Novel Object Exploration as a Potential Assay for Higher Order Repetitive Behaviors in Mice

Abstract Background Restricted and repetitive behaviors (RRBs) are core features of autism spectrum disorder (ASD) and one of the earliest behavioral signs of ASD. However, RRBs are also present in typically developing (TD) infants, toddlers, and preschool-aged children. Past work suggests that examining change in these behaviors over time is essential to distinguish between normative manifestations of these behaviors and behaviors that denote risk for a neurodevelopmental disorder. One challenge in examining changes in these behaviors over time is that most measures of RRBs have not established longitudinal measurement invariance. The aims of this study were to (1) establish measurement invariance in the Repetitive Behavior Scales for Early Childhood (RBS-EC), a parent-report questionnaire of RRBs, and (2) model developmental change in RRBs from 8 to 36 months. Methods We collected RBS-EC responses from parents of TD infants (n = 180) from 8 to 36 months (n = 606 responses, with participants contributing an average of 3-time points). We leverage a novel methodological approach to measurement invariance testing (Bauer, Psychological Models, 22(3), 507–526, 2017), moderated nonlinear factor analysis (MNLFA), to determine whether the RBS-EC was invariant across age and sex. We then generated adjusted factor score estimates for each subscale of the RBS-EC (repetitive motor, self-directed, and higher-order behaviors), and used linear mixed effects models to estimate between- and within-person changes in the RBS-EC over time. Results The RBS-EC showed some non-invariance as a function of age. We were able to adjust for this non-invariance in order to more accurately model changes in the RBS-EC over time. Repetitive motor and self-directed behaviors showed a linear decline from 8 to 36 months, while higher-order behaviors showed a quadratic trajectory such that they began to decline later in development at around 18 months. Using adjusted factor scores as opposed to unadjusted raw mean scores provided a number of benefits, including increased within-person variability and precision. Conclusions The RBS-EC is sensitive enough to measure the presence of RRBs in a TD sample, as well as their decline with age. Using factor score estimates of each subscale adjusted for non-invariance allowed us to more precisely estimate change in these behaviors over time.

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Treatment for Higher-Order Restricted, Repetitive Behaviors

Encyclopedia of Autism Spectrum Disorders ◽

10.1007/978-3-319-91280-6_102341 ◽

2021 ◽

pp. 4907-4909

Author(s):

Christie Enjey Lin

Keyword(s):

Higher Order ◽

Repetitive Behaviors ◽

Order Restricted

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Global brain volume reductions in a sub-chronic phencyclidine animal model for schizophrenia and their relationship to recognition memory

Journal of Psychopharmacology ◽

10.1177/0269881119844196 ◽

2019 ◽

Vol 33 (10) ◽

pp. 1274-1287 ◽

Cited By ~ 3

Author(s):

Nazanin Doostdar ◽

Eugene Kim ◽

Ben Grayson ◽

Michael K Harte ◽

Joanna C Neill ◽

...

Keyword(s):

Object Recognition ◽

Locomotor Activity ◽

Brain Volume ◽

Perirhinal Cortex ◽

Novel Object Recognition ◽

Novel Object ◽

Object Exploration ◽

Brain Changes ◽

Global Brain ◽

Structural Brain

Background: Cognitive deficits and structural brain changes co-occur in patients with schizophrenia. Improving our understanding of the relationship between these is important to develop improved therapeutic strategies. Back-translation of these findings into rodent models for schizophrenia offers a potential means to achieve this goal. Aims: The purpose of this study was to determine the extent of structural brain changes and how these relate to cognitive behaviour in a sub-chronic phencyclidine rat model. Methods: Performance in the novel object recognition task was examined in female Lister Hooded rats at one and six weeks after sub-chronic phencyclidine (2 mg/kg intra-peritoneal, n=15) and saline controls (1 ml/kg intra-peritoneal, n=15). Locomotor activity following acute phencyclidine challenge was also measured. Brain volume changes were assessed in the same animals using ex vivo structural magnetic resonance imaging and computational neuroanatomical analysis at six weeks. Results: Female sub-chronic phencyclidine-treated Lister Hooded rats spent significantly less time exploring novel objects ( p<0.05) at both time-points and had significantly greater locomotor activity response to an acute phencyclidine challenge ( p<0.01) at 3–4 weeks of washout. At six weeks, sub-chronic phencyclidine-treated Lister Hooded rats displayed significant global brain volume reductions ( p<0.05; q<0.05), without apparent regional specificity. Relative volumes of the perirhinal cortex however were positively correlated with novel object exploration time only in sub-chronic phencyclidine rats at this time-point. Conclusion: A sustained sub-chronic phencyclidine-induced cognitive deficit in novel object recognition is accompanied by global brain volume reductions in female Lister Hooded rats. The relative volumes of the perirhinal cortex however are positively correlated with novel object exploration, indicating some functional relevance.

