The role of hippocampal mossy cells in antidepressant actions

Hippocampus, Mossy cells, antidepressant, p11/AnxA2/Smarca3 complexMost antidepressants, including selective serotonin reuptake inhibitors (SSRIs), initiate their drug actions by rapid elevation of serotonin, but they take several weeks to achieve ther-apeutic onset. This therapeutic delay suggests slow adaptive changes in multiple neuronal subtypes and their neural circuits over prolonged periods of drug treatment. Mossy cells are excitatory neurons in the dentate hilus that regulate dentate gyrus activity and function. Here I show that neuronal activity of hippocampal mossy cells is enhanced by chronic, but not acute, SSRI administration. Behavioral and neurogenic effects of chronic treatment with the SSRI, fluoxetine, are abolished by mossy cell-specific knockout of p11 or Smarca3 or by an inhibi-tion of the p11/AnxA2/SMARCA3 heterohexamer, an SSRI-inducible protein complex. Fur-thermore, simple chemogenetic activation of mossy cells using Gq-DREADD is sufficient to elevate the proliferation and survival of the neural stem cells. Conversely, acute chemogenetic inhibition of mossy cells using Gi-DREADD impairs behavioral and neurogenic responses to chronic administration of SSRI. In addition, modulations of mossy cell activity are influence to excitation-inhibition balance in dentate gyrus. The present data establish that mossy cells play a crucial role in mediating the effects of chronic antidepressant medication. These results indicate that compounds that target mossy cell activity would be attractive candidates for the development of newer antidepressant medications.openChapter 1. Background 1 1. Major depressive disorder 1 1.1 MDD in the hippocampus 1 2. Antidepressive therapeutics 4 Chapter 2. The role of hippocampal mossy cells in antidepressant actions. 7 1. Introduction 7 1.1 Molecular mechanism of SSRI actions 7 1.2 Mossy cells in the hippocampus 10 1.3 p11, An SSRI-inducible molecule 13 2. Materials and methods 15 2.1 Materials 15 2.1.1 Antibodies 15 2.1.2 Virus strains 15 2.1.3 Recombinant DNAs 16 2.1.4 Chemicals 16 2.1.5 Experimental models 17 2.2 Methods 18 2.2.1 Animal breeding 18 2.2.2 Drug treatment 18 2.2.3 Plasmid constructions 19 2.2.4 Immunoprecipitation of p11/AnxA2/SMARCA3 complex 19 2.2.5 Stereotaxic surgery 20 2.2.6 Behavioral assessments 21 2.2.6.1 Elevated plus maze (EPM) 21 2.2.6.2 Open field test (OF) 22 2.2.6.3 Light and dark box test (LD box) 22 2.2.6.4 Novelty suppressed feeding test (NSF) 22 2.2.6.5 Tail suspension test (TST) 23 2.2.7 Chronic unpredictable mild Stress paradigm 23 2.2.8 Immunohistochemistry 25 2.2.9 BrdU labeling and neurogenesis assay 26 2.2.10 Electrophysiological recordings of mossy cells 27 2.2.10.1 Fluorescence labeling of mossy cells 27 2.2.10.2 Slice preparation 27 2.2.10.3 Electrophysiology 28 2.2.11. Data analysis and statistics 29 3. Results 30 3.1. The role of p11/AnxA2/SMARCA3 complex in hippocampal mossy cells in an-tidepressant responses 30 3.1.1 Effects of genetic deletion of p11 or Smarca3 in hippocampal mossy cells on behavioral responses to chronic SSRI administration 30 3.1.2 Effects of mossy cell-specific inhibition of the p11/AnxA2/SMARCA3 com-plex on neurogenic and behavioral responses to chronic antidepressant treatment 38 3.1.3. Effects of cell type-specific inhibition of the p11/AnxA2/SMARCA3 complex on neuronal activity of mossy cells 50 3.2. The role of hippocampal mossy cells in antidepressant responses 59 3.2.1 Effects of selective stimulation of dentate mossy cells on adult neurogenesis in the hippocampus 59 3.2.2 Effects of selective inhibition of dentate mossy cells on antidepressant actions in the hippocampus 67 3.3. Effects of modulation of mossy cells on micro-circuits in the dentate gyrus 78 4. Discussion 82 Reference 95 Summary in Korean 103Selective serotonin reuptake inhibitors(SSRI)를 포함한 대부분의 항우울제는 약물 복용 즉시 체내 세로토닌의 양이 증가하게 된다. 반면, 항우울 약물 복용으로 인한 치료 효과가 나타나기까지는 수주 동안의 시간이 필요하다. 이러한 치료 지연 현상은 약물 복용 이후 신경세포에서 장기간에 걸쳐 일어나는 유전자 발현 및 신경회로의 변화가 동반되어 나타나는 결과라고 할 수 있다. 모시세포는 치아이랑의 hilus 구역에 존재하는 흥분성 뉴런으로, 치아이랑의 활성 및 기능을 조절하는 역할을 한다고 알려져 있다. 본 연구에서는 해마 모시세포가 항우울제 단기 복용이 아닌, 장기복용에 의해서 활성이 강화 된다는 것을 보였다. 또한, SSRI, fluoxetine 장기 복용에 따른 행동학적 그리고 신경발생학적 효과가 모시세포에 한해서 p11 또는 Smarca3 단백질을 억제하거나 혹은 p11/AnxA2/Smarca3 복합체를 억제하였을 경우 사라졌음을 보였다. 더불어, Gq-DREADD 시스템을 이용한 모시세포의 활성 강화는 신경 줄기 세포의 증식과 생존을 증진시키기에 충분함을 보였다. 반대로, Gi-DREADD 시스템을 이용한 모시세포의 활성 억제는 항우울 약물 장기 복용에 의해 나타나는 행동학적 그리고 신경발생학적 효과를 손상시킴을 보였다. 모시세포의 활성 변화는 치아이랑 내부의 흥분성 / 억제성 신호의 조화에 영향을 끼치는 것 또한 확인할 수 있었다. 따라서 본연구에서는 항우울 약물 반응을 매개하는데 있어서 모시세포가 중요한 역할을 한다는 것을 입증하였다. 해당 연구 결과는 해마 내 모시세포가 새로운 항우울 약물 개발에 중요 후보군이 될 것임을 보여준다.DoctordCollectio

