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L S Crnic

Publications and source records attributed to L S Crnic.

At least 19 recordsLinked to original sources
PubMed2006

Infant mice with glutaric acidaemia type I have increased vulnerability to 3-nitropropionic acid toxicity.

Glutaric acidaemia type I (GA I) is an inborn error of metabolism caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH) and is characterized clinically by striatal degeneration that almost always occurs in early childhood. A murine knockout model of GA I has the organic aciduria seen in the human disorder, but this model does not develop striatal degeneration spontaneously. 3-Nitropropionic acid (3NP), a succinic dehydrogenase inhibitor with specificity for the striatum, was investigated as a potential initiator of striatal degeneration in GCDH-deficient mice. This study shows that GCDH-deficient mouse pups are more susceptible to 3NP than their wild-type littermates, and that all mouse pups are more sensitive to 3NP as infants than as adolescents and adults. Increased sensitivity to 3NP early in life may model the developmental window for the striatal damage observed in human GA I.

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PubMed2006

Attentional dysfunction, impulsivity, and resistance to change in a mouse model of fragile X syndrome.

On a series of attention tasks, male mice with a mutation targeted to the fragile X mental retardation 1 (Fmrl) gene (Fmrl knockout [KO] mice) committed a higher rate of premature responses than wild-type littermates, with the largest differences seen when task contingencies changed. This finding indicates impaired inhibitory control, particularly during times of stress or arousal. The KO mice also committed a higher rate of inaccurate responses than controls, particularly during the final third of each daily test session, indicating impaired sustained attention. In the selective attention task, the unpredictable presentation of potent olfactory distractors produced a generalized disruption in the performance of the KO mice, whereas for controls, the disruption produced by the distractors was temporally limited. Finally, the attentional disruption seen following an error was more pronounced for the KO mice than for controls, further implicating impaired regulation of arousal and/or negative affect. The present study provides the first evidence that the Fmrl KO mouse is impaired in inhibitory control, attention, and arousal regulation, hallmark areas of dysfunction in fragile X syndrome. The resistance to change also seen in these mice provides a behavioral index for studying the autistic features of this disorder.

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PubMed2001

Ts65Dn mice, a model for Down syndrome, have deficits in context discrimination learning suggesting impaired hippocampal function.

The Ts65Dn mouse is segmentally trisomic for a part of mouse chromosome 16 and is a genetic model for Down syndrome and Alzheimer's disease. Although many studies have examined the learning and memory processes in Ts65Dn mice, it has yet to be determined if Ts65Dn mice are specifically impaired in learning tasks that require an intact hippocampus. Context discrimination learning is dependent on the dorsal hippocampus in mice. In this task, mice learn to discriminate two similar contexts, one of which is associated with foot shock. In the current study, Ts65Dn mice learned almost identically to what has been reported for mice with dorsal hippocampal lesions, while controls behaved similarly to sham lesioned mice. Therefore, Ts65Dn mice have learning deficits in a hippocampal dependent task that may be related to the loss of cholinergic input to the hippocampus, which occurs after 6 months of age.

Age Factors↗
PubMed2001

Motor learning in Ts65Dn mice, a model for Down syndrome.

Ts65Dn mice are a genetic model for Down syndrome. Both individuals with Down syndrome and Ts65Dn mice have reduced cerebellar volumes and the cerebellum is involved in motor learning. Conflicting results have been reported on the motor learning abilities of Ts65Dn mice, which may be related to procedural differences between the motor learning tasks used in different laboratories and/or variability in phenotype because of the segregating background on which the mice are maintained. In this study, we examined learning in three types of motor tasks (peg running, accelerating rotorod, and rotating rod) which were initially easy for mice and gradually increased in difficulty. Ts65Dn mice learned the peg running task as well as controls, and learned the accelerating rotorod and rotating rod tasks as well as, and even better than, controls. These data indicate that Ts65Dn mice are not impaired in motor learning.

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PubMed2001

Self-injurious behavior: gene-brain-behavior relationships.

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.

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PubMed2001

Age-related deficits in context discrimination learning in Ts65Dn mice that model Down syndrome and Alzheimer's disease.

All individuals with Down syndrome (DS) eventually develop the neuropathology of Alzheimer's disease (AD), which is characterized by a premature loss of basal forebrain cholinergic neurons. Similarly, between 4 and 6 months of age, Ts65Dn mice, which model DS, lose cholinergic markers in their medial septal neurons. It is not known whether Ts65Dn mice have age-related learning deficits as well. Control and Ts65Dn mice were tested at several ages in context discrimination. Controls at all ages showed no deficits in learning this task. Ts65Dn mice younger than 3 months demonstrated impaired learning, suggesting a possible developmental delay in Ts65Dn mice. Four-month-old Ts65Dn mice showed no deficits, whereas Ts65Dn mice older than 5 months were impaired in learning the task. Therefore, Ts65Dn mice have an age-related learning impairment that coincides with their age-related neuroanatomical abnormalities and, consequently, may be a useful model of AD.

