The Role of G-protein Coupled Estrogen Receptor (GPER/GPR30) in Hippocampal Memory and Cell Signaling in Female Mice

The loss of estrogens at menopause significantly increases a woman\u27s risk of memory loss and Alzheimer\u27s disease because estrogens are essential trophic factors for the hippocampus. However, current hormone replacement therapies are not recommended to reduce age-related memory decline because of their adverse side effects. To develop better hormone replacement therapies, it is essential to understand the mechanisms through which estrogens regulate memory. Our laboratory has demonstrated that the ability of 17β-estradiol (E2) to enhance hippocampal memory depends on the rapid activation of extracellular-signal-regulated kinase (ERK), which occurs through activation of ERα and ERβ. The G-protein coupled estrogen receptor (GPER) is a novel membrane estrogen receptor, expressed in areas of the brain important for learning and memory such as the hippocampus. However, little is known about the role of dorsal hippocampal (DH) GPER in hippocampal memory consolidation and cell signaling. Here, the present study tested the roles of GPER in regulating hippocampal memory consolidation and cell signaling in young female mice. DH infusion of the GPER agonist, G-1, enhanced object recognition and spatial memory consolidation in ovariectomized female mice. DH infusion of the GPER antagonist, G-15, blocked the memory-enhancing effects of G-1, suggesting that GPER activation mimics the beneficial effects of E2 on hippocampal memory. Interestingly, however, G-1 did not increase ERK phosphorylation like E2, but instead significantly increased phosphorylation of the c-Jun N-terminal kinase (JNK) in the DH, suggesting that the molecular mechanisms underlying the memory-enhancing effects of GPER activation may differ from those of ERα and ERβ activation. Consistent with this notion, DH infusion of the JNK inhibitor, SP600125, blocked G-1-induced memory enhancement and JNK phosphorylation, whereas the ERK inhibitor, U0126, did not. Finally, we showed that DH infusion of SP600125 or G-15 did not prevent E2 from enhancing memory and activating ERK, demonstrating that the memory-enhancing effects of E2 are not dependent on JNK or GPER activation in the DH. These results indicate that GPER regulates memory independently from ERα and ERβ by activating JNK signaling, rather than ERK signaling. Together, the data suggest that GPER does not function as an estrogen receptor in the DH. As such, this study identifies GPER as a putative new target for reducing memory decline in menopausal women without the detrimental side effects of currently available treatment option

The Effects of G-Protein-Coupled Estrogen Receptor (GPER) on Cell Signaling, Dendritic Spines, and Memory Consolidation in the Female Mouse Hippocampus

One of the most seminal findings in the literature on hormones and cognition is that the potent estrogen 17β-estradiol (E2) significantly increases the density of dendritic spines on pyramidal neurons in the CA1 region of the dorsal hippocampus (DH). However, the extent to which this E2-induced increase in hippocampal spinogenesis is necessary for memory formation remains unclear. The memory-enhancing effects of E2 in the DH can be mediated by intracellular estrogen receptors (ERs) or by the membrane-bound ER called G-protein coupled estrogen receptor (GPER). We previously reported that infusion of a GPER agonist, G-1, into the DH of ovariectomized female mice mimicked the beneficial effects of E2 on object recognition and spatial memory consolidation in a manner that depended on phosphorylation of the signaling kinase c-Jun N-terminal kinase (JNK). However, the role of CA1 dendritic spines in mediating GPER-induced memory consolidation, as well as the signaling mechanisms that might mediate effects of GPER activation on dendritic spine density, remain unclear. Thus, the present study examined in ovariectomized mice the effects of DH-infused G-1 on dendritic spine density and determined whether such effects are necessary for G-1-induced memory consolidation. We first examined whether object training itself might induce increased CA1 dendritic spine density, and showed that spine density is increased by object training. Next, we found that G-1 significantly increased the density of dendritic spines on apical dendrites of CA1 pyramidal neurons in the DH. We next examined cellular mechanisms regulating G-1 induced spinogenesis by measuring effects of DH G-1 infusion of the phosphorylation of the protein cofilin, which actively regulates actin reorganization. We found that G-1 significantly increased cofilin phosphorylation in the DH, suggesting that activation of GPER may increase dendritic spine morphogenesis through actin polymerization. As with memory consolidation in our previous study, we also found that the effects of G-1 on apical CA1 spine density and cofilin phosphorylation were dependent on JNK phosphorylation in the DH. To verify the importance of actin polymerization in GPER-mediated dendritic spine morphogenesis and hippocampal memory enhancement, we applied an actin polymerization inhibitor, latrunculin A, which prevents actin polymerization and promotes filament disassembly. DH infusion of latrunculin A prevented G-1 from inducing apical CA1 spinogenesis and enhancing both object recognition and spatial memory consolidation. Collectively, these data demonstrate that GPER-mediated hippocampal memory consolidation and spine density changes are dependent on modulating actin dynamics via JNK-Cofilin signaling, supporting a critical role of actin polymerization in the GPER-induced regulation of hippocampal function in female mice