On the effect of the East/Japan Sea SST variability on the North Pacific atmospheric circulation in a regional climate model

Author Posting. © American Geophysical Union, 2014. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Atmospheres 119 (2014): 418–444, doi:10.1002/2013JD020523.The East/Japan Sea (EJS) is a semi-enclosed marginal sea located in the upstream of the North Pacific storm track, where the leading modes of wintertime interannual variability in sea surface temperature (SST) are characterized by the basin-wide warming-cooling and the northeast-southwest dipole. Processes leading to local and remote atmospheric responses to these SST anomalies are investigated using the Weather Research and Forecast (WRF) model. The atmosphere in direct contact with anomalous diabatic forcing exhibits a linear and symmetric response with respect to the sign, pattern, and magnitude of SST anomalies, producing increased (decreased) wind speed and precipitation response over warm (cold) SSTs. This local response is due to modulation of both the vertical stability of the marine atmospheric boundary layer and the adjustment of sea level pressure, although the latter provides a better explanation of the quadrature relationship between SST and wind speed. The linearity in the local response suggests the importance of fine-scale EJS SSTs to predictability of the regional weather and climate variability. The remote circulation response, in contrast, is strongly nonlinear. An intraseasonal equivalent barotropic ridge emerges in the Gulf of Alaska as a common remote response independent of EJS SST anomalies. This downstream blocking response is reinforced by the enhanced storm track variability east of Japan via transient eddy vorticity flux convergence. Strong nonlinearity in remote response implies that detailed EJS SST patterns may not be critical to this downstream ridge response. Overall, results demonstrate a remarkably far-reaching impact of the EJS SSTs on the atmospheric circulation.H.S. gratefully acknowledges the support from the Penzance Endowed Fund in support of Assistant Scientists at WHOI. Y.-O.K. acknowledges NSF Climate and Large-Scale Dynamics program (AGS-1035423). H.S. and Y.-O.K. also thank NASA grant (NNX13AM59G)

Distinct mechanisms of decadal subsurface heat content variations in the eastern and western Indian Ocean modulated by tropical Pacific SST

