Research Overview of the Lab. of Molecula Biology, Tohoku University Graduate School of Agricultural Science(Recent Topics of the Agricultunal Biological Science in Tohoku University)

In our laboratory, mainly three different projects described below are now carried out. 1) "Generation and application of the cell membrane permeabilized protein", 2) "Studies on epigenetic regulation of eukaryotic genes through analyses of actin-related proteins" and 3) "Generation of the oxytocin receptor KO (OXTR-/-) mice, and molecular physiological and behavioral analysis of the oxytocin receptor KO (OXTR-/-) mice." In the first project, we generated recombinant Cre protein fused to TAT PTD (protein transduction domain), and the application of this protein into several primary cells prepared from mouse, showed significant recombinase activity. In the second project, we studied epigenetic regulation of eukaryotic genes through analyses of actin-related proteins. In the third project, we obtained several new findings in reproduction, sociosexual behaviors and in physiology of energy/temperature homeostasis of mice as the functions of oxytocin/oxytocin receptor system in vivo, using the oxytocin and its receptor genes deficient (OXT-/- and OXTR-/-) mice. Here we introduce a little about those three projects, respectively

Traditional Japanese medicine Kamikihito ameliorates sucrose preference, chronic inflammation and obesity induced by a high fat diet in middle-aged mice

The high prevalence of obesity has become a pressing global public health problem and there exists a strong association between increased BMI and mortality at a BMI of 25 kg/m2 or higher. The prevalence of obesity is higher among middle-aged adults than among younger groups and the combination of aging and obesity exacerbate systemic inflammation. Increased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha (TNFα) are hallmarks of obesity, and promote the secretion of hepatic C-reactive protein (CRP) which further induces systematic inflammation. The neuropeptide oxytocin has been shown to have anti-obesity and anti-inflammation effects, and also suppress sweet-tasting carbohydrate consumption in mammals. Previously, we have shown that the Japanese herbal medicine Kamikihito (KKT), which is used to treat neuropsychological stress disorders in Japan, functions as an oxytocin receptors agonist. In the present study, we further investigated the effect of KKT on body weight (BW), food intake, inflammation, and sweet preferences in middle-aged obese mice. KKT oral administration for 12 days decreased the expression of pro-inflammatory cytokines in the liver, and the plasma CRP and TNFα levels in obese mice. The effect of KKT administration was found to be different between male and female mice. In the absence of sucrose, KKT administration decreased food intake only in male mice. However, while having access to a 30% sucrose solution, both BW and food intake was decreased by KKT administration in male and female mice; but sucrose intake was decreased in female mice alone. In addition, KKT administration decreased sucrose intake in oxytocin deficient lean mice, but not in the WT lean mice. The present study demonstrates that KKT ameliorates chronic inflammation, which is strongly associated with aging and obesity, and decreases food intake in male mice as well as sucrose intake in female mice; in an oxytocin receptor dependent manner

Targeting oxytocin receptor (Oxtr)-expressing neurons in the lateral septum to restore social novelty in autism spectrum disorder mouse models

© 2020, The Author(s). Autism spectrum disorder (ASD) is a continuum of neurodevelopmental disorders and needs new therapeutic approaches. Recently, oxytocin (OXT) showed potential as the first anti-ASD drug. Many reports have described the efficacy of intranasal OXT therapy to improve the core symptoms of patients with ASD; however, the underlying neurobiological mechanism remains unknown. The OXT/oxytocin receptor (OXTR) system, through the lateral septum (LS), contributes to social behavior, which is disrupted in ASD. Therefore, we selectively express hM3Dq in OXTR-expressing (OXTR+) neurons in the LS to investigate this effect in ASD mouse models developed by environmental and genetic cues. In mice that received valproic acid (environmental cue), we demonstrated successful recovery of impaired social memory with three-chamber test after OXTR+ neuron activation in the LS. Application of a similar strategy to Nl3R451C knock-in mice (genetic cue) also caused successful recovery of impaired social memory in single field test. OXTR+ neurons in the LS, which are activated by social stimuli, are projected to the CA1 region of the hippocampus. This study identified a candidate mechanism for improving core symptoms of ASD by artificial activation of DREADDs, as a simulation of OXT administration to activate OXTR+ neurons in the LS

Oxytocin receptor signaling contributes to olfactory avoidance behavior induced by an unpleasant odorant

Oxytocin (OXT) and its receptor (OXTR) regulate reproductive physiology (i.e. parturition and lactation), sociosexual behavior, learned patterns of behavior and olfactory behavior in social contexts. To characterize the function of OXTR in basic olfactory behavior, the present study compared the behavioral responses of homozygous, heterozygous and wild-type mice when these mice were confronted with an unpleasant odorant (butyric acid) in a custom-made Y-maze in the absence of a social context. Wild-type mice avoided the first encounter with the butyric acid odorant, whereas homozygous and heterozygous mice did not. However, both heterozygous and wild-type mice habituated when confronted with the butyric odorant again on the following 2 days. By contrast, homozygous mice failed to habituate and instead avoided the location of the odorant for at least 3 days. These data suggest that homozygous and heterozygous mice display abnormal olfactory responses to the presentation of an unpleasant odorant. Our studies demonstrate that OXTR plays a critical role in regulating olfactory behavior in the absence of a social context