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RO-10-5824 is a selective dopamine D4 receptor agonist that increases novel object exploration in C57 mice

Neuropharmacology ◽

10.1016/s0028-3908(02)00412-4 ◽

2003 ◽

Vol 44 (4) ◽

pp. 473-481 ◽

Cited By ~ 61

Author(s):

S Powell

Keyword(s):

Receptor Agonist ◽

Dopamine D4 Receptor ◽

Novel Object ◽

Object Exploration ◽

D4 Receptor ◽

Selective Dopamine

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Novel object exploration in mice: Not all objects are created equal

Behavioural Processes ◽

10.1016/j.beproc.2011.12.004 ◽

2012 ◽

Vol 89 (3) ◽

pp. 232-238 ◽

Cited By ~ 63

Author(s):

Charles J. Heyser ◽

Anthony Chemero

Keyword(s):

Novel Object ◽

Object Exploration

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Disturbances of novel object exploration and recognition in a chronic ketamine mouse model of schizophrenia

Behavioural Brain Research ◽

10.1016/j.bbr.2017.06.013 ◽

2017 ◽

Vol 332 ◽

pp. 316-326 ◽

Cited By ~ 9

Author(s):

Maria Jelena Hauser ◽

Dirk Isbrandt ◽

Jochen Roeper

Keyword(s):

Mouse Model ◽

Novel Object ◽

Object Exploration

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Treatment for Higher-Order Restricted Repetitive Behaviors (H-RRB) in Children with Autism Spectrum Disorder

Journal of Autism and Developmental Disorders ◽

10.1007/s10803-018-3637-3 ◽

2018 ◽

Vol 48 (11) ◽

pp. 3831-3845 ◽

Cited By ~ 6

Author(s):

C. Enjey Lin ◽

Robert Koegel

Keyword(s):

Autism Spectrum Disorder ◽

Children With Autism ◽

Autism Spectrum ◽

Higher Order ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Order Restricted

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Atypical Integration of Sensory-to-Transmodal Functional Systems Mediates Symptom Severity in Autism

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.699813 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shinwon Park ◽

Koen V. Haak ◽

Han Byul Cho ◽

Sofie L. Valk ◽

Richard A. I. Bethlehem ◽

...

Keyword(s):

Symptom Severity ◽

Autism Spectrum ◽

Higher Order ◽

High Order ◽

Repetitive Behaviors ◽

Functional Systems ◽

Low Level ◽

Sensory Motor ◽

Cortical Hierarchy ◽

Motor Areas

A notable characteristic of autism spectrum disorder (ASD) is co-occurring deficits in low-level sensory processing and high-order social interaction. While there is evidence indicating detrimental cascading effects of sensory anomalies on the high-order cognitive functions in ASD, the exact pathological mechanism underlying their atypical functional interaction across the cortical hierarchy has not been systematically investigated. To address this gap, here we assessed the functional organisation of sensory and motor areas in ASD, and their relationship with subcortical and high-order trandmodal systems. In a resting-state fMRI data of 107 ASD and 113 neurotypical individuals, we applied advanced connectopic mapping to probe functional organization of primary sensory/motor areas, together with targeted seed-based intrinsic functional connectivity (iFC) analyses. In ASD, the connectopic mapping revealed topological anomalies (i.e., excessively more segregated iFC) in the motor and visual areas, the former of which patterns showed association with the symptom severity of restricted and repetitive behaviors. Moreover, the seed-based analysis found diverging patterns of ASD-related connectopathies: decreased iFCs within the sensory/motor areas but increased iFCs between sensory and subcortical structures. While decreased iFCs were also found within the higher-order functional systems, the overall proportion of this anomaly tends to increase along the level of cortical hierarchy, suggesting more dysconnectivity in the higher-order functional networks. Finally, we demonstrated that the association between low-level sensory/motor iFCs and clinical symptoms in ASD was mediated by the high-order transmodal systems, suggesting pathogenic functional interactions along the cortical hierarchy. Findings were largely replicated in the independent dataset. These results highlight that atypical integration of sensory-to-high-order systems contributes to the complex ASD symptomatology.

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