Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation.

Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, the glucose level in the brain plummets, forcing neurons to utilize alternative fuels. However, the molecular mechanisms of neuronal metabolic plasticity remain poorly understood. Here, we demonstrate that glucose-deprived neurons activate the CREB and PGC1α transcriptional program, which induces expression of the mitochondrial deacetylase Sirtuin 3 (Sirt3) both in vitro and in vivo. We show that Sirt3 localizes to axonal mitochondria and stimulates mitochondrial oxidative capacity in hippocampal nerve terminals. Sirt3 plays an essential role in sustaining synaptic transmission in the absence of glucose by providing metabolic support for the retrieval of synaptic vesicles after release. These results demonstrate that the transcriptional induction of Sirt3 facilitates the metabolic plasticity of synaptic transmission.

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep, intense circuit activity, or dietary restrictions, posing significant metabolic stress. Here, we demonstrate that the mammalian brain utilizes pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability within a neuron and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation which in turn modulates mitochondrial pyruvate uptake. Importantly, our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in synaptic transmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval, functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of synaptic transmission in hippocampal terminals.

Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation.

Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, glucose levels in the brain plummet, forcing neurons to utilize alternative fuels. However, the molecular mechanisms of neuronal metabolic plasticity remain poorly understood. Here, we demonstrate that glucose-deprived neurons activate the CREB and PGC1α transcriptional program that induces the expression of the mitochondrial deacetylase Sirtuin 3 (Sirt3) both in vitro and in vivo . We show that Sirt3 localizes to axonal mitochondria and stimulates mitochondrial oxidative capacity in hippocampal nerve terminals. Sirt3 plays an essential role in sustaining synaptic transmission in the absence of glucose by powering the retrieval of synaptic vesicles after release. These results demonstrate that the transcriptional induction of Sirt3 ensures the metabolic plasticity of synaptic transmission. Highlights: Glucose deprivation drives transcriptional reprogramming of neuronal metabolism via CREB and PGC1α. Glucose or food deprivation trigger the neuronal expression of mitochondrial deacetylase sirtuin 3 (Sirt3) both in vitro and in vivo . Sirt3 stimulates oxidative ATP synthesis in nerve terminals.Sirt3 sustains the synaptic vesicle cycle in the absence of glucose.

Semiautomated analysis of an optical ATP indicator in neurons.

Significance: The firefly enzyme luciferase has been used in a wide range of biological assays, including bioluminescence imaging of adenosine triphosphate (ATP). The biosensor Syn-ATP utilizes subcellular targeting of luciferase to nerve terminals for optical measurement of ATP in this compartment. Manual analysis of Syn-ATP signals is challenging due to signal heterogeneity and cellular motion in long imaging sessions. Here, we have leveraged machine learning tools to develop a method for analysis of bioluminescence images. Aim: Our goal was to create a semiautomated pipeline for analysis of bioluminescence imaging to improve measurements of ATP content in nerve terminals. Approach: We developed an image analysis pipeline that applies machine learning toolkits to distinguish neurons from background signals and excludes neural cell bodies, while also incorporating user input. Results: Side-by-side comparison of manual and semiautomated image analysis demonstrated that the latter improves precision and accuracy of ATP measurements. Conclusions: Our method streamlines data analysis and reduces user-introduced bias, thus enhancing the reproducibility and reliability of quantitative ATP imaging in nerve terminals.

Mitochondria in Neuronal Health: From Energy Metabolism to Parkinson's Disease.

Mitochondria are the main suppliers of neuronal adenosine triphosphate and play a critical role in brain energy metabolism. Mitochondria also serve as Ca2+ sinks and anabolic factories and are therefore essential for neuronal function and survival. Dysregulation of neuronal bioenergetics is increasingly implicated in neurodegenerative disorders, particularly Parkinson's disease. This review describes the role of mitochondria in energy metabolism under resting conditions and during synaptic transmission, and presents evidence for the contribution of neuronal mitochondrial dysfunction to Parkinson's disease.

Microglia heterogeneity and neurodegeneration: The emerging paradigm of the role of immunity in Alzheimer's disease.

