Search

Restricted, repetitive behavior (RRB) is diagnostic for autism spectrum disorder (ASD) and characteristic of a number of neurodevelopmental, psychiatric, and neurological disorders. RRB seen in ASD includes repetitive motor behavior and behaviors reflecting resistance to change and insistence on sameness. C58 mice provide a robust model of repetitive motor behavior and have shown resistance to change in a reversal learning task. We further characterized resistance to change in this model by inducing habitual responding and testing for differences in the ability to suppress habitual behavior and shift to goal-directed responding. We found no differences between C58 and control (C57BL/6) mice in the acquisition of operant tasks, habit formation, and expression of habitual responding. Habitual responding, however, induced significant reversal learning and contingency reversal performance deficits in C58 mice compared with C57BL/6 mice. Decreased dendritic spine density of the dorsomedial striatum in C58 mice was related to higher repetitive motor behavior, whereas dendritic spine density in the subthalamic nucleus was significantly positively correlated with improved contingency reversal performance in both C58 and C57BL/6 mice. Our results demonstrate that induction of habitual responding markedly impaired the ability of C58 mice to shift to goal-directed behavior. Such impairment may have resulted from the effects of the induction of habitual responding on already compromised basal ganglia circuitry mediating repetitive motor behavior. These findings provide additional evidence for the translational value of the C58 model in modeling RRB in neurodevelopmental disorders. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Restricted, repetitive behavior (RRB) involves sequences of responding with little variability and no obvious function. RRB is diagnostic for autism spectrum disorder (ASD) and a significant feature in several neurodevelopmental disorders. Despite its clinical importance, relatively little is known about how RRB is mediated by broader neural circuits. In this study, we employed ultra-high field (17.6 Tesla) magnetic resonance imaging (MRI) to study the C58/J mouse model of RRB. We determined alterations in brain morphology and connectivity of C58/J mice and their relationship to repetitive motor behavior using structural MRI and diffusion tensor imaging (DTI). Compared to the genetically similar C57BL/6 control mouse strain, C58/J mice showed evidence of structural alterations in basal ganglia and cerebellar networks. In particular, C58/J mice exhibited reduced volumes of key cortical and basal ganglia regions that have been implicated in repetitive behavior, including motor cortex, striatum, globus pallidus, and subthalamic nucleus, as well as volume differences in the cerebellum. Moreover, DTI revealed differences in fractional anisotropy and axial diffusivity in cerebellar white matter of C58/J mice. Importantly, we found that RRB exhibited by C58/J mice was correlated with volume of the striatum, subthalamic nucleus, and crus II of the cerebellum. These regions are key nodes in circuits connecting the basal ganglia and cerebellum and our findings implicate their role in RRB, particularly the indirect pathway.

Repetitive behaviors are seemingly purposeless patterns of behavior that vary little in form and are characteristic of many neurodevelopmental, psychiatric, and neurologic disorders. Our work has identified an association between hypofunctioning of the indirect basal ganglia pathway and the expression of repetitive behavior in the deer mouse model. In this study, we targeted indirect pathway cells of the striatum with single drugs and drug combinations that bind to dopamine D2, adenosine A2A, and glutamate mGlu5 receptors. These receptors function both individually and as receptor heteromers. We found that only the triple drug cocktail (L-741,626+CGS21680+CDPPB) that was designed to increase striatal indirect basal ganglia pathway cell function reduced repetitive behavior in adult male deer mice. No single drug or double drug combinations were effective at selectively reducing repetitive behavior. We found this triple drug cocktail reduced repetitive behavior in both short-acting and long-acting formulations and was effective throughout 7 days of daily administration. Conversely, another triple drug cocktail (quinpirole+SCH58261+MTEP) that was designed to further reduce striatal indirect basal ganglia pathway cell function caused a significant increase in repetitive behavior. Significant and behaviorally selective effects on repetitive behavior were only achieved with the triple drug cocktails that included doses of L-741,626 and quinpirole that have off-target effects (e.g., dopamine D3 receptors). These data further a role for decreased indirect basal ganglia pathway activation in repetitive behavior and suggest that targeting these receptors and/or heteromeric complexes on the indirect pathway neurons of the striatum may offer pharmacotherapeutic benefit for individuals with repetitive behavior disorders.

Repetitive behaviors (e.g., stereotypic movements, compulsions, rituals) are common features of a number of neurodevelopmental disorders. Clinical and animal model studies point to the importance of cortical-basal ganglia circuitry in the mediation of repetitive behaviors. In the current study, we tested whether a drug cocktail (dopamine D2 receptor antagonist + adenosine A2A receptor agonist + glutamate mGlu5 positive allosteric modulator) designed to activate the indirect basal ganglia pathway would reduce repetitive behavior in C58 mice after both acute and sub-chronic administration. In addition, we hypothesized that sub-chronic administration (i.e. 7 days of twice-daily injections) would increase the functional activation of the subthalamic nucleus (STN), a key node of the indirect pathway. Functional activation of STN was indexed by dendritic spine density, analysis of GABA, glutamate, and synaptic plasticity genes, and cytochrome oxidase activity. The drug cocktail used significantly reduced repetitive motor behavior in C58 mice after one night as well as seven nights of twice-nightly injections. These effects did not reflect generalized motor behavior suppression as non-repetitive motor behaviors such as grooming, digging and eating were not reduced relative to vehicle. Sub-chronic drug treatment targeting striatopallidal neurons resulted in significant changes in the STN, including a four-fold increase in brain-derived neurotrophic factor (BDNF) mRNA expression as well as a significant increase in dendritic spine density. The present findings are consistent with, and extend, our prior work linking decreased functioning of the indirect basal ganglia pathway to expression of repetitive motor behavior in C58 mice and suggest novel therapeutic targets.