Analysis of the effect of initial conditions on the initial development of a turbulent jet

The effect of the initial condition at the jet exit on the downstream evolution, particularly within the potential core length, were numerically investigated as well as with available experimental data. In order to select the most dependable computational model for the present numerical experiment, a comparative study has been performed with different turbulence models at k-epsilon level, and it was found that the k-epsilon-gammma model yields superior prediction accuracy over other conventional models. The calculated results show that the potential core length and the spreading rate the initial mixing layer are dependent on the initial length scale as well as the turbulent kinetic energy at the jet exit. Such effect of the initial length scale increases with higher initial turbulence level. An empirical parameter has been devised to collapse the calculated data of the potential core length and the spreading rate with various initial conditions onto a single curve

Entrepreneurial Homeworkers

Open Access via Springer Compact Agreement.Peer reviewedPublisher PD

Housing design in multi-story sectional building system

Thesis (M.Arch.)--Massachusetts Institute of Technology, Dept. of Architecture, 1980.MICROFICHE COPY AVAILABLE IN ARCHIVES AND ROTCH.Includes bibliographical references.by Jin Kyoon Kim.M.Arch

Treatment for Advanced Prostatic Cancer

Recently, there has been a proliferation of experimental and clinical data supporting early androgen deprivation for advanced prostatic cancer, due to the new insights provided by a more thorough understanding of prostate cancer biology. The logn term survival of patients with prostatic metastatic disease will require the development of novel treatment strategies truly effective against anti-androgen-resistant tumor cells and their use in concert with early androgen deprivation. To date, no evidence has been generated in experimental animal or human models of prostate cancer that supports the previous concept of delayed hormonal therapy. The development of luteinizing hormone-releasing hormone (LHRH) agonists and the anti-androgens has prompted a resurgence of interest in initial total androgen blockade, and the inhibition of the activity of 5-alpha reductase could provide a safe and effective way to remove prostatic intraepithelial dihydrotestosterone, resulting in a diminishing production of growth factors. The rationale for the use of Sumarin in the treatment of stage D prostatic cancer refractory to conventional hormonal manipulation is its ability to block the activity of several growth factors, including basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF), etc. which have been postulated to have important roles in prostatic cell biolgy

A Distance Ruler for RNA Using EPR and Site-Directed Spin Labeling

AbstractAs a basic model study for measuring distances in RNA molecules using continuous wave (CW) EPR spectroscopy, site-directed spin-labeled 10-mer RNA duplexes and HIV-1 TAR RNA motifs with various interspin distances were examined. The spin labels were attached to the 2′-NH2 positions of appropriately placed uridines in the duplexes, and interspin distances were measured from both molecular dynamics simulations (MD) and Fourier deconvolution methods (FD) [13]. The 10-mer duplexes have interspin distances ranging from 10 Å to 30 Å based on MD; however, dipolar line broadening of the CW EPR spectrum is only observed for the RNAs for predicted interspin distances of 10–21 Å and not for distances over 25 Å. The conformational changes in TAR (transactivating responsive region) RNA in the presence and in the absence of different divalent metal ions were monitored by measuring distances between two nucleotides in the bulge region. The predicted interspin distances obtained from the FD method and those from MD calculations match well for both the model RNA duplexes and the structural changes predicted for TAR RNA. These results demonstrate that distance measurement using EPR spectroscopy is a potentially powerful method to help predict the structures of RNA molecules