Transgenic up-regulation of alpha-CaMKII in forebrain leads to increased anxiety-like behaviors and aggression

<p>Abstract</p> <p>Background</p> <p>Previous studies have demonstrated essential roles for alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) in learning, memory and long-term potentiation (LTP). However, previous studies have also shown that alpha-CaMKII (+/-) heterozygous knockout mice display a dramatic decrease in anxiety-like and fearful behaviors, and an increase in defensive aggression. These findings indicated that alpha-CaMKII is important not only for learning and memory but also for emotional behaviors. In this study, to understand the roles of alpha-CaMKII in emotional behavior, we generated transgenic mice overexpressing alpha-CaMKII in the forebrain and analyzed their behavioral phenotypes.</p> <p>Results</p> <p>We generated transgenic mice overexpressing alpha-CaMKII in the forebrain under the control of the alpha-CaMKII promoter. In contrast to alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in anxiety-like behaviors in open field, elevated zero maze, light-dark transition and social interaction tests, and a decrease in locomotor activity in their home cages and novel environments; these phenotypes were the opposite to those observed in alpha-CaMKII (+/-) heterozygous knockout mice. In addition, similarly with alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in aggression. However, in contrast to the increase in defensive aggression observed in alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in offensive aggression.</p> <p>Conclusion</p> <p>Up-regulation of alpha-CaMKII expression in the forebrain leads to an increase in anxiety-like behaviors and offensive aggression. From the comparisons with previous findings, we suggest that the expression levels of alpha-CaMKII are associated with the state of emotion; the expression level of alpha-CaMKII positively correlates with the anxiety state and strongly affects aggressive behavior.</p

Actinobacillus actinomycetemcomitans感染によるヒト単球細胞のアポトーシス発現について

We have reported that Actinobacillus actinomycetemcomitans infection induced apoptosis in a murine macrophage cen line, J774.1 cells. It is known that the human and murine immune cell response is different because of cell surface structure differences. In addition, mitogen - activated protein kinase (MAPK) activity is directly involved in apoptosis of infectd THP-1 cells. Previous studies have implicated protein kinase C (PKC) as an upstream regulator of MAPK. The aim of this study was to clarify whether human immune cells undergo apoptosis following A. actinomycetemcomitans infection. A. actinomycetemcomitans and human monocytic THP-1 cells (1000 : 1) were suspended in microtubes. The tubes were centrifuged at 1000 x g for 10 min and incubated at 37℃ for 30 min. Non-adherent bacterium were washed out by a series of centrifugations. Infected cells were transferred to a 24-well culture plate, and incubated for 24 h. Culture supernatant and nuclei were prepared from the infected cells to measure for LDH activity, DNA fragmentation, MAPK activity and tumour necrosis factor α (TNF-α) levels. A. actinomycetemcomitans-infected THP-1 cells were shown by an increase in the proportion of LDH release, fragmented DNA, p38 MAPK activity and TNF-α levels. The LDH release and DNA fragmentation were inhibited by the addition of p38 MAPK inhibitor (SB203580) or anti-TNF-α antibody or PKC inhibitor (H=7). The TNF=α levels in the infected cells decreased on addition of SB203580 or anti-TNF-α antibody. However, exogenous TNF-α did not induce apoptosis in uninfected THP-1 cells. Further, H-7 suppressed the p38 MAPK activity of the infected cells in a dose-dependent manner, while PKC activator (PMA) enhanced LDH release DNA fragmentation and p38 MAPK activity. These results suggested that the p38 MAPK activity was the most important signal for apoptosis. The p38 MAPK activity was regulated by PKC and TNF-α in A. actinomycetemcomitans-infected THP-1 cells

Phenotype Harmonization in the GLIDE2 Oral Health Genomics Consortium

Genetic risk factors play important roles in the etiology of oral, dental, and craniofacial diseases. Identifying the relevant risk loci and understanding their molecular biology could highlight new prevention and management avenues. Our current understanding of oral health genomics suggests that dental caries and periodontitis are polygenic diseases, and very large sample sizes and informative phenotypic measures are required to discover signals and adequately map associations across the human genome. In this article, we introduce the second wave of the Gene-Lifestyle Interactions and Dental Endpoints consortium (GLIDE2) and discuss relevant data analytics challenges, opportunities, and applications. In this phase, the consortium comprises a diverse, multiethnic sample of over 700,000 participants from 21 studies contributing clinical data on dental caries experience and periodontitis. We outline the methodological challenges of combining data from heterogeneous populations, as well as the data reduction problem in resolving detailed clinical examination records into tractable phenotypes, and describe a strategy that addresses this. Specifically, we propose a 3-tiered phenotyping approach aimed at leveraging both the large sample size in the consortium and the detailed clinical information available in some studies, wherein binary, severity-encompassing, and "precision," data-driven clinical traits are employed. As an illustration of the use of data-driven traits across multiple cohorts, we present an application of dental caries experience data harmonization in 8 participating studies (N = 55,143) using previously developed permanent dentition tooth surface-level dental caries pattern traits. We demonstrate that these clinical patterns are transferable across multiple cohorts, have similar relative contributions within each study, and thus are prime targets for genetic interrogation in the expanded and diverse multiethnic sample of GLIDE2. We anticipate that results from GLIDE2 will decisively advance the knowledge base of mechanisms at play in oral, dental, and craniofacial health and disease and further catalyze international collaboration and data and resource sharing in genomics research.Peer reviewe

Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health