Unraveling the mechanisms by which the molecular manipulation of genes of interest enhances cognitive function is important to establish genetic therapies for cognitive disorders. Although CREB is thought to positively regulate formation of long-term memory (LTM), gain-of-function effects of CREB remain poorly understood, especially at the behavioral level. To address this, we generated four lines of transgenic mice expressing dominant active CREB mutants (CREB-Y134F or CREB-DIEDML) in the forebrain that exhibited moderate upregulation of CREB activity. These transgenic lines improved not only LTM but also long-lasting long-term potentiation in the CA1 area in the hippocampus. However, we also observed enhanced short-term memory (STM) in contextual fear-conditioning and social recognition tasks. Enhanced LTM and STM could be dissociated behaviorally in these four lines of transgenic mice, suggesting that the underlying mechanism for enhanced STM and LTM are distinct. LTM enhancement seems to be attributable to the improvement of memory consolidation by the upregulation of CREB transcriptional activity, whereas higher basal levels of BDNF, a CREB target gene, predicted enhanced shorter-term memory. The importance of BDNF in STM was verified by microinfusing BDNF or BDNF inhibitors into the hippocampus of wild-type or transgenic mice. Additionally, increasing BDNF further enhanced LTM in one of the lines of transgenic mice that displayed a normal BDNF level but enhanced LTM, suggesting that upregulation of BDNF and CREB activity cooperatively enhances LTM formation. Our findings suggest that CREB positively regulates memory consolidation and affects memory performance by regulating BDNF expression.

Social recognition memory is an essential and basic component of social behavior that is used to discriminate familiar and novel animals/humans. Previous studies have shown the importance of several brain regions for social recognition memories; however, the mechanisms underlying the consolidation of social recognition memory at the molecular and anatomic levels remain unknown. Here, we show a brain network necessary for the generation of social recognition memory in mice. A mouse genetic study showed that cAMP-responsive element-binding protein (CREB)-mediated transcription is required for the formation of social recognition memory. Importantly, significant inductions of the CREB target immediate-early genes c-fos and Arc were observed in the hippocampus (CA1 and CA3 regions), medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and amygdala (basolateral region) when social recognition memory was generated. Pharmacological experiments using a microinfusion of the protein synthesis inhibitor anisomycin showed that protein synthesis in these brain regions is required for the consolidation of social recognition memory. These findings suggested that social recognition memory is consolidated through the activation of CREB-mediated gene expression in the hippocampus/mPFC/ACC/amygdala. Network analyses suggested that these four brain regions show functional connectivity with other brain regions and, more importantly, that the hippocampus functions as a hub to integrate brain networks and generate social recognition memory, whereas the ACC and amygdala are important for coordinating brain activity when social interaction is initiated by connecting with other brain regions. We have found that a brain network composed of the hippocampus/mPFC/ACC/amygdala is required for the consolidation of social recognition memory. Here, we identify brain networks composed of multiple brain regions for the consolidation of social recognition memory. We found that social recognition memory is consolidated through CREB-meditated gene expression in the hippocampus, medial prefrontal cortex, anterior cingulate cortex (ACC), and amygdala. Importantly, network analyses based on c-fos expression suggest that functional connectivity of these four brain regions with other brain regions is increased with time spent in social investigation toward the generation of brain networks to consolidate social recognition memory. Furthermore, our findings suggest that hippocampus functions as a hub to integrate brain networks and generate social recognition memory, whereas ACC and amygdala are important for coordinating brain activity when social interaction is initiated by connecting with other brain regions.

Probable arthropod vectors of avian blood protozoa, Leucocytozoon lovati, were collected in the alpine regions of Japan, the habitats of the host birds of Japanese rock ptarmigan (Lagopus mutus japonicus). Seven alpine regions of Japan, Asahidake, Chogatake, Tateyama, Jiigatake, Norikura, Kitadake, and Senjyogatake were investigated for black fly collection during 2004 to 2007. The collected 490 insects were morphologically identified as six species of female black flies, including Prosimulium hirtipes group (n = 59), Prosimulium mutata (n = 13), Prosimulium yezoense (n = 10), Similium japonicum (n = 359), Similium uchidai (n = 39), and Twinnia japonensis (n = 10). Extracted DNAs from individual black fly species were utilized for the amplification of the partial mitochondrial cytochrome b gene sequences of Leucocytozoon lovati previously reported. Four S. japonicum, two S. uchidai, and two P. hirtipes group studied were positive for the nested PCR among 490 black flies collected (1.6%; 8/490). All amplified sequences from the black flies were completely identical to those of L. lovati previously detected from Japanese rock ptarmigan. Our results suggest that at least three species of black flies, S. japonicum, S. uchidai, and P. hirtipes group, studied in this area could be regarded as potential vectors for L. lovati in the rock ptarmigan. This is the first detection case of Leucocytozoon from black flies of Japan.

This study presents a new idea for estimating the number of measurements required for determining the uncertainty in obtaining the desired water absorbed dose using the variation obtained from multicenter absorbed dose measurement data. The number of dose measurements depends on the performance of each linear accelerator (LINAC) tested and the dosimetry equipment and procedure used. However, optimising the number of data collected for the absorbed dose to water has been inadequately reported. Using the absorbed dose measurement data collected 10 times as a reference value, we will compare the changes in the variation of the measurement results caused by the difference in the number of repeated measurements of the absorbed dose. The number of measurements is determined statistically such that this variation would be smaller than the change in absorbed dose. Thus, we can determine the optimum number of measurements suitable for the variability of each LINAC.

No abstract