Environmental enrichment reduces restricted repetitive behavior by altering gray matter microstructure.

Restricted, repetitive behaviors are common symptoms in neurodevelopmental disorders including autism spectrum disorder. Despite being associated with poor developmental outcomes, repetitive behaviors remain poorly understood and have limited treatment options. Environmental enrichment attenuates the development of repetitive behaviors, but the exact mechanisms remain obscure. Using the C58 mouse model of repetitive behavior, we performed diffusion tensor imaging to examine microstructural alterations associated with the development of repetitive behavior and its attenuation by environmental enrichment. The C57BL/6 mouse strain, which displays little or no repetitive behavior, was used as a control group. We observed widespread differences in diffusion metrics between C58 mice and C57BL/6 mice. In juvenile C58 mice, repetitive motor behavior displayed strong negative correlations with fractional anisotropy in multiple gray matter regions, whereas in young adult C58 mice, high repetitive motor behavior was most strongly associated with lower fractional anisotropy and higher radial diffusivity in the striatum. Environmental enrichment increased fractional anisotropy and axial diffusivity throughout gray matter regions in the brains of juvenile C58 mice and overlapped predominantly with cerebellar and sensory regions associated with repetitive behavior. Our results suggest environmental enrichment reduces repetitive behavior development by altering gray matter microstructure in the cerebellum, medial entorhinal cortex, and sensory processing regions in juvenile C58 mice. Under standard laboratory conditions, early pathology in these regions appears to contribute to later striatal and white matter dysfunction in adult C58 mice. Future studies should examine the role these regions play in the development of repetitive behavior and the relationship between sensory processing and cerebellar deficits and repetitive behavior.

Social communication and restricted, repetitive behavior as assessed with a diagnostic tool for autism (ADOS-2) in women with anorexia nervosa.

OBJECTIVE: In anorexia nervosa (AN), the traits of autism spectrum disorder (ASD) are associated with poor outcomes. However, the subtle nature of these characteristics remains poorly understood. We investigated the in-depth patterns of ASD traits using Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) in women with AN. METHODS: Of 28 women with ICD-10 AN, 16 (age 19-30 years) participated in the ADOS-2, a video-recorded, semistructured diagnostic assessment for social communication and interaction and restricted, repetitive behaviors and interests related to ASD. None of the participants had previously been diagnosed with ASD. Other measurements included the Eating Disorder Examination Questionnaire and the Wechsler Abbreviated Scale of Intelligence-IV. RESULTS: Five individuals (18% of all, 31% of those assessed) scored above the cutoff for autism in ADOS-2. They had challenges in social communication and interaction, manifesting as sustained difficulties in social relationships and deficits in conversation skills. Few described being frequently misunderstood by others, including in the eating disorder treatment settings. Three individuals showed prominent restricted and repetitive behaviors such as ritual seeking, eating-related routines, sensory sensitivity related to food texture and selective eating, and intense interest in specific topics. The mean duration of AN in women above the cutoff was twice as long compared with those below (12.3 vs. 6.2 years). DISCUSSION: The ASD-related characteristics and behavior appear to contribute to the manifestation and duration of AN in a subgroup of women. Among these women, the traits of ASD appear to be mixed with eating disorder symptoms, which should be taken into account in the treatment.

The role of task preference in the effectiveness of response interruption and redirection.

Response interruption and redirection (RIRD) is a common treatment for automatically reinforced vocal stereotypy; it involves the contingent presentation of task instructions. Tasks that are included in RIRD are typically selected based on caregiver report, which may affect the efficacy of RIRD. The purpose of the current study was to evaluate the role of task preference in the efficacy of RIRD for four participants who engaged in vocal stereotypy. We conducted task-preference assessments and selected tasks of varying preferences to include in RIRD. For three out of four participants, the results showed that RIRD with higher preference tasks was not effective at reducing vocal stereotypy, whereas RIRD with lower preference tasks was effective for all participants.

Do housing-induced changes in brain activity cause stereotypic behaviours in laboratory mice?

