Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement

Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan-a precursor amino acid for serotonin biosynthesis in the brain-and serotonin receptor 5-hydroxytryptamine receptor 6 (HTR6) are crucial in mediating this process. We show that HTR6 inactivation diminishes DR-induced neurological alterations, including reduced dendritic complexity, increased spine density, and enhanced long-term potentiation (LTP) in hippocampal neurons. Moreover, we find that HTR6-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling is involved in DR-induced memory improvement. Our results suggest that the HTR6-mediated mTORC1 pathway may function as a nutrient sensor in hippocampal neurons to couple memory performance to dietary intake

Effects of calorie restriction on learning and memory

很多人在自然老化的過程中往往都會經歷認知功能的衰退。而這樣的結果也導致人們無法正常的學習新知識、儲存或是提取記憶。卡路里節制(Calorie Restriction, CR)除了可以增進身體健康外，在過去的研究中也發現在許多生物物種上也看到有延長壽命的效果。相反的，高脂肪(High Fat, HF)的飲食則是增加了罹患老化相關疾病的風險。本篇論文利用短期的卡路里節制(相較於正常飲食攝取的60%)和高脂肪飲食操弄來檢驗其對於年輕公鼠(10週大)學習與記憶能力的影響。在連續6到10週的飲食操弄後，正常飲食、 卡路里節制和高脂肪組別體重的變化分別為20.7%、-19.9%和28.4％。利用高空T型迷宮(Elevated T Maze, ETM)、被動規避儀(Passive Avoidance, PA)、物體辨認測驗(Novel Object Recognition, NOR)和水迷津(Morris Water Maze, MWM)等四種認知行為作業中，我發現卡路里節制顯著的增進小鼠學習與記憶能力的表現，而高脂肪飲食則是沒有顯著的影響。而在廣場測驗(Open Field Test)中，我發現三種飲食操弄組別皆不影響小鼠的行動能力，顯示卡路里節制增進學習與記憶的效果並非因為受到行動能力的干擾所導致。 我發現利用選擇性血清素回收抑制劑(Selective Serotonin Reuptake Inhibitor, SSRI) fluoxetine和血清素亞型6受體促進劑(5-HT6R Agonsit) WAY208466可以阻斷卡路里節制增進學習記憶表現的效果，顯示卡路里節制增進認知功能的效果很有可能是透過作用在5-HT6血清素亞型受體相關機制所產生。 除此之外，卡路里節制顯著降低了平時5-HT6/PKA(Protein Kinase A, PKA)訊號表現量，然而卻可增強5-HT6血清素亞型受體促進劑誘發PKA磷酸化表現的效能。而在長期給予磷酸二酯酶-4(Phosphodiesterase-4, PDE4)抑制劑rolirpam的情況下，我發現透過增加環狀一燐酸腺(Cyclic Adenosine Monophosphate, cAMP)強化PKA的活性同樣也可以阻斷卡路里節制增進學習記憶的效果。綜合這些實驗結果，我們推測卡路里節制透過調控5-HT6/PKA相關機制導致最後增進學習與記憶的效果。One common phenomenon during the natural process of aging is that most people experience a progressive decline in overall cognitive functions. This causes people to lose their ability to learn new information and store or retrieve from memory. Calorie restriction (CR) has been shown to improve health and extend lifespan in a variety of species, whereas high-fat diet may increase the risk of age-related diseases. In this study, we examine the effects of short-term CR (60% of the normal calorie intake) and high-fat (HF) diet on learning and memory in young male mice (10-week-old). After 6 to 10 weeks under normal, CR, and HF diet, animals showed 20.7%, -19.9% and 28.4% in body weight change respectively. Using elevated t maze (ETM), passive avoidance (PA), novel object recognition (NOR) and morris water maze (MWM) task, we found that CR regimen significantly improved learning and memory ability in mice while HF had no effect. In open field test, all diet regimens had no effect on motor functions, suggesting that diet-induced behavioral changes were not due to alterations in general motor activities of mice. The procognitive effects of CR were likely to act through a serotonin 6 receptor (5-HT6)-related pathway since fluoxetine, a selective serotonin reuptake inhibitor, and 5-HT6 agonsit (WAY208466 dihydrochloride) could reverse the effects of CR on learning and memory. Furthermore, CR significantly reduced basal 5-HT6/PKA signaling but enhanced the efficacy of 5-HT6 agonist induced PKA phosphorylation. Chronic treatment with rolipram, which enhances PKA activity through increasing cAMP levels, could compromise the actions of CR. In summary, our data suggested that CR might enchance cognitive function through modulating the 5-HT6/PKA related pathway

