Biomedical subjects

Mark H Lewis

Publications and source records attributed to Mark H Lewis.

11 recordsLinked to original sources

PubMed2005

Striatal opioid peptide content in an animal model of spontaneous stereotypic behavior.

Stereotypic behaviors are associated with a broad spectrum of developmental, psychiatric, and genetic disorders. Several lines of evidence indicate that these abnormal repetitive behaviors may be expressed as a consequence of imbalanced activity along the direct and indirect processing pathways of the basal ganglia. Because the activity of these two pathways is modulated, in part, by the neuropeptides dynorphin and enkephalin, we sought to determine whether spontaneous and persistent stereotypy is associated with alterations in striatal neuropeptide content. Specifically, the present study employed radioimmunoassay to measure dynorphin-A and leu-enkephalin content in the dorsolateral striatum of deer mice exhibiting different levels of spontaneous stereotypic jumping. The results indicate significantly decreased leu-enkephalin content and significantly increased dynorphin/enkephalin content ratios in high-stereotypy mice relative to low-stereotypy mice. Moreover, analyses revealed a significant negative correlation between striatal enkephalin content and frequency of stereotypy as well as a significant positive correlation between the dynorphin/enkephalin content ratio and frequency of stereotypy in these mice. These data are consistent with the hypothesis that spontaneous stereotypic behavior is expressed as a consequence of relative hyperactivity along cortico-basal ganglia-cortical feedback circuits involving the direct (facilitative) pathway, but suggest that primary perturbations to the indirect (inhibitory) pathway give rise to such imbalanced activity.

Animals↗

PubMed2004

Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics.

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 > or = 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.

Antibodies, Bacterial↗

PubMed2004

Environmental complexity and central nervous system development and function.

Environmental restriction or deprivation early in development can induce social, cognitive, affective, and motor abnormalities similar to those associated with autism. Conversely, rearing animals in larger, more complex environments results in enhanced brain structure and function, including increased brain weight, dendritic branching, neurogenesis, gene expression, and improved learning and memory. Moreover, in animal models of CNS insult (e.g., gene deletion), a more complex environment has attenuated or prevented the sequelae of the insult. Of relevance is the prevention of seizures and attenuation of their neuropathological sequelae as a consequence of exposure to a more complex environment. Relatively little attention, however, has been given to the issue of sensitive periods associated with such effects, the relative importance of social versus inanimate stimulation, or the unique contribution of exercise. Our studies have examined the effects of environmental complexity on the development of the restricted, repetitive behavior commonly observed in individuals with autism. In this model, a more complex environment substantially attenuates the development of the spontaneous and persistent stereotypies observed in deer mice reared in standard laboratory cages. Our findings support a sensitive period for such effects and suggest that early enrichment may have persistent neuroprotective effects after the animal is returned to a standard cage environment. Attenuation or prevention of repetitive behavior by environmental complexity was associated with increased neuronal metabolic activity, increased dendritic spine density, and elevated neurotrophin (BDNF) levels in brain regions that are part of cortical-basal ganglia circuitry. These effects were not observed in limbic areas such as the hippocampus.

Animals↗

PubMed2004

Behavior-related alterations of striatal neurochemistry in a mouse model of stereotyped movement disorder.

Motor stereotypy is a common component of several developmental, genetic, and neuropsychiatric disorders. In animals, these behaviors can be induced or attenuated via pharmacological manipulation of specific neural loci comprising cortico basal ganglia-cortical feedback circuits, including the striatum. The present study employed the deer mouse model of spontaneous and persistent stereotypy to assess the involvement of several endogenous neurotransmitters and neuromodulators in mediating the expression of the stereotypic behaviors (i.e., repetitive hindlimb jumping) exhibited by these mice. This was accomplished by employing a microdialysis sampling system coupled on-line to capillary electrophoresis with laser-induced fluorescence (CE-LIF) detection apparatus. Given the 13-s temporal resolution for analyte measurement afforded by this system, discrete behavior-related alterations in striatal neurochemical concentrations were detected. Rearing behavior was found to be associated with significant and selective elevations of striatal glutamate (Glu) and aspartate (Asp) concentrations. Moreover, rearing was found to most frequently precede repetitive jumping. The results also indicated that alterations in striatal serine (Ser) concentrations were involved in the modulation of locomotor activity. The present findings support a role of the striatal glutamatergic system in the mediation of spontaneous stereotypic behavior and suggest a potential neuronal mechanism by which transition to stereotypy occurs in these mice. Moreover, the present findings demonstrate the usefulness of the microdialysis system employed in studying the neurochemical substrates of rapidly transitioning behavior.

Amino Acids↗

PubMed2004

Effects of intrastriatal administration of selective dopaminergic ligands on spontaneous stereotypy in mice.

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<.05) potentiation of locomotor activity was observed following intrastriatal raclopride administration, suggesting major alterations to the modulatory characteristics of the striatal dopaminergic system in these spontaneously stereotypic animals.

Animals↗

PubMed2004

Effects of topiramate in adults with Prader-Willi syndrome.

