Assessing the developmental trajectory of mouse models of neurodevelopmental disorders: Social and communication deficits in mice with Neurexin 1α deletion

Neurexin 1α mutations are strongly associated with neurodevelopmental disorders such as autism spectrum disorders and schizophrenia in humans. Studies using the Neurexin 1α knock‐out mouse have showed behavioral abnormalities of relevance to these disorders and baseline deficits in excitatory synaptic function have been described. However, little is known about the effect of Neurexin 1α deletion on behavior during development. This study examined the effects of Neurexin 1α deletion on behavior across a range of developmental time points to determine whether potential abnormalities follow a developmental trajectory. Pups lacking Neurexin 1α emitted a reduced number of ultrasonic vocalizations early in development combined with a restricted repertoire of calls indicative of a loss in complexity in vocal production and showed delays in reaching certain developmental milestones. Behavioral testing showed that juvenile and adult male Neurexin 1α knock‐out mice exhibited social deficits and increased levels of aggression, confirming previous findings. No increases in repetitive behaviors or deficits in motor learning or olfaction were seen. In conclusion, this research showed that Neurexin 1α deletion does result in social and communication deficits that follow a developmental trajectory. These are the first experimental data that associate a deletion of Neurexin 1α with alterations in behaviors relevant to autism spectrum disorder across development and highlight the importance of assessing the developmental trajectory in mouse models of neurodevelopmental disorders.     

Interactions of glutamate and dopamine in a computational model of the striatum

A network model of simplified striatal principal neurons with mutual inhibition was used to investigate possible interactions between cortical glutamatergic and nigral dopaminergic afferents in the neostriatum. Glutamatergic and dopaminergic inputs were represented by an excitatory synaptic conductance and a slow membrane potassium conductance, respectively. Neuronal activity in the model was characterized by episodes of increased action potential firing rates of variable duration and frequency. Autocorrelation histograms constructed from the action potential activity of striatal model neurons showed that reducing peak excitatory conductance had the effect of increasing interspike intervals. On the other hand, the maximum value of the dopamine-sensitive potassium conductance was inversely related to the duration of firing episodes and the maximal firing rates. A smaller potassium conductance restored normal firing rates in the most active neurons at the expense of a larger proportion of neurons showing reduced activity. Thus, a homogeneous network with mutual inhibition can produce equally complex dynamics as have been proposed to occur in a striatal network with two neuron populations that are oppositely regulated by dopamine. Even without mutual inhibition it appears that increased dopamine concentrations could partially compensate for the effects of reduced glutamatergic input in individual neurons.     

Expanded characterization of the social interaction abnormalities in mice lacking Dvl1

Dvl1 is one of three murine Dishevelled genes widely expressed in embryonic development and in the adult central nervous system. Dishevelled proteins are a necessary component of the Wnt and planar cell polarity developmental signaling pathways. We reported previously that mice deficient in Dvl1 exhibited abnormal social interaction and sensorimotor gating. To assess the validity of our earlier findings, we replicated the previous behavioral tests and included several new assays. The behaviors assessed included: social interaction, sensorimotor reflexes, motor activity, nociception, prepulse inhibition of acoustic startle (PPI) and learning and memory. Assessments with an explicit social component included: social dominance test, whisker trimming, nest building, home-cage huddling and ultrasonic vocalization rate analysis in pups. In addition, separate cohorts of wildtype and Dvl1 -null mice were assessed for social recognition of a conspecific. Replicating the original report, Dvl1 -null mice were impaired in several tasks containing an explicit social component. However, no impairment was obser‐ ved in the social memory task. A previously observed deficit in PPI did not replicate in two institutions. In conclusion, we provide evidence that the social interaction phenotype of Dvl1 -deficient mice has a strong genetic influence, but the sensorimotor gating deficit was subject to environmental influences. The specificity of observed social interaction deficits also suggests that lack of Dvl1 is associated with deficits in the recognition of social hierarchy and dominance.     