Psychogenic Urinary Retention in Children: A Case Report

Psychogenic urinary retention occurs relatively infrequently in children and is less common than in adults. The influence of psychogenic factors on voiding generally results in an irritative syndrome, but rarely in urinary retention. A definitive diagnosis is established by excluding other pathological conditions. Evaluation includes urine culture, renal echography, spine magnetic resonance imaging, voiding cysto-urethrography, intravenous pyelography, and uroflowmetry. Here, we report on a 6-year-old girl with a 1-month history of voiding difficulty. Urology studies, including urine culture, revealed Escherichia coli, which was not present in preadmission urine cultures. Renal ultrasound and radiological images showed no gross abnormalities or vesicoureteral reflux, but uroflowmetry showed a low flow rate with residual urine. The results of imaging studies and pediatric psychiatric consultation led to a diagnosis of psychogenic urinary retention combined with urinary tract infection. Urinary rehabilitation included intermittent catheterization, bladder training, and supportive psychotherapy, after which the patient recovered and was discharged

Risk factors for progressive visual field loss in primary angle-closure glaucoma: a retrospective cohort study.

PURPOSE: To investigate risk factors associated with progressive visual field (VF) loss in primary angle closure glaucoma (PACG). METHODS: We retrospectively reviewed medical record of PACG patients who had ≥5 reliable VF examinations (central 24-2 threshold test, Humphrey Field Analyzer) and ≥2 years of follow-up. Each VF was scored using Collaborative Initial Glaucoma Treatment Study system. Progression was defined if 3 consecutive follow-up VF tests had an increased score of ≥3 above the mean of the first 2 VF scores. Factors associated with VF progression were evaluated by Cox proportional hazards models. RESULTS: A total of 89 eyes from 89 patients (mean age, 69.8 ± 7.9 years), who received a mean of 6.9 ± 2.3 VF tests (mean deviation at initial, -8.1 ± 4.4 dB) with a mean follow-up of 63.9 ± 23.9 months were included. VF progression was detected in 9 eyes (10%). The axial length (AL), anterior chamber depth, and intraocular pressure (IOP) in patients with and without progression were 22.5 ± 0.6 and 23.1 ± 0.9 mm, 2.5 ± 0.3 and 2.5 ± 0.3 mm, 14.8 ± 2.4 and 14.3 ± 2.3 mm Hg, respectively. AL was the only factor associated with progression in both Cox proportional hazards univariate (p = 0.031) and multivariate models (p = 0.023). CONCLUSION: When taking into account age, IOP, follow-up period, and number of VF tests, a shorter AL is the only factor associated with VF progression in this cohort of Chinese patients with PACG. Further studies are warranted to verify the role of AL in progressive VF loss in PACG

Cox proportional hazards multivariate analysis testing the association between age, gender, axial length, central corneal thickness, and the hazards of visual field progression.

<p>Cox proportional hazards multivariate analysis testing the association between age, gender, axial length, central corneal thickness, and the hazards of visual field progression.</p

Prognostic Factors on the Graft-versus-Host Disease-Free and Relapse-Free Survival after Adult Allogeneic Hematopoietic Stem Cell Transplantation

The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including graft-versus-host disease (GVHD), relapse, and death. A novel composite endpoint of GVHD-free/relapse-free survival (GRFS) in which events include grades 3-4 acute GVHD, chronic GVHD requiring systemic therapy, relapse, or death is censored to completely characterize the survival without mortality or ongoing morbidity. In this regard, studies attempting to identify the prognostic factors of GRFS are quite scarce. Thus, we reviewed 377 adult patients undergoing allogeneic HSCT between 2003 and 2013. The 1- and 2-year GRFS were 40.8% and 36.5%, respectively, significantly worse than overall survival and disease-free survival (log-rank p<0.001). European Group for Blood and Marrow Transplantation (EBMT) risk score > 2 (p<0.001) and hematologic malignancy (p=0.033) were poor prognostic factors for 1-year GRFS. For 2-year GRFS, EBMT risk score > 2 (p<0.001), being male (p=0.028), and hematologic malignancy (p=0.010) were significant for poor outcome. The events between 1-year GRFS and 2-year GRFS predominantly increased in relapsed patients. With prognostic factors of GRFS, we could evaluate the probability of real recovery following HSCT without ongoing morbidity