Alzheimer's disease (AD) is the most common dementia type affecting nearly 44 million people worldwide. Recent findings point to microglia as a significant contributor to neural development, neuroinflammation, and degeneration. Dysregulated immunoactivity in AD has been broadly studied, and current research on animal models enabled us to identify a new cluster of microglia (disease-associated microglia) alongside previously detected glial populations (e.g., plaque-associated microglia, dark microglia, Human Alzheimer's microglia) associated with neuroinflammation and with macrophagic activity. These distinct populations of glia show a spatial distribution within plaques with unique imaging features and distinct gene expression profile. Novel genetic approaches using single-nuclei RNA sequencing (sn-RNA seq) allowed researchers to identify gene expression profiles from fixed human samples. Recent studies, exposing transcriptomic clusters of disease-related cells and analyzing sequenced RNA from sorted myeloid cells, seem to confirm the hypothesis of the central role of glia in the pathogenesis of Alzheimer's disease. These discoveries may shed light on the effects of microglial activation and differences in gene expression profiles, furthering research towards the development of a cell-specific therapy. In this review, we examine recent studies that guide us towards recognizing the role of diverse populations of glial cells and their possible heterogeneous functional states in the pathogenesis of AD in humans.

Surgical Approaches to Benign Parapharyngeal Space Tumors-5-Year Experience.

INTRODUCTION: Various surgical approaches to parapharyngeal space (PPS) tumors are introduced to obtain complete removal with the preservation of the surrounding structures in parapharyngealneoplasms. Here, we will discuss the main techniques and their outcome. MATERIALS AND METHODS: This retrospective study was conducted on 78 patients undergone either transoral, transcervical or a combination of these two approaches for the resection of PSS tumors from January 2010 to January 2015. RESULTS: A number of 33 male and 45 female patients with the mean age of 40.9 ± 9.1 were evaluated. 42.3% of the patients were asymptomatic at the initial presentation. Pleomorphic adenoma and schwannoma were a permanent diagnosis in 61(78.2%) and 11(14.1%) patients, respectively. PPS tumors were resected using transoral, transcervical and combined approaches in 35(44.8%), 33(42.3%) and 10 (12.9%) cases, respectively. Recurrence occurred in 10 patients all of whom had apre-styloid pleomorphic adenoma, operated transcervical (P< 0.0001).Three cases of tenth nerve palsy occurred in schwannomas which were operatedtranscervically (P=0.04). Mean hospital stays were 2.11,3.69, and 4.9 days after transoral, transcervical and combined approaches, respectively (P= 0.001). CONCLUSION: Transoral, transcervical and combined approaches are all able to provide adequate visualization with comparable outcomes.

Stearoyl CoA Desaturase Is Essential for Regulation of Endoplasmic Reticulum Homeostasis and Tumor Growth in Glioblastoma Cancer Stem Cells.

Inherent plasticity and various survival cues allow glioblastoma stem-like cells (GSCs) to survive and proliferate under intrinsic and extrinsic stress conditions. Here, we report that GSCs depend on the adaptive activation of ER stress and subsequent activation of lipogenesis and particularly stearoyl CoA desaturase (SCD1), which promotes ER homeostasis, cytoprotection, and tumor initiation. Pharmacological targeting of SCD1 is particularly toxic due to the accumulation of saturated fatty acids, which exacerbates ER stress, triggers apoptosis, impairs RAD51-mediated DNA repair, and achieves a remarkable therapeutic outcome with 25%-100% cure rate in xenograft mouse models. Mechanistically, divergent cell fates under varying levels of ER stress are primarily controlled by the ER sensor IRE1, which either promotes SCD1 transcriptional activation or converts to apoptotic signaling when SCD1 activity is impaired. Taken together, the dependence of GSCs on fatty acid desaturation presents an exploitable vulnerability to target glioblastoma.

Predictors of Thyroid Gland Invasion in Laryngeal Squamous Cell Carcinoma.