Stereotypic behaviour (SB) is common in animals housed in farm, zoo or laboratory conditions, including captive Carnivora (e.g. wild ursids and felids). Neurobiological data on housing-induced SBs come from four species (macaques, two rodent species, and horses), and suggest basal ganglia (BG) dysfunction. We investigated whether similar patterns occur in Carnivora via a model, American mink, because their SB is distinctive in form and timing. We raised 32 males in non-enriched (NE) or enriched (E) cages for 2 years, and assessed two forms of SB: 1) Carnivora-typical locomotor-and-whole-body (‘loco’) SBs (e.g. pacing, weaving); 2) scrabbling with the forepaws. Neuronal activity was analysed via cytochrome oxidase (CO) staining of the dorsal striatum (caudate; putamen), globus pallidus (externus, GPe; internus, GPi), STN , and nucleus accumbens (NAc); and the GPe:GPi ratio (GPr) calculated to assess relative activation of direct and indirect pathways. NE mink stereotyped more, and had lower GPr CO-staining indicating relatively lower indirect pathway activation. However, no single BG area was affected by housing and nor did GPr values covary with SB. Independent of housing, elevated NAc CO-staining predicted more loco SB, while scrabbling, probably because it negatively correlated with loco SB, negatively covaried with NAc CO-staining in NE subjects. These results thus implicate the NAc in individual differences in mink SB. However, because they cannot explain why NE subjects showed more SB, they provide limited support for the BG dysfunction hypothesis for this species’ housing-induced SB. More research is therefore needed to understand how barren housing causes SB in captive Carnivora.

Repetitive behaviors are diagnostic for autism spectrum disorder (ASD) and commonly observed in other neurodevelopmental disorders. Currently, there are no effective pharmacological treatments for repetitive behavior in these clinical conditions. This is due to the lack of information about the specific neural circuitry that mediates the development and expression of repetitive behavior. Our previous work in mouse models has linked repetitive behavior to decreased activation of the subthalamic nucleus, a brain region in the indirect and hyperdirect pathways in the basal ganglia circuitry. The present experiments were designed to further test our hypothesis that pharmacological activation of the indirect pathway would reduce repetitive behavior. We used a combination of adenosine A1 and A2A receptor agonists that have been shown to alter the firing frequency of dorsal striatal neurons within the indirect pathway of the basal ganglia. This drug combination markedly and selectively reduced repetitive behavior in both male and female C58 mice over a six-hour period, an effect that required both A1 and A2A agonists as neither alone reduced repetitive behavior. The adenosine A1 and A2A receptor agonist combination also significantly increased the number of Fos transcripts and Fos positive cells in dorsal striatum. Fos induction was found in both direct and indirect pathway neurons suggesting that the drug combination restored the balance of activation across these complementary basal ganglia pathways. The adenosine A1 and A2A receptor agonist combination also maintained its effectiveness in reducing repetitive behavior over a 7-day period. These findings point to novel potential therapeutic targets for development of drug therapies for repetitive behavior in clinical disorders.

Motor behaviors that are repetitive and exhibit little variability in form are common in neurodevelopmental disorders (e.g., autism spectrum disorder). C58 mice exhibit persistent, high levels of repetitive motor behavior when reared in restricted, but not enriched, environments implicating epigenetic mechanisms (e.g., DNA methylation). We sought to determine if alteration of DNA methylation played a role in the development of repetitive behavior in C58 mice. Thus, we tested the hypothesis that early exposure (in utero and preweaning) to a methyl donor supplemented diet would alter the developmental trajectory of repetitive behavior. Such dietary exposure resulted in significant attenuation of repetitive motor behavior development, persisting through early adulthood. This was despite mice being housed in standard cages and maintained on a standard diet, postweaning. Early exposure to methyl donor supplementation not only affected the frequency of repetitive behavior but also its temporal structure, resulting in more variable patterns of repetitive behavior. Early exposure to the diet was also shown to induce long-lasting increases in DNA methylation in brain tissue of female mice. The role for alterations in DNA methylation in this model may be one mechanism accounting for the robust effects of the environment on the development of repetitive behavior.

Stereotyped behavior is rhythmic, repetitive movement that is essentially invariant in form. Stereotypy is common in several clinical disorders, such as autism spectrum disorders (ASD), where it is considered maladaptive. However, it also occurs early in typical development (TD) where it is hypothesized to serve as the foundation on which complex, adaptive motor behavior develops. This transition from stereotyped to complex movement in TD is thought to be supported by sensorimotor integration. Stereotypy in clinical disorders may persist due to deficits in sensorimotor integration. The present study assessed whether differences in sensorimotor processing may limit the expression of complex motor behavior in individuals with ASD and contribute to the clinical stereotypy observed in this population. Adult participants with ASD and TD performed a computer-based stimulus-tracking task in the presence and absence of visual feedback. Electroencephalography was recorded during the task. Groups were compared on motor performance (root mean square error), motor complexity (sample entropy), and neural complexity (multiscale sample entropy of the electroencephalography signal) in the presence and absence of visual feedback. No group differences were found for motor performance or motor complexity. The ASD group demonstrated greater neural complexity and greater differences between feedback conditions than TD individuals, specifically in signals relevant to sensorimotor processing. Motor performance and motor complexity correlated with clinical stereotypy in the ASD group. These findings support the hypothesis that individuals with ASD have differences in sensorimotor processing when executing complex motor behavior and that stereotypy is associated with low motor complexity.

Caudate nucleus volume is enlarged in autism spectrum disorder (ASD) and is associated with restricted and repetitive behaviors (RRBs). However, the trajectory of caudate nucleus volume in RRBs of young children remains unclear. Caudate nucleus volume was measured in 36 children with ASD and 18 matched 2–3-year-old subjects with developmentally delayed (DD) at baseline (Time 1) and at 2-year follow-up (Time 2). The differential growth rate in caudate nucleus volume was calculated. Further, the relationships between the development of caudate nucleus volume and RRBs were analyzed. Our results showed that caudate nucleus volume was significantly larger in the ASD group at both time points and the magnitude of enlargement was greater at Time 2. The rate of caudate nucleus growth during this 2-year interval was faster in children with ASD than DD. Right caudate nucleus volume growth was negatively correlated with RRBs. Findings from this study suggest developmental abnormalities of caudate nucleus volume in ASD. Longitudinal MRI studies are needed to explore the correlation between atypical growth patterns of caudate nucleus and phenotype of RRBs.

