The power of automated high-resolution behavior analysis revealed by its application to mouse models of Huntington's and prion diseases

Steele, Andrew D.; Jackson, Walker S.; King, Oliver D.; Lindquist, Susan

doi:10.1073/pnas.0610779104

Cited by 160 publications

(211 citation statements)

References 22 publications

Supporting

Mentioning

204

Contrasting

Order By: Relevance

“…Sleeping disorders are frequently reported in many psychiatric disorders, including autism (40). Because we recorded behavior over sequential dark/light intervals, we could assess the effect of 16p11.2 CNVs on light and dark cycling by using previously established methods (29). Mice are nocturnal, and indeed, each genotype was most active during the dark periods (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we believed it imperative to monitor the 16p11.2 CNV models for multiple behaviors by using as quantifiable and unbiased approaches as possible. We used HomeCageScan, a system previously used to assess behavioral alterations caused by neurodegenerative disease, neurotoxic agents, and pain (29,(34)(35)(36). We investigated behavior of a cohort of 50 male and female mice.…”

Section: Resultsmentioning

confidence: 99%

“…Here we used a similar approach to generate mouse models with deletion and duplication corresponding to those found in patients with 16p11.2 CNVs. Because of the evidence for clinical heterogeneity, we screened these models for multiple changes in brain anatomy and behavior by using a combination of high-resolution MRI (28) and a monitoring system that assesses multiple behaviors (29). We found that the deletion and the duplication affect behavior and brain anatomy in opposing ways, with deletion mice exhibiting behaviors that resemble sensorimotor deficits in rats with lateral hypothalamic and nigrostriatal lesions (30,31).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

Horev

Ellegood²,

Lerch³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

310

342

View full text Add to dashboard Cite

Recurrent copy number variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a "behavior trap" phenotype-a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. These findings indicate that 16p11.2 CNVs cause brain and behavioral anomalies, providing insight into human neurodevelopmental disorders.Home-cage | stereotypic behavior | structural variation | brain MRI A ccumulating evidence suggests the importance of copy number variations (CNVs) in the etiology of neuropsychiatric disorders, including autism (1), schizophrenia (2-4), developmental delay (5), and other complex traits (6). The 16p11.2 region is particularly intriguing. Whereas deletion of 16p11.2 has been associated with autism (7-9), duplication of 16p11.2 has been associated with autism (9, 10) as well as schizophrenia (11). 16p11.2 CNVs have also been reported in patients with developmental delay, mental retardation, repetitive behaviors (12-16), and a highly penetrant form of obesity (17). A reciprocal effect of 16p11.2 dosage on head size has been noted, as deletions are associated with large head size or macrocephaly, whereas duplications are associated with microcephaly (16). These studies reveal the variability of symptoms in patients carrying the same 16p11.2 CNV, an extreme example being a family with three affected members with symptoms so heterogeneous that they were barely overlapping (18).Mouse models allow direct assessment of CNVs while reducing variability caused by genetic and environmental factors. We and others have previously used chromosome engineering (19) to model genetic alterations found in complex human diseases including cancer (20) and genomic disorders (21-24), allowing identification of the causative gene and elucidation of the mechanism involved (20,(25)(26)(27)). Here we used a similar approach to generate mouse models with deletion and duplication corresponding to those found in patients with 16p11.2 CNVs. Because of the evidence for clinical heterogeneity, we screened these models for multiple changes in brain anatomy and behavior by usin...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

Horev

Ellegood²,

Lerch³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

310

342

View full text Add to dashboard Cite

show abstract

“…One of the most obvious phenotypes that results from RML prion disease is a dramatic increase in activity, which is reflected in the lateral distance traveled in the home cage (33). The distance traveled in a 24-hour recording period began to increase in HSF1 WT and KO mice at 4 MPI and became much more pronounced by 4.5 and 5 MPI (Fig.…”

Section: Onset Of Prion Disease Behavioral Symptoms In Hsf1 Knockoutsmentioning

confidence: 98%

“…We used video-based automated behavioral analysis technology, which robustly discriminated between mock-inoculated control mice and RML prioninfected mice at the earliest onset of disease (33). This system was able to distinguish subtle differences in prion-induced behavioral symptoms in another study (34).…”

Section: Onset Of Prion Disease Behavioral Symptoms In Hsf1 Knockoutsmentioning

confidence: 99%

Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease

Steele

Hütter

Jackson

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Prion diseases are fatal, transmissible, neurodegenerative diseases caused by the misfolding of the prion protein (PrP). At present, the molecular pathways underlying prion-mediated neurotoxicity are largely unknown. We hypothesized that the transcriptional regulator of the stress response, heat shock factor 1 (HSF1), would play an important role in prion disease. Uninoculated HSF1 knockout (KO) mice used in our study do not show signs of neurodegeneration as assessed by survival, motor performance, or histopathology. When inoculated with Rocky Mountain Laboratory (RML) prions HSF1 KO mice had a dramatically shortened lifespan, succumbing to disease Ϸ20% faster than controls. Surprisingly, both the onset of home-cage behavioral symptoms and pathological alterations occurred at a similar time in HSF1 KO and control mice. The accumulation of proteinase K (PK)-resistant PrP also occurred with similar kinetics and prion infectivity accrued at an equal or slower rate. Thus, HSF1 provides an important protective function that is specifically manifest after the onset of behavioral symptoms of prion disease.neurodegeneration ͉ HSF1 ͉ transmissible spongiform encephalopathy ͉ PrP ͉ protein misfolding

show abstract

Absence of preference for social novelty and increased grooming in integrin β3 knockout mice: Initial studies and future directions

et al. 2011

View full text Add to dashboard Cite

Scientific Abstract Elevated whole blood serotonin (5HT), or hyperserotonemia, is a common biomarker in autism spectrum disorder (ASD). The integrin β3 receptor subunit gene (ITGB3) is a quantitative trait locus for whole blood 5-HT levels. Recent work shows that integrin β3 interacts with the serotonin transporter (SERT) in both platelets and in the midbrain. Furthermore, multiple studies have now reported gene-gene interaction between the integrin β3 and SERT genes in association with ASD. Given the lack of previous data on the impact of integrin β3 on brain or behavioral phenotypes, we sought to compare mice with decreased or absent expression of the integrin β3 receptor subunit (Itgb3 +/- and -/-) with wildtype littermate controls in behavioral tasks relevant to ASD. These mice did not show deficits in activity level in the Open Field or anxiety-like behavior on the Elevated Plus Maze, two potential confounds in the evaluation of mouse social behavior. In the three-chamber social test, mice lacking integrin β3 were shown to have normal sociability but did not show a preference for social novelty. Importantly, the absence of integrin β3 did not impair olfaction or the ability to recall familiar social odors. Additionally, mice lacking integrin β3 showed increased grooming behavior in novel environments. These preliminary studies reveal altered social and repetitive behavior in these mice, which suggests that the integrin β3 subunit may be involved in brain systems relevant to ASD. Further work is needed to fully characterize these behavioral changes and the underlying brain mechanisms.

show abstract

The power of automated high-resolution behavior analysis revealed by its application to mouse models of Huntington's and prion diseases

Cited by 160 publications

References 22 publications

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease

Absence of preference for social novelty and increased grooming in integrin β3 knockout mice: Initial studies and future directions

Contact Info

Product

Resources

About