Involvement of the accumbal osteopontin-interacting transmembrane protein 168 in methamphetamine-induced place preference and hyperlocomotion in mice

Chronic exposure to methamphetamine causes adaptive changes in brain, which underlie dependence symptoms. We have found that the transmembrane protein 168 (TMEM168) is overexpressed in the nucleus accumbens of mice upon repeated methamphetamine administration. Here, we firstly demonstrate the inhibitory effect of TMEM168 on methamphetamine-induced behavioral changes in mice, and attempt to elucidate the mechanism of this inhibition. We overexpressed TMEM168 in the nucleus accumbens of mice by using an adeno-associated virus vector (NAc-TMEM mice). Methamphetamine-induced hyperlocomotion and conditioned place preference were attenuated in NAc-TMEM mice. Additionally, methamphetamine-induced extracellular dopamine elevation was suppressed in the nucleus accumbens of NAc-TMEM mice. Next, we identified extracellular matrix protein osteopontin as an interacting partner of TMEM168, by conducting immunoprecipitation in cultured COS-7 cells. TMEM168 overexpression in COS-7 cells induced the enhancement of extracellular and intracellular osteopontin. Similarly, osteopontin enhancement was also observed in the nucleus accumbens of NAc-TMEM mice, in in vivo studies. Furthermore, the infusion of osteopontin proteins into the nucleus accumbens of mice was found to inhibit methamphetamine-induced hyperlocomotion and conditioned place preference. Our studies suggest that the TMEM168-regulated osteopontin system is a novel target pathway for the therapy of methamphetamine dependence, via regulating the dopaminergic function in the nucleus accumbens

An NLR paralog Pit2 generated from tandem duplication of Pit1 fine-tunes Pit1 localization and function

NLR family proteins act as intracellular receptors. Gene duplication amplifies the number of NLR genes, and subsequent mutations occasionally provide modifications to the second gene that benefits immunity. However, evolutionary processes after gene duplication and functional relationships between duplicated NLRs remain largely unclear. Here, we report that the rice NLR protein Pit1 is associated with its paralogue Pit2. The two are required for the resistance to rice blast fungus but have different functions: Pit1 induces cell death, while Pit2 competitively suppresses Pit1-mediated cell death. During evolution, the suppression of Pit1 by Pit2 was probably generated through positive selection on two fate-determining residues in the NB-ARC domain of Pit2, which account for functional differences between Pit1 and Pit2. Consequently, Pit2 lost its plasma membrane localization but acquired a new function to interfere with Pit1 in the cytosol. These findings illuminate the evolutionary trajectory of tandemly duplicated NLR genes after gene duplication

Overexpression of transmembrane protein 168 in the mouse nucleus accumbens induces anxiety and sensorimotor gating deficit

Transmembrane protein 168 (TMEM168) comprises 697 amino acid residues, including some putative transmembrane domains. It is reported that TMEM168 controls methamphetamine (METH) dependence in the nucleus accumbens (NAc) of mice. Moreover, a strong link between METH dependence-induced adaptive changes in the brain and mood disorders has been evaluated. In the present study, we investigated the effects of accumbal TMEM168 in a battery of behavioral paradigms. The adeno-associated virus (AAV) Tmem168 vector was injected into the NAc of C57BL/6J mice (NAc-TMEM mice). Subsequently, the accumbal TMEM168 mRNA was increased approximately by seven-fold when compared with the NAc-Mock mice (controls). The NAc-TMEM mice reported no change in the locomotor activity, cognitive ability, social interaction, and depression-like behaviors; however, TMEM168 overexpression enhanced anxiety in the elevated-plus maze and light/dark box test. The increased anxiety was reversed by pretreatment with the antianxiety drug diazepam (0.3 mg/kg i.p.). Moreover, the NAc-TMEM mice exhibited decreased prepulse inhibition (PPI) in the startle response test, and the induced schizophrenia-like behavior was reversed by pretreatment with the antipsychotic drug risperidone (0.01 mg/kg i.p.). Furthermore, accumbal TMEM168 overexpression decreased the basal levels of extracellular GABA in the NAc and the high K+ (100 mM)-stimulated GABA elevation; however, the total contents of GABA in the NAc remained unaffected. These results suggest that the TMEM168-regulated GABAergic neuronal system in the NAc might become a novel target while studying the etiology of anxiety and sensorimotor gating deficits