Author Posting. © American Meteorological Society, 2018. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Climate 31 (2018): 7751-7769, doi:10.1175/JCLI-D-18-0184.1.Decadal variability of the subsurface ocean heat content (OHC) in the Indian Ocean is investigated using a coupled climate model experiment, in which observed eastern tropical Pacific sea surface temperature (EPSST) anomalies are specified. This study intends to understand the contributions of external forcing relative to those of internal variability associated with EPSST, as well as the mechanisms by which the Pacific impacts Indian Ocean OHC. Internally generated variations associated with EPSST dominate decadal variations in the subsurface Indian Ocean. Consistent with ocean reanalyses, the coupled model reproduces a pronounced east–west dipole structure in the southern tropical Indian Ocean and discontinuities in westward-propagating signals in the central Indian Ocean around 100°E. This implies distinct mechanisms by which the Pacific impacts the eastern and western Indian Ocean on decadal time scales. Decadal variations of OHC in the eastern Indian Ocean are attributed to 1) western Pacific surface wind anomalies, which trigger oceanic Rossby waves propagating westward through the Indonesian Seas and influence Indonesian Throughflow transport, and 2) zonal wind anomalies over the central tropical Indian Ocean, which trigger eastward-propagating Kelvin waves. Decadal variations of OHC in the western Indian Ocean are linked to conditions in the Pacific via changes in the atmospheric Walker cell, which trigger anomalous wind stress curl and Ekman pumping in the central tropical Indian Ocean. Westward-propagating oceanic Rossby waves extend the influence of this anomalous Ekman pumping to the western Indian Ocean.This research was supported by the Independent Research and Development Program at WHOI to CCU, an NSF OCE PO grant (NSF OCE- 1242989) to Young-Oh Kwon, NOAA CP CVP grants (NA15OAR4310176 and NA17OAR4310255) to Hyodae Seo, and a research grant fromtheMinistry of Science and Technology of the People’s Republic of China to Tsinghua University (2017YFA0603902).2019-02-1

Six-Month Comparison of Coronary Endothelial Dysfunction Associated With Sirolimus-Eluting Stent Versus Paclitaxel-Eluting Stent

ObjectivesThis study was designed to investigate whether endothelial dysfunction is related to drug-eluting stent (DES) implantation at 6 months after stenting.BackgroundCurrent available DES could delay vessel healing and subsequently impair endothelial function.MethodsEndothelial function was estimated at 6-month follow-up in 75 patients (31 men, mean age 62.1 years) with a DES (39 sirolimus-eluting stents [SES], 36 paclitaxel-eluting stents [PES]), and 10 patients with a bare-metal stent (BMS) to the left anterior descending artery, by incremental acetylcholine (Ach) infusion (20 μg/min, 50 μg/min, 100 μg/min) and nitrate (200 μg/min) into the left coronary ostium. Vascular responses were quantitatively measured in arterial segments 5 mm proximal and distal to DES and compared with corresponding segments in the BMS group and midsegments in the left circumflex artery as a reference nonstented artery. All antianginal agents were withheld for at least 72 h before coronary angiography.ResultsGreater vasoconstriction to Ach was observed in both the SES and PES groups than in the BMS group or control segments of left circumflex artery. Vasoconstriction to Ach was more prominent in arterial segments distal to stents in both SES and PES groups compared with those in the BMS group (p < 0.001). The degree of vasoconstriction to Ach was similar between the SES and PES groups. Endothelium-independent vasodilatation to nitrate did not differ significantly between the study groups.ConclusionsAbnormal vasoconstriction to Ach was found in the SES and PES groups, especially in arterial segments distal to DES at 6 months after stenting, which suggests that DES has a potential long-term adverse effect on local coronary endothelial dysfunction

Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer

Purpose Currently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC. Materials and Methods In this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models. Results AZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy. Conclusion Taken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC.

A Local Region of Interest Imaging Method for Electrical Impedance Tomography with Internal Electrodes

Electrical Impedance Tomography (EIT) is a very attractive functional imaging method despite the low sensitivity and resolution. The use of internal electrodes with the conventional reconstruction algorithms was not enough to enhance image resolution and accuracy in the region of interest (ROI). We propose a local ROI imaging method with internal electrodes developed from careful analysis of the sensitivity matrix that is designed to reduce the sensitivity of the voxels outside the local region and optimize the sensitivity of the voxel inside the local region. We perform numerical simulations and physical measurements to demonstrate the localized EIT imaging method. In preliminary results with multiple objects we show the benefits of using an internal electrode and the improved resolution due to the local ROI image reconstruction method. The sensitivity is further increased by allowing the surface electrodes to be unevenly spaced with a higher density of surface electrodes near the ROI. Also, we analyse how much the image quality is improved using several performance parameters for comparison. While these have not yet been studied in depth, it convincingly shows an improvement in local sensitivity in images obtained with an internal electrode in comparison to a standard reconstruction method