Abnormal repetitive stereotypic behaviours (SBs) (e.g. pacing, body-rocking) are common in animals with poor welfare (e.g. socially isolated/in barren housing). But how (or even whether) poor housing alters animals' brains to induce SBs remains uncertain. To date, there is little evidence for environmental effects on the brain that also correlate with individual SB performance. Using female mice from two strains (SB-prone DBA/2s; SB-resistant C57/BL/6s), displaying two forms of SB (route-tracing; bar-mouthing), we investigated how housing (conventional laboratory conditions vs. well-resourced 'enriched' cages) affects long-term neuronal activity as assessed via cytochrome oxidase histochemistry in 13 regions of interest (across cortex, striatum, basal ganglia and thalamus). Conventional housing reduced activity in the cortex and striatum. However, DBA mice had no cortical or striatal differences from C57 mice (just greater basal ganglia output activity, independent of housing). Neural correlates for individual levels of bar-mouthing (positive correlations in the substantia nigra and thalamus) were also independent of housing; while route-tracing levels had no clear neural correlates at all. Thus conventional laboratory housing can suppress cortico-striatal activity, but such changes are unrelated to SB (since not mirrored by congruent individual and strain differences). Furthermore, the neural correlates of SB at individual and strain levels seem to reflect underlying predispositions, not housing-mediated changes. To aid further work, hypothesis-generating model fit analyses highlighted this unexplained housing effect, and also suggested several regions of interest across cortex, striatum, thalamus and substantia nigra for future investigation (ideally with improved power to reduce risks of Type II error).

Investigating the gastrointestinal physiology of mature horses with and without a history of cribbing behavior in response to feeding a digestive support supplement.

Cribbing, a stereotypic oral behavior observed in horses, involves placing incisors on a fixed object, arching the neck, pulling against the object, and emitting an audible grunt. This behavior has been associated with gastrointestinal (GI) dysfunction and gastric ulceration. In this randomized crossover study, we investigated the impact of a GI support supplement (SPL) on the GI environment and physiology of four cribbing (CB) and four non-cribbing horses (NCB). Mature Quarter Horses, acclimated to individual stalls for 16 hours daily with paddock turnout in pairs for 8 hours per day, were randomly assigned to receive either the SPL or placebo for 21 days, followed by a 2-week washout period. Fecal and gastric samples were collected for pH determination and blood samples were analyzed for serum cortisol and gastrin levels. Endoscopic examinations assessed gastric ulcer severity, and cribbing frequency and bouts were recorded via video surveillance. Data were analyzed using a mixed-model ANOVA. Results showed no differences in fecal and gastric pH between cribbing statuses. However, an interaction between supplementation and cribbing status was observed for squamous mucosa ulcer scores (P=0.003). There were no differences in glandular mucosa ulcer scores, serum cortisol, serum gastrin, and crib-bite count between CB and NCB horses or between supplementation groups. Crib-bout duration did not differ with supplementation, but differences were found between periods (P<0.05) and hour ranges (P<0.001). Our findings suggest that the GI support supplement may not effectively address cribbing behavior or alter the GI environment in NCB or CB horses.

Environmental interventions reduced repetitive behavior in a mouse model.

Repetitive motor behaviors are associated with several neurodevelopmental disorders including autism spectrum disorder. Non-invasive environmental interventions that can ameliorate repetitive behavior and be introduced in early development could benefit many. In Experiment 1, we characterized the development of repetitive circling in mice reared in standard and enriched environments. Environmental enrichment was associated with reduced repetitive behavior. In Experiment 2, two weekly injections of an A2A adenosine receptor agonist reduced repetitive behavior in mice fed a ketogenic diet. Together, these two approaches modified the environment and reduced repetitive behavior with potential implications for increased functioning of the indirect basal ganglia pathway.

Physiological and behavioural adjustment of a wild rodent to laboratory conditions.