Dopamine release is impaired in a mouse model of DYT1 dystonia

Early onset torsion dystonia, the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein torsinA. This form of dystonia is referred to as DYT1. We have used a transgenic mouse model of DYT1 dystonia [human mutant-type (hMT)1 mice] to examine the effect of the mutant human torsinA protein on striatal dopaminergic function. Analysis of striatal tissue dopamine (DA) and metabolites using HPLC revealed no difference between hMT1 mice and their non-transgenic littermates. Pre-synaptic DA transporters were studied using in vitro autoradiography with [(3)H]mazindol, a ligand for the membrane DA transporter, and [(3)H]dihydrotetrabenazine, a ligand for the vesicular monoamine transporter. No difference in the density of striatal DA transporter or vesicular monoamine transporter binding sites was observed. Post-synaptic receptors were studied using [(3)H]SCH-23390, a ligand for D(1) class receptors, [(3)H]YM-09151-2 and a ligand for D(2) class receptors. There were again no differences in the density of striatal binding sites for these ligands. Using in vivo microdialysis in awake animals, we studied basal as well as amphetamine-stimulated striatal extracellular DA levels. Basal extracellular DA levels were similar, but the response to amphetamine was markedly attenuated in the hMT1 mice compared with their non-transgenic littermates (253 +/- 71% vs. 561 +/- 132%, p < 0.05, two-way anova). These observations suggest that the mutation in the torsinA protein responsible for DYT1 dystonia may interfere with transport or release of DA, but does not alter pre-synaptic transporters or post-synaptic DA receptors. The defect in DA release as observed may contribute to the abnormalities in motor learning as previously documented in this transgenic mouse model, and may contribute to the clinical symptoms of the human disorder.     

Reduced scent marking and ultrasonic vocalizations in the BTBR T+tf/J mouse model of autism

Qualitative impairments in communication, such as delayed language and poor interactive communication skills, are fundamental to the diagnosis of autism. Investigations into social communication in adult BTBR T+tf/J (BTBR) mice are needed to determine whether this inbred strain incorporates phenotypes relevant to the second diagnostic symptom of autism, communication deficits, along with its strong behavioral phenotypes relevant to the first and third diagnostic symptoms, impairments in social interactions and high levels of repetitive behavior. The aim of the present study was to simultaneously measure female urine‐elicited scent marking and ultrasonic vocalizations in adult male BTBR mice, in comparison with a standard control strain with high sociability, C57BL/6J (B6), for the assessment of a potential communication deficit in BTBR. Adult male BTBR mice displayed lower scent marking and minimal ultrasonic vocalization responses to female urine obtained from both B6 and BTBR females. Lower scent marking and ultrasonic vocalizations in a social setting by BTBR, as compared with B6, are consistent with the well‐replicated social deficits in this inbred mouse strain. Our findings support the interpretation that BTBR incorporate communication deficits, and suggest that scent marking and ultrasonic vocalizations offer promising measures of interest in social cues that may be widely applicable to investigations of mouse models of autism.     

神农架川金丝猴投食群的社会行为谱

为探讨人工投食条件下川金丝猴的社会行为类型,2007年1月-2008年10月,采用行为取样法和全事件记录法对湖北神农架自然保护区投食猴群的社会行为进行观察。确定投食群有45种典型社会行为,其中打架、抢食、抱腰、吻背、爬伏、邀配与以往对笼养和野生川金丝猴的研究有差别。     

ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model

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Specific inhibition of nitric oxide synthases at different time points in a murine model of pulmonary sepsis

Excessive production of nitric oxide (NO) by NO synthase (NOS) and a subsequent oxidative stress reaction are thought to be critically involved in the pathophysiology of sepsis. Previous studies suggested that NO production by neuronal NOS (nNOS) and inducible NOS (iNOS) is implemented in the disease process at different time points after the injury. Here we tested the roles of selective pharmacological inhibition of nNOS and iNOS at different time points in a murine model of pulmonary sepsis. The injury was induced by intranasal administration of live Pseudomonas aeruginosa (3.2 × 10⁷ colony-forming units) in C57BL/6 wild-type mice. The animals received no treatment (control) or treatment with a specific nNOS inhibitor (4 or 8 h), iNOS inhibitor (4 or 8 h), or non-specific NOS inhibitor (4 or 8 h). In controls, the injury was associated with excessive releases of pro-inflammatory cytokines in the plasma, enhanced tissue lipid peroxidation, and decreased survival. Non-specific NOS inhibition at either time point did not influence survival and was not further investigated. While nNOS inhibition at 4 h was associated with a trend toward improved survival and significantly reduced contents of lung nitrite/nitrate (NO_x) and liver malondialdehyde, the blockade of nNOS at 8 h had no effect on these parameters. In contrast, early iNOS inhibition was associated with a trend toward decreased survival and no effects on lung NO_x and liver malondialdehyde contents, whereas later iNOS blockade was associated with decreased malondialdehyde content in liver homogenates. In conclusion, pulmonary sepsis in mice may be beneficially influenced by specific pharmacological nNOS inhibition at an earlier time point and iNOS inhibition at a later time points post-injury. Future investigations should identify the time changes of the expression and activation of NOS isoforms.     

