A High-fat, High-sugar ‘Western’ Diet Alters Dorsal Striatal Glutamate, Opioid, and Dopamine Transmission in Mice

Understanding neuroadaptations involved in obesity is critical for developing new approaches to treatment. Diet-induced neuroadaptations within the dorsal striatum have the capacity to drive excessive food seeking and consumption. Five-week-old C57BL/6J mice consumed a high-fat, high-sugar ‘western diet’ (WD) or a control ‘standard diet’ (SD) for 16 weeks. Weight gain, glucose tolerance, and insulin tolerance were measured to confirm an obese-like state. Following these 16 weeks, electrophysiological recordings were made from medium spiny neurons (MSNs) in the medial (DMS) and lateral (DLS) portions of dorsal striatum to evaluate diet effects on neuronal excitability and synaptic plasticity. In addition, fast-scan cyclic voltammetry evaluated dopamine transmission in these areas. WD mice gained significantly more weight and consumed more calories than SD mice and demonstrated impaired glucose tolerance. Electrophysiology data revealed that MSNs from WD mice demonstrated increased AMPA-to-NMDA receptor current ratio and prolonged spontaneous glutamate-mediated currents, specifically in the DLS. Evoked dopamine release was also significantly greater and reuptake slower in both subregions of WD striatum. Finally, dorsal striatal MSNs from WD mice were significantly less likely to demonstrate mu-opioid receptor-mediated synaptic plasticity. Neuronal excitability and GABAergic transmission were unaffected by diet in either striatal subregion. Our results demonstrate that a high-fat, high-sugar diet alters facets of glutamate, dopamine, and opioid signaling within the dorsal striatum, with some subregion specificity. These alterations within a brain area known to play a role in food motivation/consumption and habitual behavior are highly relevant for the clinical condition of obesity and its treatment

Input-selective adenosine A1 receptor-mediated synaptic depression of excitatory transmission in dorsal striatum

The medial (DMS) and lateral (DLS) dorsal striatum differentially drive goal-directed and habitual/compulsive behaviors, respectively, and are implicated in a variety of neuropsychiatric disorders. These subregions receive distinct inputs from cortical and thalamic regions which uniquely determine dorsal striatal activity and function. Adenosine A1 receptors (A1Rs) are prolific within striatum and regulate excitatory glutamate transmission. Thus, A1Rs may have regionally-specific effects on neuroadaptive processes which may ultimately influence striatally-mediated behaviors. The occurrence of A1R-driven plasticity at specific excitatory inputs to dorsal striatum is currently unknown. To better understand how A1Rs may influence these behaviors, we first sought to understand how A1Rs modulate these distinct inputs. We evaluated A1R-mediated inhibition of cortico- and thalamostriatal transmission using in vitro whole-cell, patch clamp slice electrophysiology recordings in medium spiny neurons from both the DLS and DMS of C57BL/6J mice in conjunction with optogenetic approaches. In addition, conditional A1R KO mice lacking A1Rs at specific striatal inputs to DMS and DLS were generated to directly determine the role of these presynaptic A1Rs on the measured electrophysiological responses. Activation of presynaptic A1Rs produced significant and prolonged synaptic depression (A1R-SD) of excitatory transmission in the both the DLS and DMS of male and female animals. Our findings indicate that A1R-SD at corticostriatal and thalamostriatal inputs to DLS can be additive and that A1R-SD in DMS occurs primarily at thalamostriatal inputs. These findings advance the field’s understanding of the functional roles of A1Rs in striatum and implicate their potential contribution to neuropsychiatric diseases

Genetic disruption of the PI3K regulatory subunits, p85 alpha, p55 alpha, and p50 alpha partially normalizes gain-of-function PTPN11- induced hypersensitivity to GM-CSF in hematopoietic progenitors