Wild animals are brought to captivity for different reasons, for example to be kept in zoos and rehabilitation centres, but also for basic research. Such animals usually undergo a process of adjustment to captive conditions. While this adjustment occurs on the behavioural and the physiological level, those are usually studied separately. The aim of this study was to assess both the physiological and behavioural responses of wild wood mice, Apodemus sylvaticus, while adjusting to laboratory conditions. Over the course of four weeks, we measured in wild-caught mice brought to the laboratory faecal corticosterone metabolites and body mass as physiological parameters, stereotypic behaviour and nest-quality, as welfare-linked behavioural parameters, and four personality measures as additional behavioural parameters. The results of our study indicate that mice exhibited an adjustment in both behaviour and physiology over time in the laboratory. While the hormonal stress response decreased significantly, body mass and the proportion of stereotypic behaviours showed a tendency to increase over time. The slight increase of stereotypic behaviours, although not statistically significant, suggests the development of repetitive and non-functional behaviours as a response to laboratory conditions. However, we suggest that those behaviours might have been used by animals as a coping strategy to decrease the physiological stress response. Other behavioural parameters measured, such as boldness and nestbuilding behaviour were stable over time. The information obtained in the present study hints at a complex interplay between behavioural and physiological adjustments of wild animals to laboratory conditions, which should be considered when intending to use wild animals in experimental research.

The Partial M1 Muscarinic Cholinergic Receptor Agonist, CDD-0102A, Differentially Modulates Glutamate Efflux in Striatal Subregions during Stereotyped Motor Behavior in the BTBR Mouse Model of Autism.

The BTBR T+ Itpr3tf/J (BTBR) mouse displays elevated repetitive motor behaviors. Treatment with the partial M1 muscarinic receptor agonist, CDD-0102A, attenuates stereotyped motor behaviors in BTBR mice. The present experiment investigated whether CDD-0102A modifies changes in striatal glutamate concentrations during stereotyped motor behavior in BTBR and B6 mice. Using glutamate biosensors, change in striatal glutamate efflux was measured during bouts of digging and grooming behavior with a 1 s time resolution. Mice displayed both decreases and increases in glutamate efflux during such behaviors. Magnitude of changes in glutamate efflux (decreases and increases) from dorsomedial and dorsolateral striatum were significantly greater in BTBR mice compared to those of B6 mice. In BTBR mice, CDD-0102A (1.2 mg/kg) administered 30 min prior to testing significantly reduced the magnitude change in glutamate decreases and increases from the dorsolateral striatum and decreased grooming behavior. Conversely, CDD-0102A treatment in B6 mice potentiated glutamate decreases and increases in the dorsolateral striatum and elevated grooming behavior. The findings suggest that activation of M1 muscarinic receptors modifies glutamate transmission in the dorsolateral striatum and self-grooming behavior.

Effect of vibrostimulatory wearable technology on stereotyped behaviour in a child with autism and intellectual disability.

The aim of the work has been to report on the effects of vibrostimulation, administered through wearable technology, on stereotyped behaviour of a child in middle childhood, with autism, intellectual disability and severe behaviour in the 'stereotypic behaviour' subscale of the Restricted and Repetitive Behaviour Revised Scale. He received vibrostimulation (210 Hz, 2.8 µm), with a continuous pattern of vibration: three vibrations of 700 ms, each separated by a rest period of 500 ms and a pause of 8000 ms. Vibration was delivered bilaterally by two devices, repeating the vibration pattern for 3 min. The measures were repeated four times alternately, with the device turned off and on. The outcome measure was frequency of stereotyed behaviour, which was evaluated for 3 min with and without vibrostimulation. The results and observations, over 3 min of stimulation, showed the disappearance of stereotyped movements during vibrostimulation and better precision in intentional hand movements. Subjectively, the child enjoyed vibrostimulation.

A comparison of RIRD within chained and multiple schedules in the treatment of vocal stereotypy.

Slaton and Hanley (2016) compared the effects of multiple and chained schedules on stereotypy and item engagement for 2 individuals who exhibited automatically maintained motor stereotypy. Contingent access to motor stereotypy (i.e., chained schedules) was more effective than time-based access (i.e., multiple schedules) at reducing motor stereotypy, increasing item engagement, and establishing stimulus control for both participants. We systematically replicated Slaton and Hanley with 2 participants by a) targeting vocal stereotypy, b) including response interruption and redirection as a treatment component across conditions, c) conducting sessions in the natural environment with teaching assistants as change agents, and d) conducting an analysis of the effective treatment component(s). Chained schedules were more effective for 1 participant, whereas both treatments were effective for the other participant. The component analysis showed that different components were necessary for effective treatment for each participant.