Sensorimotor processing alterations are a growing focus in the assessment and treatment of Autism Spectrum Disorders (ASD). The rotational vestibulo-ocular reflex (rVOR), which functions to maintain stable vision during head movements, is a sensorimotor system that may be useful in understanding such alterations and their underlying neurobiology. In this study, we assessed post-rotary nystagmus elicited by continuous whole body rotation among children with high-functioning ASD and typically developing children. Children with ASD exhibited increased rVOR gain, the ratio of eye velocity to head velocity, indicating a possible lack of cerebellar inhibitory input to brainstem vestibular nuclei in this population. The ASD group also showed less regular or periodic horizontal eye movements as indexed by greater variance accounted for by multiple higher frequency bandwidths as well as greater entropy scores compared to typically developing children. The decreased regularity or dysrhythmia in the temporal structure of nystagmus beats in children with ASD may be due to alterations in cerebellum and brainstem circuitry. These findings could potentially serve as a model to better understand the functional effects of differences in these brain structures in ASD. Autism Res 2017, 10: 251-266. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Repetitive behaviors are seemingly purposeless patterns of behavior that vary little in form and are characteristic of many neurodevelopmental, psychiatric, and neurologic disorders. Our work has identified an association between hypofunctioning of the indirect basal ganglia pathway and the expression of repetitive behavior in the deer mouse model. In this study, we targeted indirect pathway cells of the striatum with single drugs and drug combinations that bind to dopamine D

Restricted, repetitive behaviors (RRBs) are patterns of behavior that exhibit little variation in form and have no obvious function. RRBs although transdiagonstic are a particularly prominent feature of certain neurodevelopmental disorders, yet relatively little is known about the neural circuitry of RRBs. Past work in this area has focused on isolated brain regions and neurotransmitter systems, but implementing a neural circuit approach has the potential to greatly improve understanding of RRBs. Magnetic resonance imaging (MRI) is well-suited to studying the structural and functional connectivity of the nervous system, and is a highly translational research tool. In this review, we synthesize MRI research from both neurodevelopmental disorders and relevant animal models that informs the neural circuitry of RRB. Together, these studies implicate distributed neural circuits between the cortex, basal ganglia, and cerebellum. Despite progress in neuroimaging of RRB, there are many opportunities for conceptual and methodological improvement. We conclude by suggesting future directions for MRI research in RRB, and how such studies can benefit from complementary approaches in neuroscience.

Repetitive behaviors are diagnostic for autism spectrum disorders, common in related neurodevelopmental disorders, and normative in typical development. In order to identify factors that mediate repetitive behavior development, it is necessary to characterize the expression of these behaviors from an early age. Extending previous findings, we characterized further the ontogeny of stereotyped motor behavior both in terms of frequency and temporal organization in deer mice. A three group trajectory model provided a good fit to the frequencies of stereotyped behavior across eight developmental time points. Group based trajectory analysis using a measure of temporal organization of stereotyped behavior also resulted in a three group solution. Additionally, as the frequency of stereotyped behavior increased with age, the temporal distribution of stereotyped responses became increasingly regular or organized indicating a strong association between these measures. Classification tree and principal components analysis showed that accurate classification of trajectory group could be done with fewer observations. This ability to identify trajectory group membership earlier in development allows for examination of a wide range of variables, both experiential and biological, to determine their impact on altering the expected trajectory of repetitive behavior across development. Such studies would have important implications for treatment efforts in neurodevelopmental disorders such as autism.

Restricted, repetitive behaviors are diagnostic for autism and prevalent in other neurodevelopmental disorders. These behaviors cluster as repetitive sensory-motor behaviors and behaviors reflecting resistance to change. The C58 mouse strain is a promising model for these behaviors as it emits high rates of aberrant repetitive sensory-motor behaviors. The purpose of the present study was to extend characterization of the C58 model to resistance to change. This was done by comparing C58 to C57BL/6 mice on a reversal learning task under either a 100% or 80%/20% probabilistic reinforcement schedule. In addition, the effect of environmental enrichment on performance of this task was assessed as this rearing condition markedly reduces repetitive sensory-motor behavior in C58 mice. Little difference was observed between C58 and control mice under a 100% schedule of reinforcement. The 80%/20% probabilistic schedule of reinforcement generated substantial strain differences, however. Importantly, no strain difference was observed in acquisition, but C58 mice were markedly impaired in their ability to reverse their pattern of responding from the previously high density reinforcement side. Environmental enrichment did not impact acquisition under the probabilistic reinforcement schedule, but enriched C58 mice performed significantly better than standard housed C58 mice in reversal learning. Thus, C58 mice exhibit behaviors that reflect both repetitive sensory motor behaviors as well as behavior that reflects resistance to change. Moreover, both clusters of repetitive behavior were attenuated by environmental enrichment. Such findings, along with the reported social deficits in C58 mice, increase the translational value of this mouse model to autism.

Complex motor behavior is believed to be dependent on sensorimotor integration – the neural process of using sensory input to plan, guide, and correct movements. Previous studies have shown that the complexity of motor output is low when sensory feedback is withheld during precision motor tasks. However, much of this research has focused on motor behavior rather than neural processing, and therefore, has not specifically assessed the role of sensorimotor neural functioning in the execution of complex motor behavior. The present study uses a stimulus-tracking task with simultaneous electroencephalography (EEG) recording to assess the effect of visual feedback on motor performance, motor complexity, and sensorimotor neural processing in healthy adults. The complexity of the EEG signal was analyzed to capture the information content in frequency bands (alpha and beta) and scalp regions (central, parietal, and occipital) that are associated with sensorimotor processing. Consistent with previous literature, motor performance and its complexity were higher when visual feedback was provided relative to when it was withheld. The complexity of the neural signal was also higher when visual feedback was provided. This was most robust at frequency bands (alpha and beta) and scalp regions (parietal and occipital) associated with sensorimotor processing. The findings show that visual feedback increases the information available to the brain when generating complex, adaptive motor output.

The favorable consequences of environmental enrichment (EE) on brain and behavior development are well documented. Much less is known, however, about transgenerational benefits of EE on non-enriched offspring. We explored whether transgenerational effects of EE might extend to the development of repetitive motor behaviors in deer mice. Repetitive motor behaviors are invariant patterns of movement that, across species, can be reduced by EE. We found that EE not only attenuated the development of repetitive behavior in dams, but also in their non-enriched offspring. Moreover, maternal behavior did not seem to mediate the transgenerational effect we found, although repetitive behavior was affected by reproductive experience. These data support a beneficial transgenerational effect of EE on repetitive behavior development and suggest a novel benefit of reproductive experience.