poster abstractJuvenile Myelomonocytic Leukemia (JMML) is a lethal myeloproliferative disorder (MPD) of children, characterized by hyperproliferation of myelomonocytic cells and hypersensitivity to Granulocyte-Monocyte Colony-Stimulating Factor (GM-CSF). JMML is frequently associated with gain-of-function mutations in PTPN11, which encodes the protein tyrosine phosphatase, Shp2, and which is known to positively regulate Ras signaling. The role of MAPK signaling in gain-of-function mutant Shp2-induced leukemogenesis is well established. In addition, phosphoAkt levels are elevated in the presence of gain-of-function Shp2 mutations, suggesting a role for Phosphatidyl-Inositol-3-Kinase (PI3K) signaling (Yang, et al, 2008). Class IA PI3K is a lipid kinase heterodimer composed of one of two regulatory subunits—p85 alpha or p85 beta—and one of three catalytic subunits—p110 alpha, p110 beta, or p110 delta. PI3K mediates proliferative and anti-apoptotic signals. We have found that there is increased interaction between the p85 alpha regulatory subunit and the p110 alpha catalytic subunit in gain-offunction mutant Shp2-expressing cells compared to WT Shp2-expressing cells. The p85 alpha regulatory subunit, along with its splice variants, p55 alpha and p50 alpha, is encoded by the gene Pik3r1. To investigate the hypothesis that p85 alpha-dependent PI3K signaling contributes to gain-of-function mutant Shp2-induced GM-CSF hypersensitivity, WT and Pik3r1-/- fetal liver-derived hematopoietic progenitor cells were transduced with WT Shp2 or gain-of-function mutant Shp2 E76K. Ablation of all the Pik3r1 isoforms resulted in a significant, but incomplete, correction of GM-CSF hypersensitivity in Shp2 E76K-expressing cells. Consistently, upon genetic disruption of Pik3r1, Akt phosphorylation was reduced in both WT Shp2- and Shp2 E76K-expressing cells compared to that seen in Pik3r1+/+ cells, but was not completely absent. Additionally, Erk activation was reduced in Pik3r1-/- cells expressing Shp2 E76K compared to that in Pik3r1+/+ cells, indicating that interruption of Shp2-mediated PI3K signaling affects the MAPK pathway as well, which likely contributes to the reduction in GM-CSF-stimulated proliferation in the Pik3r1-/- cells. Finally, treatment with the PI3K inhibitor, LY294002 resulted in complete abrogation of Akt phosphorylation in Pik3r1-/- cells transduced with Shp2 E76K, indicating that residual PI3K activity in the absence of Pik3r1 likely contributes to the incomplete correction of GM-CSF hypersensitivity and suggesting that although p85 alpha plays an important role in gain-of-function mutant Shp2-induced hyperactivation of PI3K signaling, additional p85 alpha-independent mechanisms contribute as well

Mu opioid receptors on vGluT2‐expressing glutamatergic neurons modulate opioid reward

The role of Mu opioid receptor (MOR)-mediated regulation of GABA transmission in opioid reward is well established. Much less is known about MOR-mediated regulation of glutamate transmission in the brain and how this relates to drug reward. We previously found that MORs inhibit glutamate transmission at synapses that express the Type 2 vesicular glutamate transporter (vGluT2). We created a transgenic mouse that lacks MORs in vGluT2-expressing neurons (MORflox-vGluT2cre) to demonstrate that MORs on the vGluT2 neurons themselves mediate this synaptic inhibition. We then explored the role of MORs in vGluT2-expressing neurons in opioid-related behaviors. In tests of conditioned place preference, MORflox-vGluT2cre mice did not acquire place preference for a low dose of the opioid, oxycodone, but displayed conditioned place aversion at a higher dose, whereas control mice displayed preference for both doses. In an oral consumption assessment, these mice consumed less oxycodone and had reduced preference for oxycodone compared with controls. MORflox-vGluT2cre mice also failed to show oxycodone-induced locomotor stimulation. These mice displayed baseline withdrawal-like responses following the development of oxycodone dependence that were not seen in littermate controls. In addition, withdrawal-like responses in these mice did not increase following treatment with the opioid antagonist, naloxone. However, other MOR-mediated behaviors were unaffected, including oxycodone-induced analgesia. These data reveal that MOR-mediated regulation of glutamate transmission is a critical component of opioid reward

The Ets Transcription Factor GABP Is a Component of the Hippo Pathway Essential for Growth and Antioxidant Defense