Effects of browsing enrichment associated with the temperature-humidity index and landscaping trees in giraffes (Giraffa camelopardalisreticulata).

Enclosure environments for captive giraffes can be improved by promoting species-specific behaviors and extending foraging behavior. To date, however, the effects of climatic (temperature-humidity index, THI) and environmental factors (landscaping trees) on the enrichment of captive settings have not been studied. Therefore, the present study explored the effects of browsing enrichment on the licking behavior of captive giraffes. From May 2019 to February 2020, three giraffes in the Kyoto City Zoo, Japan, were observed for 270 h over two consecutive seasons (pre- and post-deciduous). Overall, branch foraging behavior and licking behavior were weakly and negatively correlated. In the pre-deciduous period, THI was significantly and negatively correlated with giraffe activity, and some individuals exhibited significantly reduced foraging behavior. Therefore, browsing enrichment under extreme heat may not improve giraffe rearing environments. Moreover, in the post-deciduous period, with decreased availability of leaves on landscaping trees, the non-branch foraging behavior of giraffes was significantly increased, with a corresponding significant increase in licking behavior. Therefore, landscaping trees affect the foraging behavior of captive giraffes.

Benefits of a ketogenic diet on repetitive motor behavior in mice.

Repetitive motor behaviors are repetitive and invariant movements with no apparent function, and are common in several neurological and neurodevelopmental disorders, including autism spectrum disorders (ASD). However, the neuropathology associated with the expression of these abnormal stereotypic movements is not well understood, and effective treatments are lacking. The ketogenic diet (KD) has been used for almost a century to treat intractable epilepsy and, more recently, disorders associated with inflexibility of behavioral routines. Here, we show a novel application for KD to reduce an abnormal repetitive circling behavior in a rodent model. We then explore potential mediation through the striatum, as dysregulation of cortico-basal ganglia circuitry has previously been implicated in repetitive motor behavior. In Experiments 1 and 2, adult FVB mice were assessed for levels of repetitive circling across a 3-week baseline period. Mice were then switched to KD and repetitive circling was assessed for an additional 3 weeks. In Experiment 1, time on KD was associated with reduced repetitive behavior. In Experiment 2, we replicated these benefits of KD and assessed dendritic spine density in the striatum as one potential mechanism for reducing repetitive behavior, which yielded no differences. In Experiment 3, adult female circling mice were given a single administration of a dopamine D2 receptor antagonist (L-741,646) that was associated with reduced repetitive behavior over time. Future research will explore the relationship between KD and dopamine within basal ganglia nuclei that may be influencing the benefits of KD on repetitive behavior.

The Emergence of Stereotyped Kinematic Synergies when Mice Reach to Grasp Following Stroke.

Reaching tasks are commonly used in preclinical and clinical studies to assess the acquisition of fine motor skills and recovery of function following stroke. These tasks are often used to assess functional deficits in the absence of quantifying the quality of movement which requires kinematic analysis. To meet this need, this study uses a kinematic analysis in mice performing the Montoya staircase task at 5 and 14 days following a cortical photothrombosis-induced stroke. Following stroke, the mice had reaching impairments associated with sustained deficits including longer, unsmooth, and less individuated paw trajectories. Two weeks after stroke we also detected the emergence of abnormal elbow and shoulder angles, flexion/extensions, and stereotyped kinematic synergies. These data suggest that proximal and distal segments acting in concert is paramount during post-stroke reaching and encourage further analysis of synergies within the translational pipeline of preclinical to clinical studies.

Relationships Between Emotion Regulation, Social Communication and Repetitive Behaviors in Autism Spectrum Disorder.

The relationship between emotion regulation, social interaction and different types of restricted and repetitive behaviors is poorly understood. In the present study, structural equation modeling based on information about 239 individuals with autism was used to examine whether emotion regulation and social communication were associated with self-injury and stereotyped behaviors. Results showed that poor emotion regulation had a unique association with self-injury while difficulties with social communication was uniquely associated with stereotyped behaviors. Emotion regulation and social communication were strongly associated and self-injury and stereotyped behaviors moderately associated. This implies that these types of behaviors are often expressions of broader negative emotional states in autism. Treatments that help improve coping and social communication strategies may benefit individuals with autism.