Aberrant repetitive behaviors are commonly observed in a variety of neurodevelopmental, neurological, and neuropsychiatric disorders. Little is known about the specific neurobiological mechanisms that underlie such behaviors, however, and effective treatments are lacking. Valid animal models can aid substantially in identifying pathophysiological factors mediating aberrant repetitive behavior and aid in treatment development. The C58 inbred mouse strain is a particularly promising model, and we have further characterized its repetitive behavior phenotype. Compared to C57BL/6 mice, C58 mice exhibit high rates of spontaneous hindlimb jumping and backward somersaulting reaching adult frequencies by 5 weeks post-weaning and adult temporal organization by 2 weeks post-weaning. The development of repetitive behavior in C58 mice was markedly attenuated by rearing these mice in larger, more complex environments. In addition to characterizing repetitive motor behavior, we also assessed related forms of inflexible behavior that reflect restricted and perseverative responding. Contrary to our hypothesis, C58 mice did not exhibit increased marble burying nor did they display reduced exploratory behavior in the holeboard task. The C58 strain appears to be a very useful model for the repetitive motor behavior characteristic of a number of clinical disorders. As an inbred mouse strain, studies using the C58 model can take full advantage of the tool kit of modern genetics and molecular neuroscience. This technical advantage makes the model a compelling choice for use in studies designed to elucidate the etiology and pathophysiology of aberrant repetitive behavior. Such findings should, in turn, translate into effective new treatments.

Background Self-injurious behaviour (SIB) is a devastating problem observed in individuals with various neurodevelopmental disorders, including specific genetic syndromes as well as idiopathic intellectual and developmental disability. Although an increased prevalence of SIB has been documented in specific genetic mutations, little is known about the neurobiological basis of SIB. This makes vulnerability assessment and pharmacological treatment incredibly challenging. Method Here we review evidence that SIB and other repetitive, invariant behaviours, such as stereotypy, compulsions and tics, share many phenotypic similarities, are often co-morbidly expressed and have common inducing conditions. This argues for shared or overlapping pathophysiology. As much more is known about the neurobiology of these related disorders, this should make the neurobiology of SIB a more tractable problem. Results Stereotypy, compulsions and tics are diagnostic for disorders that have received focused neurobiological investigation (autism, obsessive compulsive disorder, Tourette syndrome, respectively). In addition, animal models of these repetitive behaviours have been well characterised. Collectively, these studies have found that cortical basal ganglia circuitry dysfunction mediates repetitive behaviour. Moreover, these studies provide more detailed information and potentially testable hypotheses about specific aspects of the circuitry that may be operative in SIB. Conclusions We can use available information from clinical and animal models to make more precise hypotheses regarding the particular pathophysiology driving SIB. The results of testing such hypotheses should generate pharmacological strategies that may prove efficacious in reducing SIB.

jir_ 1485 Abstract Background Self-injurious behaviour (SIB) is prevalent in neurodevelopmental disorders, but its expression is highly variable within, and between diagnostic categories. This raises questions about the factors that contribute to aetiology and expres- sion of SIB. Expression of SIB is generally described in relation to social reinforcement. However, variables that predispose vulnerability have not been as clearly characterised. This study reports the aetiology and expression of self-injury in an animal model of pemoline-induced SIB. It describes changes in gross neuronal activity in selected brain regions after chronic treatment with pemoline, and it describes the impact that a history of social defeat stress has on the subsequent expres- sion of SIB during pemoline treatment. Methods Experiment 1 - Male Long-Evans rats were injected on each of five consecutive days with pemoline or vehicle, and the expression of SIB was evaluated using a rating scale. The brains were har- vested on the morning of the sixth day, and were assayed for expression of cytochrome oxidase, an

Restricted and repetitive behavior (RRB) is a group of heterogeneous maladaptive behaviors. RRB is one of the key diagnostic features of autism spectrum disorders (ASDs) and also commonly observed in Prader–Willi syndrome (PWS). In this study, we assessed RRB using the Repetitive Behavior Scale-Revised (RBS-R) in two ASD samples (University of Illinois at Chicago [UIC] and University of Florida [UF]) and one PWS sample. We compared the RBS-R item endorsements across three ASD cohorts (UIC, UF and an ASD sample from Lam, The Repetitive Behavior Scale-Revised: independent validation and the effect of subject variables, PhD thesis, 2004), and a PWS sample. We also compared the mean RBS-R subscale/sum scores across the UIC, UF and PWS samples; across the combined ASD (UIC + UF), PWS-deletion and PWS-disomy groups; and across the combined ASD sample, PWS subgroup with a Social Communication Questionnaire (SCQ) score ≥15, and PWS subgroup with a SCQ score

Repetitive motor behaviors are common in neurodevelopmental, psychiatric, and neurological disorders. Despite their prevalence in certain clinical populations, our understanding of the neurobiological cause of repetitive behavior is lacking. Likewise, not knowing the pathophysiology has precluded efforts to find effective drug treatments. Our comparisons between mouse strains that differ in their expression of repetitive behavior revealed an important role of the subthalamic nucleus. In mice with high rates of repetitive behavior, we found significant differences in dendritic spine density, gene expression, and neuronal activation in the subthalamic nucleus. Taken together, these data demonstrate a hypoglutamatergic state. Furthermore, by using environmental enrichment to reduce repetitive behavior, we found evidence of increased glutamatergic tone in the subthalamic nucleus with our measures of spine density and gene expression. These results suggest the subthalamic nucleus is a major contributor to repetitive behavior expression and highlight the potential of drugs that increase subthalamic nucleus function to reduce repetitive behavior in clinical populations.

Stereotyped motor behaviors are a common consequence of environmental restriction in a wide variety of species. Although environmental enrichment has been shown to substantially reduce stereotypy levels, the various components of enrichment have not been evaluated independently to determine which is responsible for this effect. Exercise, particularly voluntary wheel running, is a promising candidate based on several lines of behavioral and neurobiological evidence. To test the hypothesis that access to wheel running will reduce stereotyped motor behavior, we reared deer mice from weaning with continuous access to either a functional running wheel or a locked wheel. We assessed running behavior throughout this time period and stereotypy levels in a test context at 30 and 45 days post-weaning. We found that exercise did not significantly affect stereotypy level nor was there an association between wheel running and stereotypy. Thus, exercise alone, unlike environmental enrichment, does not prevent the development of stereotypy. These results have important implications for animal welfare.