Maternal and offspring methylenetetrahydrofolate‐reductase genotypes interact in a mouse model to induce autism spectrum disorder‐like behavior

Individuals with autism constitute a variable population whose members are spread along the autism spectrum. Subpopulations within that spectrum exhibit other conditions, such as anxiety, intellectual disabilities, hyperactivity and epilepsy, with different severities and co‐occurrences. Among the genes associated with the increased risk for autism is the methylenetetrahydrofolate‐reductase (MTHFR) 677C>T polymorphism, which impairs one‐carbon (C1) metabolic pathway efficiency. The frequency of the MTHFR677TT homozygote is markedly higher among autism patients and their mothers than in the general population. Here, we report on the Mthfr heterozygous knockout (KO) mouse as a rodent model of autism that shows the contributions of maternal and offspring genotypes to the development of autistic‐like behaviors. Maternal Mthfr‐deficiency was associated with developmental delays in morphogenic features and sensory‐motor reflexes in offspring. In the adult male mouse, behaviors representing core autism symptoms, such as repetitive behavior and restricted interest, were affected by maternal genotype while social behaviors were affected by both maternal and offspring genotypes. In females and males, behaviors associated with autism such as memory impairment, social aggression and anxiety were affected by both the maternal and offspring Mthfr genotypes, with sex‐dependent differences. Mthfr‐deficient male mice with observable impacts on behavior presented a particular laminar disturbance in parvalbumin interneuron density and innervation in superficial and deep layers of the cingulate cortex. This mouse model of autism will help to elucidate the molecular mechanisms that predispose a significant subgroup of autistic patients to abnormal development and to distinguish between the in‐utero and autonomous factors involved in autism.     

Effects of advanced paternal age on trajectories of social behavior in offspring

Our study is the first investigation of the effects of advanced paternal age (APA) on the developmental trajectory of social behavior in rodent offspring. Given the strong epidemiological association between APA and sexually dimorphic neurodevelopmental disorders that are characterized by abnormalities in social behavior (autism, schizophrenia), we assessed sociability in male and female inbred mice (C57BL/6J) across postnatal development (N = 104) in relation to paternal age. We found differences in early social behavior in both male and female offspring of older breeders, with differences in this social domain persisting into adulthood in males only. We showed that these social deficits were not present in the fathers of these offspring, confirming a de novo origin of an altered social trajectory in the offspring generation. Our results, highly novel in rodent research, support the epidemiological observations in humans and provide evidence for a causal link between APA, age‐related changes in the paternal sperm DNA and neurodevelopmental disorders in their offspring.     

Living and Robotic Dogs as Elicitors of Social Communication Behavior and Regulated Emotional Responding in Individuals with Autism and Severe Language Delay: A Preliminary Comparative Study

The inclusion of animals and robots in therapeutic interventions for Autism Spectrum Disorder (ASD) has become more common. This study provides a first comparison between the potential of living versus robotic dogs to elicit social communication behavior and regulated emotional responses in individuals with ASD. Ten children and thirteen adults with ASD and severe lan- guage delay were tested for appropriate social communication behavior and cardiac autonomic functioning during a planned, structured interaction with an experimenter alone (no-stimulus condition), an experimenter accompanied by a living dog (dog condition), and an experimenter accompanied by a robotic dog (robot condition). A within-subjects design was followed to expose all participants to all three experimental conditions. Overall, participants (children and adults) showed a higher percentage of appropriate social behaviors in Living and Robotic Dogs as Elicitors of Social Communication Behavior and Regulated Emotional?…?the dog and the robot conditions than in the no-stimulus condition. In children, the living dog was more effective than the robotic dog in promoting social communication behavior. In adults, no such difference was found between the dog and the robot condition. Only the dog appeared to elicit a positive effect in cardiac autonomic functioning by increasing heart rate variability (HRV) and buffer- ing the decrease in parasympathetic activity due to interaction with the experimenter. The data are preliminary but relevant and warrant replication in larger-scale studies.     