INTRODUCTION: Laryngeal squamous cell carcinoma (SCC) can invade the thyroid gland leading to unnecessary thyroidectomies with subsequent hypothyroidism and hyperparathyroidism. Thus, clinicopathological variables should be defined in order to predict thyroid gland invasion preoperatively. MATERIALS AND METHODS: We performed a retrospective analysis of 1,465 patients with laryngeal SCC referred to our center between March 2009 and January 2016. Among these patients, 60 individuals underwent total laryngectomy and either thyroid lobectomy and isthmectomy or total thyroidectomy. RESULTS: Thyroid gland invasion was observed in 20% of samples. The following variables were associated with thyroid gland invasion: transglottic spread of the tumor (odds ratio [OR]: 2.04, 95% confidence interval [CI]: 1.15-5.81, P=0.004), thyroid cartilage involvement (OR: 1.53, 95% CI: 0.94-2.50, P=0.02), and anterior commissure involvement (OR: 5.75, 95% CI: 0.86-38.42, P=0.01). In addition, the largest dimension of the tumor was significantly associated with thyroid gland involvement (r=0.36, 95% CI 0.05-0.67, P=0.004). Multivariate linear regression analysis confirmed these findings. CONCLUSION: The rate of thyroidectomies performed in cases of laryngeal SCC is much higher than the actual rate of thyroid gland invasion. Thus, preoperative evaluation to find transglottic spread of the tumor, thyroid cartilage, and anterior commissure involvement should be considered.

Involvement of NO/NMDA-R pathway in the behavioral despair induced by amphetamine withdrawal.

Abrupt discontinuation of chronic amphetamine consumption leads to withdrawal symptoms including depression, anhedonia, dysphoria, fatigue, and anxiety. These irritating symptoms may result in continuing to take the drug or can lead to suicidal behavior. Past studies have shown the involvement of various biologic systems in depression induced following amphetamine withdrawal (AW). However, there is no evidence about the relation between nitric oxide (NO) with NMDA receptors on depression following AW. In this study, we examined the involvement of the NO/NMDA pathways on depressive-like behaviors after 24 h withdrawal following 5 continuous days of amphetamine administration in male NMRI mice. Behavioral tasks used for depression assessment included the forced swimming test (FST), the Splash test and the open field test (OFT). In order to evaluate the role of NO/NMDA pathways animals treated with MK-801 (NMDA-R antagonist), Aminoguanidine (AG), a selective iNOS inhibitor, Nω-Nitro-l-arginine (L-NNA), a non-selective NOS inhibitor and 7-Nitro indazole (7-NI), a selective nNOS inhibitor. We also measured the level of nitrite in the hippocampus. Our data showed that AW induced the depressive-like effect in the FST and the Splash test. We showed that administration of AG, L-NNA, and MK-801 mitigated AW induced depression, however, 7-NI was failed to decrease depressive-like behaviors. Also, the antidepressant-like effect of co-injection of sub-effective doses of MK-801 with AG suggested that inducible nitric oxide synthase (iNOS) is associated with NMDA-R in AW induced depression. In conclusion, both NO and NMDA-R pathways are involved and related to each other in depression induced following AW.

Comparing the length of penile mucosa in men with and without premature ejaculation.

BACKGROUND: Premature ejaculation is one of the prevalent disorders in men; almost one out of three men between 18 and 59 years old have this disorder with its leading sequel such as lack of self-confidence, anxiety, depression and unsatisfactory intercourse in men and their partners. This study aimed to compare the length of penile mucosa in men with and without premature ejaculation. METHOD: Three hundred and eighty patients referring to our hospital from March 2009 to March 2010 were enrolled in the study. First group comprised 190 men with premature ejaculation and second group included 190 men without premature ejaculation as control group that were chosen randomly. A questionnaire was designed to collect data and was completed for both groups. Height, weight, body mass index (BMI), length of penile mucosa, length of penis and intravaginal ejaculation latency time (IELT) were measured. RESULTS: The mean IELT in premature ejaculation group and control group were 47.58 ± 29.55 and 410.38 ± 190.2 s, respectively (p = 0.001). The mean penis length in premature ejaculation group and control group were 127.25 ± 16.23 and 127.03 ± 17.42 mm, respectively (p = 0.901, with nonsignificant difference); the mean penile mucosa in premature ejaculation group was 33.83 ± 11.54 mm and in control group was 31.40 ± 11.97 mm (p = 0.014, with significant difference). CONCLUSION: Longer penile mucosa can be one of the factors in causing premature ejaculation.