Aging↗
PubMed2000

Loss of cholinergic phenotype in basal forebrain coincides with cognitive decline in a mouse model of Down's syndrome.

Mice with segmental trisomy of chromosome 16 (Ts65Dn) have been used as a model for Down's syndrome. These mice are born with a normal density of basal forebrain cholinergic neurons but, like patients with Down's syndrome, undergo a significant deterioration of these neurons later in life. The time course for this degeneration of cholinergic neurons has not been studied, nor is it known if it correlates with the progressive memory and learning deficits described. Ts65Dn mice that were 4, 6, 8, and 10 months old were sacrificed for evaluation of basal forebrain morphology. Separate groups of mice were tested on visual or spatial discrimination learning and reversal. We found no alterations in cholinergic markers in 4-month-old Ts65Dn mice, but thereafter a progressive decline in density of cholinergic neurons, as well as significant shrinkage of cell body size, was seen. A parallel loss of staining for the high-affinity nerve growth factor receptor, trkA, was observed at all time points, suggesting a biological mechanism for the cell loss involving this growth factor. Other than transient difficulty in learning the task requirements, there was no impairment of trisomic mice on visual discrimination learning and reversal, whereas spatial learning and reversal showed significant deficits, particularly in the mice over 6 months of age. Thus, the loss of ChAT-immunoreactive neurons in the basal forebrain was coupled with simultaneous deficits in behavioral flexibility on a spatial task occurring for the first time around 6 months of age. These findings suggest that the loss of cholinergic function and the simultaneous decrease in trkA immunoreactivity in basal forebrain may directly correlate with cognitive impairment in the Ts65Dn mouse

Animals↗
PubMed2000

Analysis of the expression of murine glutaryl-CoA dehydrogenase: in vitro and in vivo studies.

Glutaric acidemia type I (GAI) is an autosomal recessive organic acidemia caused by a mutation in the gene encoding glutaryl-CoA dehydrogenase (GCD). Clinically, GAI is characterized by progressive dystonia, resulting from degeneration of neurons in the caudate and putamen nuclei of the striatum. In an attempt to understand the basis for the specific neuropathology in GAI, we have analyzed the expression of the murine GCD gene using both in vitro and in vivo approaches. Transfection studies mapped the mouse GCD promoter to a 500-bp region of DNA 5' of the translation start site. The promoter lacks a TATA consensus sequence, but includes possible binding sites for several transcription factors with roles in the regulation of nuclear genes encoding mitochondrial proteins. Western blot and RT/PCR analyses of mouse tissues demonstrated that GCD is ubiquitously expressed, with the highest levels of expression in liver and kidney, consistent with its role in amino acid oxidation. Expression in multiple regions of the brain was also detected by Western blotting. Based on these results we conclude that the specific neuropathology associated with GCD deficiency in GAI cannot be accounted for by its expression pattern.

3T3 Cells↗
PubMed2000

Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome.

Two animal models of Down syndrome (human trisomy 21) with segmental trisomy for all (Ts65Dn) or part (Ts1Cje) of human chromosome 21-homologous region of mouse chromosome 16 have cognitive and behavioral abnormalities. To compare these trisomies directly and to assess the phenotypic contribution of the region of difference between them, Ts65Dn, Ts1Cje, and a new segmental trisomic (Ms1Ts65) for the region of difference (APP: to Sod1) have been generated as littermates and tested in parallel. Although the performance of Ts1Cje mice in the Morris water maze is similar to that of Ts65Dn mice, the reverse probe tests indicate that Ts65Dn is more severely affected. By contrast, the deficits of Ms1Ts65 mice are significantly less severe than those of Ts65Dn. Therefore, whereas triplication of Sod1 to Mx1 plays the major role in causing the abnormalities of Ts65Dn in the Morris water maze, imbalance of APP: to Sod1 also contributes to the poor performance. Ts65Dn mice are hyperactive and Ts1Cje mice are hypoactive; the activity of Ms1Ts65 mice is not significantly above normal. These findings indicate that genes in the Ms1Ts65 trisomic region must interact with others in the Ts1Cje region to produce hyperactivity in Ts65Dn mice.

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PubMed1999

Reduced corticotropin-releasing factor and enhanced vasopressin gene expression in brains of mice with autoimmunity-induced behavioral dysfunction.