Behavioural effects of high fat diet in a mutant mouse model for the schizophrenia risk gene neuregulin 1

Schizophrenia patients are often obese or overweight and poor dietary choices appear to be a factor in this phenomenon. Poor diet has been found to have complex consequences for the mental state of patients. Thus, this study investigated whether an unhealthy diet [i.e. high fat diet (HFD)] impacts on the behaviour of a genetic mouse model for the schizophrenia risk gene neuregulin 1 (i.e. transmembrane domain Nrg1 mutant mice: Nrg1 HET). Female Nrg1 HET and wild‐type‐like littermates (WT) were fed with either HFD or a control chow diet. The mice were tested for baseline (e.g. anxiety) and schizophrenia‐relevant behaviours after 7 weeks of diet exposure. HFD increased body weight and impaired glucose tolerance in all mice. Only Nrg1 females on HFD displayed a hyper‐locomotive phenotype as locomotion‐suppressive effects of HFD were only evident in WT mice. HFD also induced an anxiety‐like response and increased freezing in the context and the cued version of the fear conditioning task. Importantly, CHOW‐fed Nrg1 females displayed impaired social recognition memory, which was absent in HFD‐fed mutants. Sensorimotor gating deficits of Nrg1 females were not affected by diet. In summary, HFD had complex effects on the behavioural phenotype of test mice and attenuated particular cognitive deficits of Nrg1 mutant females. This topic requires further investigations thereby also considering other dietary factors of relevance for schizophrenia as well as interactive effects of diet with medication and sex.     

Activation of the medial preoptic area (MPOA) ameliorates loss of maternal behavior in a Shank2 mouse model for autism

Impairments in social relationships and awareness are features observed in autism spectrum disorders (ASDs). However, the underlying mechanisms remain poorly understood. Shank2 is a high‐confidence ASD candidate gene and localizes primarily to postsynaptic densities (PSDs) of excitatory synapses in the central nervous system (CNS). We show here that loss of Shank2 in mice leads to a lack of social attachment and bonding behavior towards pubs independent of hormonal, cognitive, or sensitive deficits. Shank2 ^−/− mice display functional changes in nuclei of the social attachment circuit that were most prominent in the medial preoptic area (MPOA) of the hypothalamus. Selective enhancement of MPOA activity by DREADD technology re‐established social bonding behavior in Shank2 ^−/− mice, providing evidence that the identified circuit might be crucial for explaining how social deficits in ASD can arise.     

Social behavior, foraging strategies, and fecal glucocorticoids in female blue monkeys (Cercopithecus mitis): potential fitness benefits of high rank in a forest guenon

Socioecological theory predicts that aggressive feeding competition is associated with linear dominance hierarchies and reproductive advantages for high-ranking females. Female blue monkeys contest fruits and have a linear dominance hierarchy, yet previous research has shown no evidence that high-ranking females benefit from greater feeding success or fertility. Here, we assess whether individuals differ in fecal glucocorticoid (fGC) excretion and examine proximate determinants of such differences to infer potential fitness correlates of rank, using data collected from two study groups in the Kakamega Forest, Kenya. We found that higher ranking females had preferential access to fruits in both groups, although the behavioral mechanisms leading to this effect varied between groups. Despite a consistent rank difference in feeding on fruits, an overall rank effect on fGCs emerged in only one group; females of this group spent comparatively more time feeding on fruits, fruits accounted for a greater proportion of the diet, and females engaged in more frequent food-related agonism. In addition, more females in this group were lactating during a period of low fruit availability, when rank effects on fGCs were particularly strong. Regardless of fruit availability, among lactating females of both groups higher rank was associated with lower fGC levels, indicating lower energetic stress in higher ranking females when energy demands were particularly high. Individual rates of agonism, a potential psychological stressor, were unrelated to fGCs at all times. After we accounted for rates of agonism and feeding on fruits, females of one group who groomed others more had lower fGCs, suggesting that variable social coping behavior can contribute to fGC variation in some groups. This study provides the first empirical evidence that high-ranking female blue monkeys may obtain fitness benefits from their social status, by gaining priority of access to fruits during critical times in the reproductive cycle.