这是周大旺教授继2009年首次发现了Hippo信号通路在哺乳动物中控制器官大小及肿瘤发生具有重要作用后的又一重大研究成果，该研究系统阐述了 YAP基因在转录调控水平上的的调控机理，进一步完善了人们对Hippo信号通路的认识，也为由YAP调控异常所引发的癌症提供了一个潜在的治疗靶点。 该论文的第一作者为博士生吴黉坦和硕士生肖玉波和张世浩, 通讯作者是周大旺教授和陈兰芬副教授，该工作是与厦门市中医院、中山医院和医学高等专科学校等单位合作完成的。周大旺教授是中央首批“青年千人计划”入选者并获得国家首批“优秀青年科学基金”资助。The transcriptional coactivator Yes-associated protein (YAP) plays an important role in organ-size control and tumorigenesis. However, how Yap gene expression is regulated remains unknown. This study shows that the Ets family member GABP binds to the Yap promoter and activates YAP transcription. The depletion of GABP downregulates YAP, resulting in a G1/S cell-cycle block and increased cell death, both of which are substantially rescued by reconstituting YAP. GABP can be inactivated by oxidative mechanisms, and acetaminophen-induced glutathione depletion inhibits GABP transcriptional activity and depletes YAP. In contrast, activating YAP by deleting Mst1/Mst2 strongly protects against acetaminophen-induced liver injury. Similar to its effects on YAP, Hippo signaling inhibits GABP transcriptional activity through several mechanisms. In human liver cancers, enhanced YAP expression is correlated with increased nuclear expression of GABP. Therefore, we conclude that GABP is an activator of Yap gene expression and a potential therapeutic target for cancers driven by YAP

Alcohol exposure disrupts mu opioid receptor-mediated long-term depression at insular cortex inputs to dorsolateral striatum

µ-opioid receptors (MOR) are known to modulate the reward effects of drugs of abuse, and MOR activation induces long-term depression (LTD) at striatal synapses. Here the authors show that alcohol exposure disrupts MOR-induced LTD only at specific cortical inputs to the striatum

Three-dimensional surface inspection for semiconductor components with fringe projection profilometry

With the increasing integration level of components in modern electronic devices, three-dimensional automated optical inspection has been widely used in the manufacturing process of electronic and communication industries to improve the product quality. In this paper, we develop a three-dimensional inspection and metrology system for semiconductor components with fringe projection profilometry, which is composed of industry camera, telecentric lens and projection module. This system is used to measure the height, flatness, volume, shape, coplanarity for quality checking. To detect the discontinuous parts in the internal surface of semiconductor components, we employ the fringes with multiple spatial frequencies to avoid the measurement ambiguity. The complete three-dimensional information of semiconductor component is obtained by fusing the absolute phase maps from different views. The practical inspection results show that the depth resolution of our system reaches 10 μm. This system can be further embedded for the online inspection of various electronic and communication products

Triterpenoids from the Herbs of Salicornia bigelovii

A new nortriterpene saponin, 3-O-β-d-glucuronopyranosyl-30-norolean-12,20(29)-dien-23- oxo-28-oic acid, namely bigelovii D (11), was isolated from the hydroalcoholic extract of herbs of Salicornia bigelovii along with 10 known saponins (1–10). Their chemical structures were identified on the basis of spectroscopic analyses including two-dimensional NMR and a comparison with literature data. Some of these compounds showed potent antifungal activities in vitro. Compounds 3, 4, 5, 6, 7, 10 and 11 demonstrated potent inhibitory activities against Colletotrichum gloeosporioides and compound 11 displayed broad-spectrum inhibitory activity against Alternaria alternata, A. solani, Botrytis cinerea, C. gloeosporioides, Fusarium graminearum, F. verticilloides, Thanatephorus cucumeris and Sclerotinia sclerotiorum, with EC50 values ranging from 13.6 to 36.3 μg/mL

Genetic disruption of the scaffolding protein, Kinase Suppressor of Ras 1 (KSR1), differentially regulates GM-CSF-stimulated hyperproliferation in hematopoietic progenitors expressing activating PTPN11 mutants D61Y and E76K

Activating PTPN11 mutants promote hematopoietic progenitor hyperactivation of Erk and hypersensitivity to GM-CSF. We hypothesized that Kinase Suppressor of Ras 1 (KSR1) contributes to activating PTPN11-induced GM-CSF hypersensitivity. Bone marrow progenitors from WT and KSR1−/− mice expressing WT Shp2, Shp2E76K, or Shp2D61Y were evaluated functionally and biochemically. KSR1 activation and interaction with phospho-Erk was enhanced in Shp2D61Y- and ShpE76K-expressing cells. Genetic disruption of KSR1 partially normalized Shp2E76K-induced GM-CSF hypersensitivity, but failed to correct Shp2D61Y-induced GM-CSF hypersensitivity. Collectively, these studies suggest that cells expressing Shp2E76K have a greater dependence on KSR1 for GM-CSF hypersensitivity than cells expressing Shp2D61Y