The spontaneous development of autoimmune disease in MRL-lpr mice induces behavioral and endocrine changes that resemble effects of chronic stressors. To further examine the correspondence between autoimmune disease and chronic stress, we asked whether the brains of autoimmune mice show a shift in the corticotropin-releasing factor (CRF) to vasopressin (AVP) ratio. Using in situ hybridization histochemistry with 35S-labelled mouse riboprobes, the levels of mRNA transcripts encoding CRF and AVP were compared between autoimmune MRL-lpr and control MRL +/+ brains. CRF transcript levels were lower in the hypothalamic paraventricular nucleus and in the central nucleus of the amygdala in MRL-lpr mice. AVP transcript levels were higher in the paraventricular and the supraoptic nuclei in MRL-lpr mice compared to controls. CRF mRNA levels were inversely related to performance in stress-sensitive tasks and to measures of autoimmunity. As found previously for behavioral performance, immunosuppressive treatment with cyclophosphamide abolished the group difference in neuropeptide gene expression. These results indicate that an autoimmune disease process is necessary for the shift in the brain CRF:AVP ratio. Furthermore, they support the parallel between chronic stress and chronic autoimmunity/inflammation, and suggest common central mechanisms relevant to endocrine function and behavior.

Animals↗
PubMed1998

Attenuation of behavioral abnormalities in autoimmune mice by chronic soluble interferon-gamma receptor treatment.

NZB x NZW F1 hybrid (B/W) mice develop altered behavior in the elevated plus maze and novel object tasks between 6 and 12 weeks of age in parallel with lupus-like autoimmune disease. To confirm the relationship between disease progression and development of behavioral abnormalities, B/W and nonautoimmune NZW mice received chronic treatment with a soluble IFN gamma receptor (sIFN gamma R), a treatment known to retard autoimmune disease progression, or vehicle, beginning at 6 weeks of age. After 6 weeks of treatment, elevated plus maze and novel object testing revealed that although sIFN gamma R treated B/W mice still differed from NZW mice, chronic sIFN gamma R treatment significantly retarded the development of behavioral abnormalities in the B/W mice, while the NZW mice were not affected by this treatment. sIFN gamma R treated B/W mice were more active in both the plus maze and novel object tasks, and displayed less plus maze anxiety behavior and more exploratory activity in the novel object task compared to vehicle treated B/W mice. To clarify the role of acute action of the sIFN gamma R on the elevated IFN gamma levels of B/W mice, a second experiment examined the effects of a single injection of sIFN gamma R on B/W and NZW mice. Unlike chronic treatment, acute treatment with the same dose of sIFN gamma R did not affect plus maze or novel object behavior in 12-week-old mice. These results add to the growing evidence that lupus-associated behavioral abnormalities are a direct effect of the autoimmune disease.

Animals↗
PubMed1996

Anxiety behavior, exploratory behavior, and activity in NZB x NZW F1 hybrid mice: role of genotype and autoimmune disease progression.

Behavioral changes often accompany the autoimmune disease systemic lupus erythematosus (SLE) in humans and animals. In a mouse model of SLE, the NZB x NZW F1 (B/W) hybrid, 12-week-old mice display more anxiety behavior, less activity, and less exploratory behavior than non-autoimmune female NZW mice. To determine whether these behaviors result from the autoimmune disease or genetic differences between B/W and NZW mice, they were assessed prior to and during disease emergence (6 and 12 weeks of age, respectively). B/W mice were less active at both ages, suggesting a genetic component to this behavioral difference. Anxiety behavior and exploratory behavior did not differ between B/W and NZW mice at 6 weeks; however, at 12 weeks B/W mice displayed more anxiety behavior and less exploratory behavior, indicating that these behaviors were related with the development of autoimmune disease. Prior experience with these tasks increased anxiety behavior in B/W but not NZW mice, suggesting that B/W mice may be more sensitive to anxiogenic experiences.

Aging↗
PubMed1996

Behavioral assessment of the Ts65Dn mouse, a model for Down syndrome: altered behavior in the elevated plus maze and open field.

The Ts65Dn mouse carries a partial trisomy for mouse chromosome 16 in a region that has high homology to the Down syndrome (DS) region of human chromosome 21 and is, thus, a potential animal model of DS. The focus of the present study was to begin to characterize the behavioral phenotype of this mouse to assess its usefulness as a model of aspects of the DS phenotype. The behavior of Ts65Dn and littermate control mice was assessed in the elevated plus maze, lighted and dark open field, and a step-down passive avoidance task. The behavior of Ts65Dn mice in these tests differed considerably from the nontrisomic controls. In the elevated plus maze, Ts65Dn had more total arm visits than controls, showed a higher percentage of arm visits to the open arms than control mice, and showed no preference for the closed arms. Ts65Dn mice were more active in both open-field situations, regardless of light condition, and ventured into the center of the arena more than controls. Lighting in the open field had moderate effects on the activity of the Ts65Dn mice, but control mice were, as expected, much more active in the dark than the light. The trisomic mice learned and retained the step-down passive avoidance task in the same number of trials as the controls. Overall, these data indicate that Ts65Dn mice are more active than control mice in two testing situations. Most striking is the finding that the Ts65Dn mice were much less responsive to variations in environmental cues to which normal mice are quite sensitive. These data not only begin to characterize systematically the Ts65Dn phenotype, but also raise several interesting issues about the sources of the aberrant behaviors observed in these mice.

