Neuroscience
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Social withdrawal is associated with a variety of neuropsychiatric disorders, including neurodevelopmental disorders. Rodent studies provide the opportunity to study neurobiological mechanisms underlying social withdrawal, however, homologous paradigms to increase translatability of social behaviour between human and animal observation are needed. Standard behavioural rodent assays have limited ethological validity in terms of number of interaction partners, type of behaviour, duration of observation and environmental conditions. ⋯ Results from both laboratories confirmed previous findings of reduced social interaction in BTBR mice revealing a high level of reproducibility for this mouse phenotype using longitudinal colony assessments. In addition, we showed that detector settings contribute to laboratory specific findings as part of the behavioural data analysis procedure. Our cross-site study demonstrates reproducibility and robustness of reduced social interaction in BTBR mice using automated analysis in an ethologically relevant context.
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Autism is a complex spectrum of disorders characterized by core behavioral deficits in social communicative behavior, which are also required for comprehensive analysis of preclinical mouse models. As animal models of the core behavioral deficits in autism, two inbred mouse strains, BTBR T+ Itpr3tf/J (BTBR) and BALB/cJ (BALB), were compared with the standard social strain, C57BL/6J (B6), regarding a variety of behavioral factors underlying social communicative interactions, including olfactory and tactile sensory processes, social recognition abilities and behavioral expression strategies. Although both female BTBR and BALB mice can express social recognition and approach behavior depending on the stimuli they encounter, the available sensory modalities, along with modulation of the serotonergic system, differ between the two strains. ⋯ Systemic injection of the serotonin (5-HT1A) agonist buspirone has little effect on these social deficits, suggesting a congenitally degraded serotonergic system in BALB mice. In contrast, BTBR mice exhibit impaired body coordination and social motivation-modified olfactory signals, which are relevant to a reduced social approach. A systemic injection of the 5-HT1A agonist restored these social deficits in BTBR mice, indicating that a downregulated serotonergic system is involved in the social deficits exhibited by BTBR mice.
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Central release of the neuropeptide oxytocin (OXT) modulates neural substrates involved in socio-affective behavior. This property has prompted research into the use of intranasal OXT administration as an adjunctive therapy for brain conditions characterized by social impairment, such as autism spectrum disorders (ASD). However, the neural circuitry and brain-wide functional networks recruited by intranasal OXT administration remain elusive. ⋯ Importantly, this connectional reconfiguration was accompanied by a paradoxical reduction in social interaction and communication in wild-type mice. Our results identify the network substrates engaged by exogenous OXT administration, and show that repeated OXT dosing leads to a substantial reconfiguration of brain-wide connectivity, entailing an aberrant functional coupling between cortico-limbic structures involved in socio-communicative and affective functions. Such divergent patterns of network connectivity might contribute to discrepant clinical findings involving acute or long-term OXT dosing in clinical populations.
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Prenatal viral/bacterial infections are considered risk factors for autism spectrum disorders (ASD) and rodent models of maternal immune activation (MIA) have been developed and extensively used in preclinical studies. Poly inosinic-cytidylic acid (Poly I:C) was injected in C57BL6/J dams to mimic a viral infection on gestational day 12.5; the experimental design includes 10/12 litters in each treatment group and data were analysed always considering the litter-effect; neonatal (spontaneous motor behaviour and ultrasonic vocalizations) and adult [open field, marble burying, social approach, fear conditioning, prepulse inhibition (PPI)] offspring of both sexes were tested. In vivo magnetic resonance imaging/spectroscopy (MRI-MRS) and high-performance liquid chromatography (HPLC) to quantify both aminoacid and/or neurotransmitter concentration in cortical and striatal regions were also carried out. ⋯ As a whole prenatal Poly I:C induced relevant long-term alterations in explorative-stereotyped motor responses and in sensory gating, sparing cognitive and social competences. When systematically assessing differences between male and female siblings within each litter, no significant sex differences were evident except for increased variability of four aminoacid levels in male brains. As a whole, prenatal Poly I:C paradigms appear to be a useful tool to investigate the profound and translationally-relevant effects of developmental immune activation on brain and behavioural development, not necessarily recapitulating the full ASD symptomatology.
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Neurodevelopmental disorders (NDDs) caused by aberrant brain growth and development are life-long, debilitating illnesses that markedly impair the quality of life. Animal models are a valuable tool for studying NDD pathobiology and therapies. ⋯ Here, we summarize experimental models of NDDs in zebrafish and highlight the growing translational significance of zebrafish NDD-related phenotypes. We also emphasize the need in further development of zebrafish models of NDDs to improve our understanding of their pathogenesis and therapeutic treatments.