The Collaborative Cross, a community resource for the genetic analysis of complex traits.

The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.

Enhancing sleep after training improves memory in down syndrome model mice.

Down syndrome (DS) is a genetic disorder caused by the presence of all or part of the third copy of chromosome 21. DS is associated with cognitive disabilities, for which there are no drug therapies. In spite of significant behavioral and pharmacological efforts to treat cognitive disabilities, new and continued efforts are still necessary. Over 60% of children with DS are reported to have sleep apnea that disrupt normal sleep. Normal and adequate sleep is necessary to maintain optimal cognitive functions. Therefore, we asked whether improved quality and/or quantity of sleep could improve cognitive capacities of people with DS. To investigate this possibility, we used the Ts65Dn mouse model of DS and applied two methods for enhancing their sleep following training on mouse memory tasks. A behavioral method was to impose sleep deprivation prior to training resulting in sleep rebound following the training. A pharmacologic method, hypocretin receptor 2 antagonist, was used immediately after the training to enhance subsequent sleep knowing that hypocretin is involved in the maintenance of wake. Our behavioral method resulted in a sleep reorganization that decreased wake and increased rapid eye movement sleep following the training associated with an improvement of recognition memory and spatial memory in the DS model mice. Our pharmacologic approach decreased wake and increased non-rapid eye movement sleep and was associated with improvement only in the spatial memory task. These results show that enhancing sleep after the training in a memory task improves memory consolidation in a mouse model of DS.

Handling, task complexity, time-of-day, and sleep deprivation as dynamic modulators of recognition memory in mice.

Sleep is essential for optimal cognitive functioning. Although we lack a complete understanding of the role of sleep in memory consolidation, we know that various factors that disturb sleep or sleep quality have consequences for cognitive performance. Such factors can be unintended components of behavioral experiments on rodents and other experimental animals that generate differing results from different labs. These experimental variables include habituation to handling, intended or unintended sleep deprivation, task complexity, time of testing, and environmental features. We have examined how these variables impact recognition memory in C57BL/6 mice. Handled mice outperformed their non-handled counterparts across different combinations of delay phase duration and lighting conditions. Results also suggest that simple task recall is more resistant to diurnal variation and the impairing effects of sleep deprivation than is complex task recall. This study underscores the role of protocol and environmental factors in recognition memory and in conflicting results from different laboratories.

Usp16 modulates Wnt signaling in primary tissues through Cdkn2a regulation.

Regulation of the Wnt pathway in stem cells and primary tissues is still poorly understood. Here we report that Usp16, a negative regulator of Bmi1/PRC1 function, modulates the Wnt pathway in mammary epithelia, primary human fibroblasts and MEFs, affecting their expansion and self-renewal potential. In mammary glands, reduced levels of Usp16 increase tissue responsiveness to Wnt, resulting in upregulation of the downstream Wnt target Axin2, expansion of the basal compartment and increased in vitro and in vivo epithelial regeneration. Usp16 regulation of the Wnt pathway in mouse and human tissues is at least in part mediated by activation of Cdkn2a, a regulator of senescence. At the molecular level, Usp16 affects Rspo-mediated phosphorylation of LRP6. In Down's Syndrome (DS), triplication of Usp16 dampens the activation of the Wnt pathway. Usp16 copy number normalization restores normal Wnt activation in Ts65Dn mice models. Genetic upregulation of the Wnt pathway in Ts65Dn mice rescues the proliferation defect observed in mammary epithelial cells. All together, these findings link important stem cell regulators like Bmi1/Usp16 and Cdkn2a to Wnt signaling, and have implications for designing therapies for conditions, like DS, aging or degenerative diseases, where the Wnt pathway is hampered.