Interleukin-2 (IL-2) has been implicated in the pathogenesis of neurodevelopmental and neurodegenerative disorders. Studies from our lab have shown that adult IL-2 knockout (KO) mice exhibit septohippocampal pathology and related behavioral deficits. Compared to IL-2 wild-type (WT) mice, IL-2 KO mice have a marked and selective loss of septal cholinergic neurons that occurs between the third postnatal week and adulthood. Given that the development of septal neurons is completed by embryonic day 17 and that IL-2 KO mice exhibit peripheral autoimmunity that develops progressively post-weaning, our data and others led us to postulate that the loss of septal neurons in adult IL-2 KO mice is due to selective autoimmune neurodegeneration that coincides with increasing levels of peripheral autoimmunity. Thus, the present study tested the hypotheses: (1) that T cells selectively target the septum, and; (2) that T lymphocyte infiltration to the septum would correlate with peripheral autoimmune disease. We quantified CD3(+) T cells in the septum, hippocampus, and cerebellum of IL-2 KO and IL-2 WT mice at ages ranging from 2 to 14 weeks. T cells infiltrated the brains of IL-2 deficient mice, but were not selective for the septum. Brain T lymphocyte levels in IL-2 KO mice correlated positively with the degree of peripheral autoimmunity. We did not detect CD19(+) B lymphocytes, IgG-positive lymphocytes or IgG deposition indicative of autoantibodies in the brains of IL-2 KO mice. Further study is needed to understand how IL-2 deficiency-induced autoimmune T lymphocytes interact with endogenous brain cells to alter function and promote disease.

Stereotyped behavior is commonly observed in neurodevelopmental disorders (e.g., autism, intellectual and developmental disability) and in a wide variety of animal species maintained in restricted environments. Stereotyped behavior can also be induced by psychostimulants, an effect potentiated by repeated intermittent exposure to these drugs (behavioral sensitization). The present study evaluated whether similar neuroadaptations in cortical–basal ganglia circuitry underlie the expression and development of spontaneous stereotypy and psychostimulant-induced sensitization. Sensitization was induced in deer mice with the degree of sensitization being dependent on housing condition but not age or environmental context. Environmentally enriched animals showed the least behavioral sensitization. Despite demonstrating robust sensitization in both older and younger animals, independent of context, behavioral sensitization was not associated with any alteration in the development or expression of spontaneous stereotypy in deer mice. Moreover, the frequency of baseline spontaneous stereotypy did not predict response to amphetamine challenge in either sensitized or non-sensitized mice. Thus, the present findings do not support the notion that sensitization-related neuroadaptations in cortical–basal ganglia circuitry are similar to those neuroadaptations that underlie spontaneous or environmentally linked stereotypy.

Restricted, repetitive behaviors (RRBs) are heterogeneous ranging from stereotypic body movements to rituals to restricted interests. RRBs are most strongly associated with autism but occur in a number of other clinical disorders as well as in typical development. There does not seem to be a category of RRB that is unique or specific to autism and RRB does not seem to be robustly correlated with specific cognitive, sensory or motor abnormalities in autism. Despite its clinical significance, little is known about the pathophysiology of RRB. Both clinical and animal models studies link repetitive behaviors to genetic mutations and a number of specific genetic syndromes have RRBs as part of the clinical phenotype. Genetic risk factors may interact with experiential factors resulting in the extremes in repetitive behavior phenotypic expression that characterize autism. Few studies of individuals with autism have correlated MRI findings and RRBs and no attempt has been made to associate RRB and post-mortem tissue findings. Available clinical and animal models data indicate functional and structural alterations in cortical-basal ganglia circuitry in the expression of RRB, however. Our own studies point to reduced activity of the indirect basal ganglia pathway being associated with high levels of repetitive behavior in an animal model. These findings, if generalizable, suggest specific therapeutic targets. These, and perhaps other, perturbations to cortical basal ganglia circuitry are mediated by specific molecular mechanisms (e.g., altered gene expression) that result in long-term, experience-dependent neuroadaptations that initiate and maintain repetitive behavior. A great deal more research is needed to uncover such mechanisms. Work in areas such as substance abuse, OCD, Tourette syndrome, Parkinson’s disease, and dementias promise to provide findings critical for identifying neurobiological mechanisms relevant to RRB in autism. Moreover, basic research in areas such as birdsong, habit formation, and procedural learning may provide additional, much needed clues. Understanding the pathophysioloy of repetitive behavior will be critical to identifying novel therapeutic targets and strategies for individuals with autism.

The relationship of cardiac activity to stereotyped behaviour was studied in profoundly mentally retarded persons, using both intra- and inter-group comparisons. The first intra-group comparison involved examining the relative magnitude of an orienting response to an auditory stimulus during the occurrence or nonoccurrence of stereotyped body rocking. While no differences were found between periods of rocking and non-rocking when behavioural measures of orienting were used, smaller changes in post-tone heart rate were observed during periods of stereotyped rocking. A second intra-group comparison found that stereotyped behaviour was associated with a significant increase in heart rate but no change in heart rate variability when compared to periods of no stereotyped activity. Finally, using an inter-group comparison, individuals who displayed stereotyped body rocking exhibited higher tonic heart rates and lower heart rate variability during periods of no stereotyped behaviour than was observed in matched control subjects. This result suggests that stereotyped behaviour may be correlated with reduced vagal tone.

Little is known about the mechanisms mediating the development of repetitive behaviors in human or animals. Deer mice reared with environmental enrichment (EE) exhibit fewer repetitive behaviors and greater indirect basal ganglia pathway activation as adults than those reared in standard cages. The developmental progression of these behavioral and neural circuitry changes has not been characterized. We assessed the development of repetitive behavior in deer mice using both a longitudinal and cohort design. Repeated testing negated the expected effect of EE, but cohort analyses showed that progression of repetitive behavior was arrested after one week of EE and differed significantly from controls after 3 weeks. Moreover, EE reductions in repetitive behavior were associated with increasing activation of indirect pathway nuclei in males across adolescence, but not females. These findings provide the first assessment of developmental trajectories within EE and support indirect pathway mediation of repetitive behavior in male deer mice.