Collapse of complexity of brain and body activity due to excessive inhibition and MeCP2 disruption.

Complex body movements require complex dynamics and coordination among neurons in motor cortex. Conversely, a long-standing theoretical notion supposes that if many neurons in motor cortex become excessively synchronized, they may lack the necessary complexity for healthy motor coding. However, direct experimental support for this idea is rare and underlying mechanisms are unclear. Here we recorded three-dimensional body movements and spiking activity of many single neurons in motor cortex of rats with enhanced synaptic inhibition and a transgenic rat model of Rett syndrome (RTT). For both cases, we found a collapse of complexity in the motor system. Reduced complexity was apparent in lower-dimensional, stereotyped brain-body interactions, neural synchrony, and simpler behavior. Our results demonstrate how imbalanced inhibition can cause excessive synchrony among movement-related neurons and, consequently, a stereotyped motor code. Excessive inhibition and synchrony may underlie abnormal motor function in RTT.

Professional actors demonstrate variability, not stereotypical expressions, when portraying emotional states in photographs.

It is long hypothesized that there is a reliable, specific mapping between certain emotional states and the facial movements that express those states. This hypothesis is often tested by asking untrained participants to pose the facial movements they believe they use to express emotions during generic scenarios. Here, we test this hypothesis using, as stimuli, photographs of facial configurations posed by professional actors in response to contextually-rich scenarios. The scenarios portrayed in the photographs were rated by a convenience sample of participants for the extent to which they evoked an instance of 13 emotion categories, and actors' facial poses were coded for their specific movements. Both unsupervised and supervised machine learning find that in these photographs, the actors portrayed emotional states with variable facial configurations; instances of only three emotion categories (fear, happiness, and surprise) were portrayed with moderate reliability and specificity. The photographs were separately rated by another sample of participants for the extent to which they portrayed an instance of the 13 emotion categories; they were rated when presented alone and when presented with their associated scenarios, revealing that emotion inferences by participants also vary in a context-sensitive manner. Together, these findings suggest that facial movements and perceptions of emotion vary by situation and transcend stereotypes of emotional expressions. Future research may build on these findings by incorporating dynamic stimuli rather than photographs and studying a broader range of cultural contexts.

Toward better characterization of restricted and repetitive behaviors in individuals with germline heterozygous PTEN mutations.

This study aimed to further our understanding of restricted and repetitive behaviors (RRB) among individuals with germline pathogenic mutations in PTEN by providing multimethod characterization and comparison of key RRB subdomains across individuals with PTEN mutations with autism spectrum disorder (ASD) (PTEN-ASD), with PTEN mutations without ASD (PTEN-No ASD) and with ASD and macrocephaly but without PTEN mutations (Macro-ASD). Of 86 total research participants, 38 had PTEN-ASD (Mage  = 8.93 years, SDage  = 4.75), 25 Macro-ASD (Mage  = 11.99 years; SDage  = 5.15), and 23 PTEN-No ASD (Mage  = 8.94 years; SDage  = 4.85). The Repetitive Behavior Scale-Revised (RBS-R) and the Autism Diagnostic Interview-Revised (ADI-R) were used as measures of distinct RRB domains. There were significant group differences in the RBS-R repetitive motor behaviors (RMB; F = 4.52, p = 0.014, ω2  = 0.08), insistence on sameness (IS; F = 4.11, p = 0.02, ω2  = 0.05), and circumscribed interests (CI; F = 7.80, p = 0.001, ω2  = 0.14) scales. Post hoc comparisons showed that the PTEN-No ASD group had significantly lower RMB, IS, and CI scores compared to both PTEN-ASD and Macro-ASD groups. Importantly, PTEN-No ASD group still showed elevated RRB levels. Furthermore, there was a portion of individuals in PTEN-No ASD group whose Full-Scale Intelligence Quotient (FSIQ) was >70 that did not show floor level scores in the RMB domain. After adjusting for age and FSIQ scores, group differences were no longer statistically significant. RMB, IS, and CI domains showed distinct association patterns with sex, age, and FSIQ. This investigation provides the largest and most comprehensive characterization of distinct RRB domains in individuals with PTEN mutations to date. Despite the limitations, our findings have important assessment and treatment implications.