Animals↗
PubMed1996

The role of performance factors in the active avoidance-conditioning deficit in autoimmune mice.

Prior studies with autoimmune mice demonstrated deficits in 2-way active avoidance conditioning that correlated with the degree of autoimmunity. In this study, autoimmune female NZB x NZW F1 hybrid (B/W) mice were tested in shock-motivated discrimination learning, 1-way avoidance conditioning, and a modified 2-way avoidance task and compared to nonautoimmune female NZW mice. The discrimination and 1-way conditioning results indicated that B/W mice can learn shock-motivated tasks that involve minimal fatigue and no conflict. B/W mice were also able to learn the 2-way avoidance task when it was made easier by increasing conditioned-stimulus cue salience, clarifying contingencies, and increasing trial spacing to decrease possible cognitive, emotional, and physical fatigue. Thus, poor performance in 2-way avoidance appears to be a consequence of altered attention, motivation, or emotionality and can be overcome by altering task parameters.

Animals↗
PubMed1996

Increased anxiety behaviors in autoimmune mice.

The human autoimmune disorder systemic lupus erythematosus (SLE) is often accompanied by psychiatric manifestations including anxiety. In this study, the performance of SLE-prone NZB x NZW F1 (B/W) hybrid mice was compared with nonautoimmune NZW control mice on 3 anxiety tasks: the elevated plus maze, the open-field drink test, and the novel-object task. B/W mice displayed decreased activity as well as an anxiety profile in all 3 tasks, which was characterized by avoidance of open and exposed places even when the motivation to explore these areas was high. Cytokines are overexpressed in autoimmune disease, and NZW controls injected with the cytokine interferon-alpha displayed an anxiety profile in the plus maze. Thus, cytokines may play a role in the genesis of the behavioral manifestations of autoimmune disease.

Animals↗
PubMed1994

Sensitivity to foot shock in autoimmune NZB x NZW F1 hybrid mice.

Prior studies have demonstrated deficits in active avoidance learning in young (12-week-old) mice that develop lupus-like autoimmunity. Because foot shock is the motivating stimulus in this task, sensitivity to foot shock was assessed in autoimmune NZB x NZW F1 hybrid (B/W) and nonautoimmune NZW female mice. Responses to shock at levels ranging from 0.05 to 1.6 mA were recorded twice during the development of autoimmunity. At 12 weeks of age, B/W mice did not differ from NZW mice in sensitivity to shock. However, at 24 weeks of age, when antibody levels were elevated, sensitivity to foot shock decreased in B/W mice at low shock levels and increased at high shock levels. A neurological battery revealed no deficits that could account for these effects. However, IgM anti-DNA antibody levels were positively correlated with responsiveness to high levels of shock. The change in the pattern of sensitivity at 24 weeks may be due to a combination of disease-related sensory impairment at low shock levels and hyperalgesia at high shock levels. The response to high levels of shock may also be an indication of enhanced emotionality, an interpretation consistent with reports in other lupus-prone strains and affective disorders in humans with lupus.

Age Factors↗
PubMed1993

Repeated injections of interferon-alpha A/D in Balb/c mice: behavioral effects.

Interferon-alpha decreases food intake and activity in mice and humans. The present study further explores parallels between effects of this protein in humans and mice, using a hybrid recombinant interferon-alpha A/D (INF-alpha A/D) that has antiviral and hepatic activity in mice. Measures of activity (open field), muscle strength (forelimb grip strength), and motor ability (swim posture and endurance with 0, 3, and 6% added weight) were examined in Balb/c mice injected with 1600 U/g of hybrid rhuIFN-alpha A/D daily for 5 days (n = 9) or with IFN vehicle (n = 11). Open field activity was significantly depressed in the group exposed to IFN. The number of times the nose dipped under the water when swimming with 3% added body weight was higher in the IFN-treated mice, while float time was decreased with 6% added weight. The IFN-treated mice were slower to adopt the new strategies necessary to swim with added weight. Depression of motor activity is a robust, general effect of IFN treatment observed in this as well as previously published studies. Together, these studies demonstrate activity decrements in two different strains of mice, two different activity measures, acute and chronic injections, and recombinant and nonrecombinant IFN preparations.

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