Repetitive motor behaviors are observed in many neurodevelopmental and neurological disorders (e.g., autism spectrum disorders, Tourette syndrome, fronto-temporal dementia). Despite their clinical importance, the neurobiology underlying these highly stereotyped, apparently functionless behaviors is poorly understood. Identification of mechanisms that mediate the development of repetitive behaviors will aid in the discovery of new therapeutic targets and treatment development. Using a deer mouse model, we have shown that decreased indirect basal ganglia pathway activity is associated with high levels of repetitive behavior. Environmental enrichment (EE) markedly attenuates the development of such aberrant behaviors in mice, although mechanisms driving this effect are unknown. We hypothesized that EE would reduce repetitive motor behaviors by increasing indirect basal ganglia pathway function. We assessed neuronal activation and dendritic spine density in basal ganglia of adult deer mice reared in EE and standard housing. Significant increases in neuronal activation and dendritic spine densities were observed only in the subthalamic nucleus (STN) and globus pallidus (GP), and only for those mice that exhibited an EE-induced decrease in repetitive motor behavior. As the STN and GP lie within the indirect pathway, these data suggest that EE-induced attenuation of repetitive motor behaviors is associated with increased functional activation of the indirect basal ganglia pathway. These results are consistent with our other findings highlighting the importance of the indirect pathway in mediating repetitive motor behaviors.

Repetitive behavior refers to a highly heterogeneous set of responses associated with a wide range of conditions, including normative development. Treatment studies for aberrant repetitive behavior are limited although one promising approach involves conceptualizing such behavior as a generalized inflexibility or lack of variability in responding. Relatively little is known about the neurobiological mechanisms that mediate the development and expression of repetitive behavior, information critical to the design of effective pharmacotherapies, early interventions, and prevention strategies. We will review clinical findings in repetitive behavior as well as findings from animal models highlighting environmental factors and the role of cortical-basal ganglia circuitry in mediating the development and expression of these behaviors. Findings from animal models have included identification of a specific neural pathway important in mediating repetitive behavior. Moreover, pharmacological studies that support the importance of this pathway have led to the identification of novel potential therapeutic targets. Expanding the evidence base for environmental enrichment-derived interventions and focusing on generalized variability in responding will aid in addressing the broader problem of rigidity or inflexibility.

Sensorimotor processing alterations are a growing focus in the assessment and treatment of Autism Spectrum Disorders (ASD). The rotational vestibulo-ocular reflex (rVOR), which functions to maintain stable vision during head movements, is a sensorimotor system that may be useful in understanding such alterations and their underlying neurobiology. In this study, we assessed post-rotary nystagmus elicited by continuous whole body rotation among children with high-functioning ASD and typically developing children. Children with ASD exhibited increased rVOR gain, the ratio of eye velocity to head velocity, indicating a possible lack of cerebellar inhibitory input to brainstem vestibular nuclei in this population. The ASD group also showed less regular or periodic horizontal eye movements as indexed by greater variance accounted for by multiple higher frequency bandwidths as well as greater entropy scores compared to typically developing children. The decreased regularity or dysrhythmia in the temporal structure of nystagmus beats in children with ASD may be due to alterations in cerebellum and brainstem circuitry. These findings could potentially serve as a model to better understand the functional effects of differences in these brain structures in ASD. Autism Res 2017, 10: 251-266. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Spontaneous and persistent stereotypies exhibited by deer mice appear to be prevented by post-weaning rearing in a larger, more complex environment. We sought to determine: (1) if exposure to an enriched environment later in development would still be efficacious in reducing stereotypy, and (2) if exposure to an enriched environment would prevent the development of stereotypy after animals were returned to standard laboratory cages. Enriched housing (24–84 days of age) was associated with substantially lower levels of stereotypy. Moreover, environmental enrichment experienced later in development (84–124 days of age) was as effective as early enrichment. This was not the case, however, for older animals (11–14 months of age) that experienced the same duration of enriched housing. The beneficial effects of early enrichment were found to persist as mice placed in standard cages following enrichment exhibited lower levels of stereotypy than controls. These findings support a sensitive period for the amelioration of abnormal repetitive behavior and suggest a neuroprotective effect of this form of early experience.

Background A subgroup of children with obsessive-compulsive and tic disorders are proposed to have an infectious trigger. The purpose of this study was to investigate the relationship between group A streptococcal titers and symptom fluctuations in children with a clinical course resembling that described for pediatric autoimmune neuropsychiatric disorders associated with streptococcus. Methods Twenty-five children with obsessive-compulsive disorder and/or tic disorder were evaluated for neuropsychiatric severity and group A streptococcal antibody titers (streptolysin O, deoxyribonuclease B, and carbohydrate A) at 6-week intervals for ≥ six consecutive evaluations (total visits=277). Results Children with large symptom fluctuations ( n = 15) were compared with children without dramatic fluctuations ( n = 10). Co-movements of obsessive-compulsive/tic severity and group A streptococcal antibodies were assessed. In subjects with large symptom changes, positive correlations were found between streptococcal titers and obsessive-compulsive severity rating changes ( p = .0130). These subjects were also more likely to have elevated group A streptococcal titers during the majority of observations ( p = .001). Tic symptom exacerbations occurred more often in the fall/winter months than spring/summer months ( p = .03). Conclusions Patients with marked obsessive-compulsive/tic symptom changes may be characterized by streptococcal titer elevations and exhibit evidence of seasonal tic exacerbations.