Social impairments in mice lacking the voltage-gated potassium channel Kv3.1.

Parvalbumin (PV)-expressing neurons have been implicated in the pathology of autism spectrum disorders (ASD). Loss of PV expression and/or reduced number of PV-expressing neurons have been reported not only in genetic and environmental rodent models of ASD, but also in post-mortem analyses of brain tissues from ASD vs. healthy control human subjects. PV-expressing neurons play a pivotal role in the maintenance of the balance between excitation and inhibition within neural circuits in part because of their fast-spiking properties. Their high firing rate is mostly regulated by the voltage-gated potassium channel Kv3.1. It is yet unknown whether disturbances in the electrophysiological properties of PV-expressing neurons per se can lead to behavioral disturbances. We assessed locomotor activity, social interaction, recognition and memory, and stereotypic behaviors in Kv3.1 wild-type (WT) and knockout (KO) mice. We then used Western Blot analyses to measure the impact of Kv3.1 deficiency on markers of GABA transmission (PV and GAD67) and neural circuit activity (Egr1). Deficiency in Kv3.1 channel is sufficient to induce social deficits, hyperactivity and stereotypic behaviors. These behavioral changes were independent of changes in GAD67 levels and associated with increased levels of PV protein in the prefrontal cortex and striatum. These findings reveal that a loss of PV expression is not a necessary factor to induce an ASD-like phenotype in mice and support the need for further investigation to fully understand the contribution of PV-expressing neurons to ASD pathology.

Stereotypy and spontaneous alternation in deer mice and its response to anti-adenosinergic intervention.

Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD). Such behaviors are typified by complex interactions between cognitive and neurobiological processes which most likely contribute to the suboptimal treatment responses often observed. To this end, exploration of the adenosinergic system may be useful, since adenosine-receptor modulation has previously shown promise to restore control over voluntary behavior and improve cognition in patients presenting with motor repetition. Here, we employed the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavioral persistence, seeking to investigate possible associations between stereotypic motor behavior and cognitive flexibility as measured in the T-maze continuous alternation task (T-CAT). The effect of istradefylline, a selective adenosine A2A receptor antagonist at two doses (10 and 20 mg kg-1  day-1 ) on the expression of stereotypy and T-CAT performance in high (H) and non-(N) stereotypical animals, was investigated in comparison to a control intervention (six groups; n = 8 or 9 per group). No correlation between H behavior and T-CAT performance was found. However, H but not N animals presented with istradefylline-sensitive spontaneous alternation and stereotypy, in that istradefylline at both doses significantly improved the spontaneous alternation scores and attenuated the stereotypical expression of H animals. Thus, evidence is presented that anti-adenosinergic drug action improves repetitive behavior and spontaneous alternation in stereotypical deer mice, putatively pointing to a shared psychobiological construct underlying naturalistic stereotypy and alterations in cognitive flexibility in deer mice.

The effects of two stressors on working memory and cognitive flexibility in zebrafish (Danio rerio): The protective role of D1/D5 agonist on stress responses.

Acute stressors are recurrent in multiple species' lives and can facilitate or impair cognition. The use of zebrafish (Danio rerio) as a translational species to understand the mechanisms by which stress induces different behavioral phenotypes has been widely studied. Two acute stressors are recognized when using this species: (1) conspecific alarm substance (CAS); and (2) net chasing. Here, we tested if CAS or net chasing would affect working memory and cognitive flexibility by testing performance in the FMP Y-maze after exposure to stress. We observed that CAS altered zebrafish behavioral phenotypes by increasing repetitive behavior; meanwhile, animals showed different patterns of repetitive behavior when exposed to net chasing, depending on the chasing direction. Because D1 receptors were previously studied as a potential mechanism underlying stress responses in different species, here, we pretreated fish with a D1/D5 agonist (SKF-38393) to assess whether this system plays a role in repetitive behavior in the FMP Y-maze. The pretreatment with D1/D5 agonist significantly decreased repetitive behavior in CAS exposed animals, and cortisol levels for both stressed groups, suggesting that the dopaminergic system plays an important role in zebrafish stress-related responses.