Different Photoperiodic Responses in Four Lines of Japanese Quail

Organisms measure day length to better adapt to seasonal changes in the environment; this phenomenon is called photoperiodism. The Japanese quail has a highly sophisticated photoperiodic mechanism and is an excellent model for the study of photoperiodism. Various lines of quail have been established during the domestication process. In the present study, we examined the effect of long day (LD) followed by short day (SD) on testicular weight in four lines of quail (L, AMRP, NIES-Br, and WE). When the quail were raised under SD conditions, testicular development was suppressed in all examined lines. The speed of the LD-induced testicular development of NIES-Br line was faster than that of AMRP line, while the speed of the SD-induced testicular regression of L line was significantly faster than that of WE line. These quail lines provide excellent model to uncover the underlying mechanism of seasonal testicular regression

Giant pedunclated lipoma of the esophagus: A case report

Introduction: Although Esophageal lipoma is extremely rare and pathologically benign, surgical excision of the lipoma is recommended when symptomatic or uncertain biological behavior. In general, some of the esophageal lipoma has a stalk. The pedunclated non-invasive tumor can be removed by stalk ligation, which is either endoscopic or surgical approache. Therefore, the preoperative evaluation is essential. We herein present a case of a huge esophageal lipoma. Case report: A 82-year-old man, with a wet cough and dyspnea for 6 months, who had the huge mass that almost completely occupied the esophageal lumen, was referred to our institution for the treatment.We diagnosed the mass as non-invasive tumor that has a stalk at the close to the esophageal orifice, by the CT image using air injection into esophageal lumen. We performed excision of the pedunclated huge mobile mass by esophagotomy via right thoracic approach with use of endoloop. Pathological examination showed a lipoma. Conclusion: In conclusion, an adequate preoperative evaluation to identify the correct origin of the stalk is mandatory for a successful treatment. In order to do the adequate preoperative evaluation and successful surgery, our diagnostic method of CT image can be effective

Reversal of sensorimotor gating deficit in the PPI task following the administration of risperidone in the NAc-TMEM mice.

<p>(A) Risperidone (0.01 mg/kg i.p.) or saline was administrated 30 min before the task performance. Startle responses was measured at 70, 80, 90, 100, 110, and 120 dB, respectively (background noise: 70 dB), <i>N</i> = 8; values are presented as mean ± S.E.M. No significant difference between NAc-TMEM and NAc-Mock mice (two-way ANOVA followed by the Bonferroni’s post hoc tests). (B) Risperidone (0.01 mg/kg i.p.) or saline was administered 30 min before the task performance. PPI was measured for 74, 78, 82, and 86 dB respectively, of prepulse intensity (background noise: 70 dB), <i>N</i> = 8; values are presented as mean ± S.E.M. **<i>p</i> < 0.01, *<i>p</i> < 0.05 vs. NAc-TMEM (VEH) (two-way ANOVA followed by the Bonferroni’s post hoc tests). VEH: saline administration group, RIS: risperidone administration group.</p

Increased anxiety and decreased PPI in the NAc-TMEM mice compared with the NAc-Mock mice.

<p>(A) Number of entries spent on open arms were measured for 10 min in the elevated plus-maze task; <i>N</i> = 9; Values are presented as mean ± S.E.M. *<i>p</i> < 0.05 vs. NAc-Mock (Student-<i>t</i> test). (B) Time spent on open arms was measured for 10 min in the elevated plus-maze task; <i>N</i> = 9; Values are presented as mean ± S.E.M. *<i>p</i> < 0.05 vs. NAc-Mock (Student-<i>t</i> test). (C) Time in the light box was measured for 10 min in the light/dark box task; N = 9; Values are presented as mean ± S.E.M. *<i>p</i> < 0.05 vs. NAc-Mock (Student-<i>t</i> test). (D) Startle responses were measured at 70, 80, 90, 100, 110, and 120 dB, respectively (background noise: 70 dB). <i>N</i> = 9; Values are presented as mean ± S.E.M. No significant difference between NAc-TMEM and NAc-Mock mice (ANOVA followed by the Bonferroni’s post hoc tests). (E) PPI was measured for 74, 78, 82, and 86 dB, respectively, of the prepulse intensity (background noise: 70 dB). Values are presented as mean ± S.E.M. <i>N</i> = 9. *<i>p</i> < 0.05 vs NAc-Mock (ANOVA followed by the Bonferroni’s post hoc tests).</p