Abnormal repetitive behaviors are often associated with specific developmental, genetic, and neuropsychiatric disorders. Repetitive motor behaviors, often referred to as stereotypies, have been studied extensively as they can be readily induced by certain drugs (e.g., amphetamine). Recent work has shown, however, that such drug-induced models of stereotypy may not accurately reflect the neurobiological perturbations responsible for the spontaneous manifestation of these behaviors. The present study employed the deer mouse model of spontaneous and persistent stereotypy to evaluate the capacity of several selective dopaminergic agonists (apomorphine, SKF81297, and quinpirole) to exacerbate levels of spontaneously emitted stereotypic topographies when administered intrastriatally. Additionally, the effects of intrastriatal administration of the D(2)R antagonist raclopride on the expression of spontaneous stereotypic jumping were evaluated. No induction or exacerbation of stereotypy was observed following administration of the selective D(1)- or D(2)- receptor agonists, and the mixed agonist apomorphine induced hyperlocomotion and excessive grooming but failed to exacerbate spontaneous stereotypy. Thus, a dissociation was observed between spontaneously emitted and drug-induced stereotypy, suggesting significant limitations to the use of dopamine agonist-induced stereotypy as a model of clinical stereotyped movement disorder. Furthermore, an unexpected and statistically significant (P

Traditional models of toxicity have relied on dissecting chemical action into pharmacokinetic and pharmacodynamic processes. However, the integration of genomic information with toxicology will enhance our basic understanding of these processes and significantly change the way we apply toxicological information to risk assessment and regulatory problems. In this article, we summarize the application of gene expression information and polymorphism discovery to four areas in toxicology: toxicity testing, cross-species extrapolation, understanding mechanism of action, and susceptibility.

The present study evaluated whether environmental enrichment-related effects on the development of stereotyped behavior in deer mice were associated with alterations in neuronal metabolic activity. Deer mice were reared under either enriched or standard housing conditions for 60 days following weaning. All mice were then placed in automated photocell detectors and classified as either stereotypic or non-stereotypic. Neuronal metabolic activity was then assessed using cytochrome oxidase (CO) histochemistry. The results demonstrated that environmental enrichment significantly increased neuronal metabolic activity in the motor cortex. Furthermore, non-stereotypic mice exhibited significantly more CO activity than stereotypic mice in the cortex, striatum, nucleus accumbens, thalamus, hippocampus and amygdala. This latter effect was due to the enriched mice as evidenced by a significant interaction between housing condition and behavioral status in the cortex, striatum, nucleus accumbens, thalamus and hippocampus. Thus, the observed increase in CO activity reflected increased neuronal metabolic activity in non-stereotypic enriched mice relative to stereotypic enriched mice. These results suggest that, in a developmental model of spontaneous stereotypy, the enrichment-related prevention of stereotyped behavior is associated with increased CO activity.

Sensorimotor issues are of increasing focus in the assessment and treatment of Autism Spectrum Disorders (ASD). The oculomotor system is a sensorimotor network that can provide insights into functional neurobiology and has well-established methodologies for investigation. In this study, we assessed oculomotor performance among children with high functioning ASD and typically developing children, ages 6-12 years. Children with ASD exhibited greater horizontal saccade latency and greater phase lag during vertical smooth pursuit. Saccades and smooth pursuit are mediated by spatially distant brain regions and the long-fiber tracts connecting them, many of which are implicated in ASD. Training paradigms for oculomotor deficits have shown positive outcomes in other clinical populations, and deficits described here may provide useful targets for interventions.

This paper summarizes a conference held at the National Institute of Child Health and Human Development on December 6-7, 1999, on self-injurious behavior [SIB] in developmental disabilities. Twenty-six of the top researchers in the U.S. from this field representing 13 different disciplines discussed environmental mechanisms, epidemiology, behavioral and pharmacological intervention strategies, neurochemical substrates, genetic syndromes in which SIB is a prominent behavioral phenotype, neurobiological and neurodevelopmental factors affecting SIB in humans as well as a variety of animal models of SIB. Findings over the last decade, especially new discoveries since 1995, were emphasized. SIB is a rapidly growing area of scientific interest to both basic and applied researchers. In many respects it is a model for the study of gene-brain-behavior relationships in developmental disabilities.

Stereotyped behaviors (e.g., body rocking) occur at high rates in individuals with mental retardation (e.g., Down syndrome). To determine if spontaneous stereotypy occurs in a murine model of Down syndrome, the home cage behavior of Ts65Dn and control mice was monitored during the dark cycle. Motor activity was further assessed in novel automated test chambers, with acoustic startle and rotor rod paradigms providing additional environmental challenges. Spontaneous stereotypy (repetitive jumping and cage top twirling) was observed in the home cage in approximately half of the Ts65Dn mice, compared with approximately 10% of diploid controls. Repetitive jumping was observed exclusively in the Ts65Dn mice. In the open field, although no differences were found between Ts65Dn and control mice, stereotypic Ts65Dn mice exhibited significantly less locomotor activity and rearing relative to control and nonstereotypic Ts65Dn mice. Ts65Dn mice attained significantly lower rotor rod speeds but did not differ from controls in the amplitude of the acoustic startle response. These environmental challenges did not increase stereotypy over home cage rates but induced stereotypy in two additional animals. The Ts65Dn model may aid in identifying genes associated with the development and expression of stereotypy.

Systematic study of abnormal repetitive behaviors in autism has been lacking despite the diagnostic significance of such behavior. The occurrence of specific topographies of repetitive behaviors as well as their severity was assessed in individuals with mental retardation with and without autism. The occurrence of each behavior category, except dyskinesias, was higher in the autism group and autistic subjects exhibited a significantly greater number of topographies of stereotypy and compulsions. Both groups had significant patterns of repetitive behavior co-occurrence. Autistic subjects had significantly greater severity ratings for compulsions, stereotypy, and self-injury. Repetitive behavior severity also predicted severity of autism. Although abnormal repetition is not specific to autism, an elevated pattern of occurrence and severity appears to characterize the disorder.