Prader-Willi syndrome is a multisystem neurogenetic obesity disorder with behavioral manifestations, including hyperphagia, compulsive behavior, self-injury, and mild to moderate mental retardation. In an 8-week open-label study, we evaluated adjunctive therapy with the anticonvulsant topiramate in 8 adults with Prader-Willi syndrome. Appetite was measured by a 1-hour access to food four times throughout the study and quantified with a visual analogue scale. Topiramate did not significantly change calories consumed, Body Mass Index, or increase self-reported appetite. In addition, there were no significant changes in compulsions. Surprisingly, topiramate treatment resulted in a clinically significant improvement in the self-injury (i.e., skin-picking) that is characteristic of this syndrome. Potential benefits of topiramate for self-injury should be evaluated further in controlled trials.

Adolescent↗

PubMed2003

Environmental enrichment: effects on stereotyped behavior and dendritic morphology.

We evaluated whether environmental enrichment-related effects on the development of stereotyped behavior in deer mice were associated with alterations in dendritic morphology. Deer mice were reared under enriched or standard housing conditions and then tested in automated photocell detectors and classified as stereotypic or nonstereotypic. Dendritic morphology was assessed in layer V pyramidal neurons of the motor cortex, medium spiny neurons of the dorsolateral striatum, and granule cells of the dentate gyrus using Golgi-Cox histochemistry. Enriched nonstereotypic mice exhibited significantly higher dendritic spine densities in the motor cortex and the striatum than enriched stereotypic or standard-cage mice. Significant increases in dendritic arborization following environmental enrichment also were observed. These results suggest that the enrichment-related prevention of stereotyped behavior is associated with increased dendritic spine density.

Animals↗

PubMed2003

Environmental enrichment: effects on stereotyped behavior and neurotrophin levels.

The present study evaluated whether environmental enrichment-related effects on the development of stereotyped behavior in deer mice were associated with alterations in neurotrophin levels. Deer mice were reared in enriched or standard cage conditions for 60 days. The mice were then tested in automated photocell detectors and classified as either stereotypic or nonstereotypic. This testing paradigm yielded four behaviorally distinct groups: enriched stereotypic, enriched nonstereotypic, standard cage stereotypic, and standard cage nonstereotypic. The motor cortex, striatum, and hippocampus were dissected, and the levels of brain-derived neurotrophin factor (BDNF) and nerve growth factor (NGF) in each brain region were analyzed using Promega ELISA kits. There were no differences in either NGF or BDNF in either the motor cortex or the hippocampus. In the striatum, the enriched nonstereotypic mice exhibited significantly more BDNF than the enriched stereotypic, the standard cage nonstereotypic, or the standard cage stereotypic mice. There were no differences in NGF in the striatum. These results provide evidence that the enrichment-related prevention of stereotyped behavior in deer mice is associated with increased BDNF in the striatum.

Animals↗

PubMed2003

Selective blockade of spontaneous motor stereotypy via intrastriatal pharmacological manipulation.

Abnormal repetitive behavior, including stereotypy, is often observed in conjunction with developmental, neuropsychiatric, and genetic disorders. The present work employed the deer mouse model of spontaneous and persistent stereotypy to identify basal ganglia involvement in the mediation of these abnormal behaviors. To evaluate the hypothesis that stereotypy is expressed in these mice due to alterations in the activity of cortico-basal ganglia motor circuits, intrastriatal pharmacological manipulations aimed at attenuating the spontaneously emitted stereotypy were performed. Bilateral striatal infusion of the NMDA or dopamine D(1) receptor antagonists MK-801 or SCH23390, respectively, produced a substantial reduction in levels of stereotypic jumping without inhibiting nonstereotypic motor behavior. These findings support the hypothesis that environmentally related stereotypy is expressed as a consequence of elevated feedback activity occurring along motor circuits of the basal ganglia.

Animals↗

PubMed2002

Environmental enrichment: effects on stereotyped behavior and regional neuronal metabolic activity.

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.

Animals↗

PubMed2002

Dissociation between spontaneously emitted and apomorphine-induced stereotypy in Peromyscus maniculatus bairdii.

Stereotyped behavior is repetitive, topographically invariant motor activity that lacks an obvious function. We have previously characterized the spontaneous and persistent stereotypies that occur in deer mice housed in standard laboratory cages. Providing these animals with enriched environments markedly reduces their vulnerability to develop stereotypic behavioral repertoires, thus enabling us to generate behaviorally distinct (stereotypic and nonstereotypic) mice of the same species. As stereotypic behaviors are readily induced by systemic administration of a dopamine (DA) agonist, the present study tested whether apomorphine would induce stereotypies in environmentally enriched (nonstereotypic) deer mice that were topographically similar to the stereotypies that are spontaneously emitted by standard-caged (stereotypic) deer mice. The effects of apomorphine were also evaluated in the standard-caged (stereotypic) deer mice. DA agonist-induced behaviors in nonstereotypic mice included stereotypies that were largely topographically distinct from spontaneously emitted stereotypies; apomorphine failed to produce statistically significant elevations in two of the three stereotypic behaviors typical of standard-caged deer mice. Furthermore, there was no evidence of increased DA receptor sensitivity in stereotypic mice. Thus, environmentally related stereotypy is distinct from systemically administered DA agonist-induced stereotypy, and is not exacerbated by such drug treatment. The results obtained do provide support, however, for a limited involvement of the DA system in the mediation of these behaviors.

Animals↗