Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the R6/2 Mouse Model of HD

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related. © 2013 Rattray et al

Prevalence of mental disorders from adolescence through early adulthood in American Indian and First Nations communities

Indigenous communities lack representation in psychiatric epidemiology despite disproportionate exposure to risk factors. We document the cumulative and 12-month prevalence of psychiatric disorders across the early life course among a sample of Indigenous young adults and compare prospective and retrospective reporting of lifetime mental disorders. This community-based participatory research includes data from 735 Indigenous people from 8 reservations/reserves. Personal interviews were conducted between 2002–2010 and 2017–2018 totaling 9 waves; diagnostic assessments of DSM-IV-TR alcohol abuse/dependence, marijuana use/dependence, other substance abuse/dependence, generalized anxiety disorder, major depressive disorder, dysthymic disorder, and attention deficit/hyperactivity disorder occurred at waves 1 (mean age = 11.1 years), 4 (mean age = 14.3 years), 6 (mean age = 16.2 years), 8 (mean age = 18.3 years), and 9 (mean age = 26.3 years). Cumulative lifetime psychiatric disorders reached 77.3% and lifetime comorbidity 56.4% by wave 9. Past-year prevalence and comorbidity at wave 9 were 28.7% and 6.7%, respectively. Substance use disorders (SUDs) were most common with peak past-year prevalence observed when participants were on average 16.3 years old then declining thereafter. Trends in early life course psychiatric disorders in this study with Indigenous participants highlight cultural variations in psychiatric epidemiology including surprisingly low rates of internalizing disorders in the face of risk factors, disproportionately high rates of early-onset and lifetime SUD, and lower rates of past-year SUD in early adulthood compared with prior research.Peer reviewedSociolog

Enhancing preschoolers' executive functions through embedding cognitive activities in shared book reading

Given evidence that early executive functioning sets the stage for a broad range of subsequent outcomes, researchers have sought to identify ways to foster these cognitive capacities. An increasingly common approach involves computerized ‘brain training’ programs, yet there are questions about whether these are well suited for fostering the early development of executive functions (EFs). The current series of studies sought to design, develop, and provide evidence for the efficacy of embedding cognitive activities in a commonplace activity – shared reading of a children’s book. The book, Quincey Quokka’s Quest, required children to control their thinking and behaviour to help the story’s main character through a series of obstacles. The first study investigated effects of reading with embedded cognitive activities in individual and group contexts on young children’s executive functions (EFs). The second study compared reading with embedded cognitive activities against a more-active control condition (dialogic reading) that similarly engaged children in the reading process yet lacked clear engagement of EFs. The third study sought to investigate whether the effect of reading the story with embedded EF activities changed across differing doses of the intervention and whether effects persisted 2 months post-intervention. Findings provide converging evidence of intervention effects on working memory and shifting in as little as 3 weeks (compared to more traditional reading) and maintenance of these gains 2 months later. This suggests the efficacy of embedding cognitive activities in the context of everyday activities, thereby extending the range of users and contexts in which this approach can be used

Correlations of behavioral deficits with brain pathology assessed through longitudinal MRI and histopathology in the R6/1 mouse model of huntington's disease

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6 mouse models of HD express a mutant version of exon 1 HTT and typically develop motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Unlike the more commonly used R6/2 mouse line, R6/1 mice have fewer CAG repeats and, subsequently, a less rapid pathological decline. Compared to the R6/2 line, fewer descriptions of the progressive pathologies exhibited by R6/1 mice exist. The association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood in many models of HD. In attempt to link these factors in the R6/1 mouse line, we have performed detailed assessments of behavior and of regional brain abnormalities determined through longitudinal, in vivo magnetic resonance imaging (MRI), as well as an end-stage, ex vivo MRI study and histological assessment. We found progressive decline in both motor and non-motor related behavioral tasks in R6/1 mice, first evident at 11 weeks of age. Regional brain volumes were generally unaffected at 9 weeks, but by 17 weeks there was significant grey matter atrophy. This age-related brain volume loss was validated using a more precise, semi-automated Tensor Based morphometry assessment. As well as these clear progressive phenotypes, mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the R6/1 brain and was accompanied by neuronal loss. Despite these seemingly concomitant, robust pathological phenotypes, there appeared to be little correlation between the three main outcome measures: behavioral performance, MRI-detected brain atrophy and histopathology. In conclusion, R6/1 mice exhibit many features of HD, but the underlying mechanisms driving these clear behavioral disturbances and the brain volume loss, still remain unclear. © 2013 Rattray et al

Quantifying the Spatial Ecology of Wide-Ranging Marine Species in the Gulf of California: Implications for Marine Conservation Planning

There is growing interest in systematic establishment of marine protected area (MPA) networks and representative conservation sites. This movement toward networks of no-take zones requires that reserves are deliberately and adequately spaced for connectivity. Here, we test the network functionality of an ecoregional assessment configuration of marine conservation areas by evaluating the habitat protection and connectivity offered to wide-ranging fauna in the Gulf of California (GOC, Mexico). We first use expert opinion to identify representative species of wide-ranging fauna of the GOC. These include leopard grouper, hammerhead sharks, California brown pelicans and green sea turtles. Analyzing habitat models with both structural and functional connectivity indexes, our results indicate that the configuration includes large proportions of biologically important habitat for the four species considered (25–40%), particularly, the best quality habitats (46–57%). Our results also show that connectivity levels offered by the conservation area design for these four species may be similar to connectivity levels offered by the entire Gulf of California, thus indicating that connectivity offered by the areas may resemble natural connectivity. The selected focal species comprise different life histories among marine or marine-related vertebrates and are associated with those habitats holding the most biodiversity values (i.e. coastal habitats); our results thus suggest that the proposed configuration may function as a network for connectivity and may adequately represent the marine megafauna in the GOC, including the potential connectivity among habitat patches. This work highlights the range of approaches that can be used to quantify habitat protection and connectivity for wide-ranging marine species in marine reserve networks

Genetic and Environmental Causes of Variation in Trait Resilience in Young People

The aim of this multi-informant twin study was to determine the relative role of genetic and environmental factors in explaining variation in trait resilience in adolescents. Participants were consenting families (N = 2,638 twins in 1,394 families), from seven national cohorts (age 12–18 years, both sexes) of monozygotic and dizygotic twins reared together. Questionnaire data on the adolescents’ Ego-resilience (ER89) was collected from mothers, fathers and twins, and analysed by means of multivariate genetic modelling. Variance in trait resilience was best represented in an ADE common pathways model with sex limitation. Variance in the latent psychometric resilience factor was largely explained by additive genetic factors (77% in boys, 70% in girls), with the remaining variance (23 and 30%) attributable to non-shared environmental factors. Additive genetic sources explained more than 50% of the informant specific variation in mothers and fathers scores. In twins, additive and non-additive genetic factors together explained 40% and non-shared environmental factor the remaining 60% of variation. In the mothers’ scores, the additive genetic effect was larger for boys than for girls. The non-additive genetic factor found in the twins’ self ratings was larger in boys than in girls. The remaining sex differences in the specific factors were small. Trait resilience is largely genetically determined. Estimates based on several informants rather than single informants approaches are recommended