Abnormal repetitive behaviors such as stereotypies are associated with neurodevelopmental disorders and are often observed under conditions of environmental restriction, particularly early in development. Few studies, however, have systematically assessed the effects of environmental enrichment and almost no information is available as to whether a sensitive period exists for such enrichment effects. We hypothesized that spontaneous stereotypies exhibited by deer mice housed under standard laboratory conditions were the result of environmental restriction and that a sensitive period exists for the development/prevention of stereotypies. Exposure to a more complex environment early in the post-weaning period resulted in substantially less stereotypy in the complex environment. Importantly, this outcome was maintained even after mice were housed in standard cages for an identical period of time. Later exposure to the more complex environment also resulted in significantly lower levels of stereotypy compared to controls. These effects were observed in the experimental housing condition as well as in a standard test context. The effects of early and late enrichment support the importance of environmental restriction in the genesis of stereotypye and provide support for the efficacy of early and late enrichment in the prevention of stereotypies. © 2000 John Wiley & Sons, Inc. Dev Psychobiol 37: 100–108, 2000

Brain-derived neurotrophic factor (BDNF) was expressed via injection of viral vector into the substantia nigra pars compacta (SNc) to investigate its influence on nigrostriatal dopaminergic activity and locomotor behavior. The recombinant adeno-associated virus (rAAV) vector, pTR-BDNFmyc, incorporated the neuron-specific enolase (NSE) promoter and the internal ribosome entry site (IRES) element driving expression of both epitope-tagged BDNF and green fluorescent protein (GFP) bicistronically. The control vector, pTR-UF4, incorporated NSE promoter-driven GFP expression only. Transgene expression persisted in both vector groups throughout the 9 month course of the study. Partial 6-hydroxydopamine (6-OHDA) lesions were conducted in the SNc ipsilateral to, and 6 months after, transduction with either the pTR-BDNFmyc or the pTR-UF4. Transgenic BDNFmyc had no effect on the number of tyrosine hydroxylase (TH)-labeled neurons in the SNc after 6-OHDA-lesions, but did block the amphetamine-induced, ipsiversive, turning-behavior caused by the lesion in the pTR-UF4 group. The BDNFmyc-transduced group also demonstrated more locomotor activity and rotational activity contralateral to the lesioned side than did the pTR-UF4-transduced group. Long-term, stable expression of BDNF can therefore modulate locomotor activity without significantly affecting nigrostriatal dopaminergic survival.

In previous studies, we found differences in cellular immune responsiveness in Institute for Cancer Research (ICR) mice selectively bred for high and low levels of aggression. Compared to the high aggressive line, the low aggressive line had low levels of natural killer (NK) and T cell activity and increased susceptibility to tumor development. To dissect further this novel association, experiments were designed to test two competing hypotheses. The first hypothesis was that the phenotypic expression of the line differences in NK cell activity are dependent on and regulated by the expression of high and low levels aggressive behavior in the lines. The alternative hypothesis was that the differences in immune status are independent of the expression of aggression by the lines, suggesting linkage between a subset of genes involved in determining these complex behavioral and immunological traits or pleiotropic gene effects on both traits. In Experiment 1, three conditions of postweaning social experience (mice singly housed, group housed within line, or group housed between lines) were tested in males to determine whether experiential conditions which modify the expression of aggression would in turn modify the line differences in NK cell activity. This experiment revealed that the difference in NK cell activity between high aggressive and low aggressive male mice was attributable to line only. The different postweaning social conditions examined had no effect on modifying the differences in NK activity, and social dominance hierarchy did not correlate with levels of NK cell activity. Whereas males of the high and low lines exhibit differences in aggressive behaviors across most contexts, females do not exhibit such differences except in response to an intruder during the postpartum period. Therefore, in Experiment 2 we compared the NK cell activity of nulliparous females of the high and low aggressive lines. Under these conditions, females of the low aggressive line had low levels of NK activity compared to high aggressive females (differences comparable to those seen between males of the high and low lines). Taken together, these experiments lend support to the hypothesis that this association may be due to a genetic linkage between subsets of genes involved in determining these complex behavioral and immunological traits, or may possibly represent a fortuitous association which occurred during the selective breeding.

Stereotypies are patterns of motor behavior that are repetitive, excessive, topographically invariant, and that lack any obvious function or purpose. In humans, stereotyped behaviors are associated with psychiatric, neurological, and developmental disorders. In animals, stereotypy has been frequently associated with adverse environmental circumstances and often related to alterations in striatal dopamine. To assess the development of stereotyped behaviors and to test the hypothesis that these behaviors are associated with environmental restriction, deer mice were housed in either standard laboratory cages or larger, enriched cages, and the development of stereotypy was followed from weaning over a 17-week period. Standard-caged deer mice engaged in stereotyped behaviors at a higher rate and developed these behaviors more quickly when compared to animals in enriched caging. Additionally, enriched caging was associated with higher rates of patterned running, whereas jumping and backward somersaulting were typically observed in standard cages. In addition, there was a significant effect of litter, but no effect of sex or cage, on the time to develop stereotypy. No differences were found in the density of either striatal D1 or D2 dopamine receptors or the concentration of striatal dopamine or its metabolites as a function of rearing condition or as a function of whether the animals developed stereotypy. These results characterize the development of stereotypies in this species, demonstrate the importance of environmental conditions in the genesis of stereotypy, and suggest that alterations in striatal dopamine content or dopamine receptor density do not account for the expression of stereotyped behaviors in this model.

The myristoylated alanine-rich C kinase substrate (MARCKS) is a prominent protein kinase C (PKC) substrate in brain that is expressed highly in hippocampal granule cells and their axons, the mossy fibers. Here, we examined hippocampal infrapyramidal mossy fiber (IP-MF) limb length and spatial learning in heterozygous Macs mutant mice that exhibit an ≈50% reduction in MARCKS expression relative to wild-type controls. On a 129B6(N3) background, the Macs mutation produced IP-MF hyperplasia, a significant increase in hippocampal PKCɛ expression, and proficient spatial learning relative to wild-type controls. However, wild-type 129B6(N3) mice exhibited phenotypic characteristics resembling inbred 129Sv mice, including IP-MF hypoplasia relative to inbred C57BL/6J mice and impaired spatial-reversal learning, suggesting a significant contribution of 129Sv background genes to wild-type and possibly mutant phenotypes. Indeed, when these mice were backcrossed with inbred C57BL/6J mice for nine generations to reduce 129Sv background genes, the Macs mutation did not effect IP-MF length or hippocampal PKCɛ expression and impaired spatial learning relative to wild-type controls, which now showed proficient spatial learning. Moreover, in a different strain (B6SJL(N1), the Macs mutation also produced a significant impairment in spatial learning that was reversed by transgenic expression of MARCKS. Collectively, these data indicate that the heterozygous Macs mutation modifies the expression of linked 129Sv gene(s), affecting hippocampal mossy fiber development and spatial learning performance, and that MARCKS plays a significant role in spatial learning processes.