in acute slice preparation. Sub-chronic treatment with a low dose of the novel OXTR agonist following CPA interferes with the emergence of PFC circuit dysfunction, abnormal social behavior and specific transcriptomic changes.DiscussionThese results demonstrate that sustained PFC hyperactivity modifies circuit characteristics and social behaviors in ways that can be modulated by selective OXTR activation and that this model may be used to understand the circuit recruitment of prosocial therapies in drug discovery

Reproducibility via coordinated standardization:A multi-center study in a Shank2 genetic rat model for Autism Spectrum Disorders

Inconsistent findings between laboratories are hampering scientific progress and are of increasing public concern. Differences in laboratory environment is a known factor contributing to poor reproducibility of findings between research sites, and well-controlled multisite efforts are an important next step to identify the relevant factors needed to reduce variation in study outcome between laboratories. Through harmonization of apparatus, test protocol, and aligned and non-aligned environmental variables, the present study shows that behavioral pharmacological responses in Shank2 knockout (KO) rats, a model of synaptic dysfunction relevant to autism spectrum disorders, were highly replicable across three research centers. All three sites reliably observed a hyperactive and repetitive behavioral phenotype in KO rats compared to their wild-type littermates as well as a dose-dependent phenotype attenuation following acute injections of a selective mGluR1 antagonist. These results show that reproducibility in preclinical studies can be obtained and emphasizes the need for high quality and rigorous methodologies in scientific research. Considering the observed external validity, the present study also suggests mGluR1 as potential target for the treatment of autism spectrum disorders

Measuring Behavior in the Home Cage : Study Design, Applications, Challenges, and Perspectives

FUNDING This research was supported by NIH grants R00AG056662, P20GM125528, AG057424 to WS and SLPeer reviewedPublisher PD

A time to remember : Consequences of ageing on the circadian memory modulation in rodents

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A time to remember : consequences of ageing on the circadian memory modulation in rodents

Dít proefschrift bevatstudies die zijn uitgevoerd in het kader van de NWO prioriteitenprogramma "Geheugenproces en dementie", en die tot doel hadden te onderzoeken hoe circadiane processen geheugenfunctie beinvloeden, en of veroudering deze interacties verandert. dissertaties ... Zie: Samenvatting

Apple Antioxidant Properties as an Effect of N Dose and Rate—Mycorrhization Involvement: A Long-Term Study

The genetic and/or the agronomic approaches are two main ways to enhance concentrations of biologically active compounds in fruits and vegetables. In this study, the apple antioxidant status was evaluated from the second to the fourth year after planting in relation to an increasing N-dose applied—with or without plant microbial inoculation in the field conditions. Cultivar ‘Šampion Arno’ was selected to test these relationships. In the growing season, N treatment and inoculation effects were monitored for the apple peel total phenolics and selected individual phenolic compounds ((+)-catechin, (−)-epicatechin, chlorogenic and caffeic acids, rutin and phloridzin) and total ascorbate concentration. Additionally, as an environmental stress marker measurement of glutathione reductase, ascorbate peroxidase and catalase activity were conducted. The year effect was most pronounced, while the N or applied inoculum effects were much weaker. Great differences in antioxidative enzyme activity and phenolic concentrations between years were revealed. Nitrogen fertilization reduced the fruit’s global phenolic accumulation compared to the control, but the N-effect varied depending on individual phenolic compounds, N dose and N application method. None of the tested factors influenced the ascorbate concentration. There was a certain tendency to increase antioxidant properties in the control group (without mineral N fertilization) but with the application of bio-fertilizer, which may seem promising for future research in this scope

Distinct Defects in Synaptic Differentiation of Neocortical Neurons in Response to Prenatal Valproate Exposure

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders characterized by impairments in social interactions and stereotyped behaviors. Valproic acid (VPA) is frequently used to treat epilepsy and bipolar disorders. When taken during pregnancy, VPA increases the risk of the unborn child to develop an ASD. In rodents, in utero VPA exposure can precipitate behavioral phenotypes related to ASD in the offspring. Therefore, such rodent models may allow for identification of synaptic pathophysiology underlying ASD risk. Here, we systematically probed alterations in synaptic proteins that might contribute to autism-related behavior in the offspring of in utero VPA-exposed mice. Moreover, we tested whether direct VPA exposure of cultured neocortical neurons may recapitulate the molecular alterations seen in vivo. VPA-exposed neurons in culture exhibit a significant increase in the number of glutamatergic synapses accompanied by a significant decrease in the number of GABAergic synapses. This shift in excitatory/inhibitory balance results in substantially increased spontaneous activity in neuronal networks arising from VPA-exposed neurons. Pharmacological experiments demonstrate that the alterations in GABAergic and glutamatergic synaptic proteins and structures are largely caused by inhibition of histone deacetylases. Therefore, our study highlights an epigenetic mechanism underlying the synaptic pathophysiology in this ASD model