Repetitive transcranial magnetic stimulation activates specific regions in rat brain

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique to induce electric currents in the brain. Although rTMS is being evaluated as a possible alternative to electroconvulsive therapy for the treatment of refractory depression, little is known about the pattern of activation induced in the brain by rTMS. We have compared immediate early gene expression in rat brain after rTMS and electroconvulsive stimulation, a well-established animal model for electroconvulsive therapy. Our result shows that rTMS applied in conditions effective in animal models of depression induces different patterns of immediate-early gene expression than does electroconvulsive stimulation. In particular, rTMS evokes strong neural responses in the paraventricular nucleus of the thalamus (PVT) and in other regions involved in the regulation of circadian rhythms. The response in PVT is independent of the orientation of the stimulation probe relative to the head. Part of this response is likely because of direct activation, as repetitive magnetic stimulation also activates PVT neurons in brain slices.

Glucocorticoid-mediated repression of nuclear factor-κBdependent transcription involves direct interference with transactivation

Glucocorticoids exert multiple anti-inflammatory activities, one of which is the inhibition of transcription dependent on the nuclear factor (NF)-κB. It has been suggested that the effect of dexamethasone (DEX), a glucocorticoid analog, is attributed to an increased production of the inhibitory IκB molecule, which in turn would bind and remove activated, DNA-bound NF-κB complexes in the cell nucleus. Upon investigating DEX-mediated repression of interleukin-6 expression induced by tumor necrosis factor, DEX treatment was found to act directly on NF-κB-dependent transcription, without changing the expression level of IκB. Neither the mRNA of IκB nor the protein was significantly elevated by a combined treatment with tumor necrosis factor and DEX of murine endothelial or fibroblast cells. The DNA-binding activity of induced NF-κB also remained unchanged after stimulation of cells with DEX. Evidence for a direct nuclear mechanism of action was obtained by analysis of cell lines stably expressing a fusion protein between the DNA-binding domain of the yeast Gal4 protein and the transactivating p65 subunit of NF-κB. Expression of a Gal4-dependent luciferase reporter gene activated by this nuclear fusion protein was also strongly repressed after addition of DEX. Because the DNA-binding activity of the Gal4 fusion protein was not affected by DEX, it can be concluded that the reduction of gene activation was caused by interference of the activated glucocorticoid receptor with the transactivation potential of the NF-κB p65 subunit.

The affective component of pain in rodents: Direct evidence for a contribution of the anterior cingulate cortex

Numerous human and animal studies indirectly implicate neurons in the anterior cingulate cortex (ACC) in the encoding of the affective consequences of nociceptor stimulation. No causal evidence, however, has been put forth linking the ACC specifically to this function. Using a rodent pain assay that combines the hind-paw formalin model with the place-conditioning paradigm, we measured a learned behavior that directly reflects the affective component of pain in the rat (formalin-induced conditioned place avoidance) concomitantly with “acute” formalin-induced nociceptive behaviors (paw lifting, licking, and flinching) that reflect the intensity and localization of the nociceptive stimulus. Destruction of neurons originating from the rostral, but not caudal, ACC reduced formalin-induced conditioned place avoidance without reducing acute pain-related behaviors. These results provide evidence indicating that neurons in the ACC are necessary for the “aversiveness” of nociceptor stimulation.

Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity.

Tumor necrosis factor (TNF) is selectively cytotoxic to some types of tumor cells in vitro and exerts antitumor activity in vivo. Reactive oxygen intermediates (ROIs) have been implicated in the direct cytotoxic activity of TNF. By using confocal microscopy, flow cytometry, and the ROI-specific probe dihydrorhodamine 123, we directly demonstrate that intracellular ROIs are formed after TNF stimulation. These ROIs are observed exclusively under conditions where cells are sensitive to the cytotoxic activity of TNF, suggesting a direct link between both phenomena. ROI scavengers, such as butylated hydroxyanisole, effectively blocked the formation of free radicals and arrested the cytotoxic response, confirming that the observed ROIs are cytocidal. The mitochondrial glutathione system scavenges the major part of the produced ROIs, an activity that could be blocked by diethyl maleate; under these conditions, TNF-induced ROIs detectable by dihydrorhodamine 123 oxidation were 5- to 20-fold higher.

Regulated localization of rab18 to lipid droplets - Effects of lipolytic stimulation and inhibition of lipid droplet catabolism

Rab GTPases are crucial regulators of membrane traffic. Here we have examined a possible association of Rab proteins with lipid droplets (LDs), neutral lipid-containing organelles surrounded by a phospholipid monolayer, also known as lipid bodies, which have been traditionally considered relatively inert storage organelles. Although we found close apposition between LDs and endosomal compartments labeled by expressed Rab5, Rab7, or Rab11 constructs, there was no detectable labeling of the LD surface itself by these Rab proteins. In contrast, GFP-Rab18 localized to LDs and immunoelectron microscopy showed direct association with the monolayer surface. Green fluorescent protein (GFP)-Rab18-labeled LDs underwent oscillatory movements in a localized area as well as sporadic, rapid, saltatory movements both in the periphery of the cell and toward the perinuclear region. In both adipocytes and non-adipocyte cell lines Rab18 localized to a subset of LDs. To gain insights into this specific localization, Rab18 was co-expressed with Cav3(DGV), a truncation mutant of caveolin-3 shown to inhibit the catabolism and motility of lipid droplets. GFP-Rab18 and mRFP-Cav3(DGV) labeled mutually exclusive subpopulations of LDs. Moreover, in 3T3-L1 adipocytes, stimulation of lipolysis increased the localization of Rab18 to LDs, an effect reversed by beta-adrenergic antagonists. These results show that a Rab protein localizes directly to the monolayer surface of LDs. In addition, association with the LD surface was increased following stimulation of lipolysis and inhibited by a caveolin mutant suggesting that recruitment of Rab18 is regulated by the metabolic state of individual LDs.

Higher-order CpG-DNA stimulation reveals distinct activation requirements for marginal zone and follicular B cells in lupus mice

Mouse follicular B cells express TLR9 and respond vigorously to stimulation with single-stranded CpG-oligodeoxynucleotides (ODN). Surprisingly, follicular B cells do not respond to direct stimulation with other TLR9 ligands, such as bacterial DNA or class A(D) CpG-ODN capable of forming higher-order structures, unless other cell types are present. Here, we show that priming with interferons or with B cell-activating factor, or simultaneous co-engagement of the B cell receptor for antigen (BCR), can overcome this unresponsiveness. The effect of interferons occurs at the transcriptional level and is mediated through an autocrine/paracrine loop, which is dependent on IRF-1, IL-6 and IL-12 p40. We hypothesize that the lack of bystander activation of follicular B cells with more complex CpG ligands may be an important safety mechanism for avoiding autoimmunity. This will prevent resting B cells from responding to foreign or self-derived hypomethylated double-stranded CpG ligands unless these ligands are either delivered through the B cell receptor or under conditions where B cells are simultaneously co-engaged by activated plasmacytoid dendritic cells or TH1 cells. A corollary is that the heightened responsiveness of lupus B cells to TLR9-induced stimulation cannot be ascribed to unprimed follicular B cells, but is rather mediated by hypersensitive marginal zone B cells.

The topographic distribution of the magnetic P100M to full- and half-field stimulation

Visual evoked magnetic responses were recorded to full-field and left and right half-field stimulation with three check sizes (70′, 34′ and 22′) in five normal subjects. Recordings were made sequentially on a 20-position grid (4 × 5) based on the inion, by means of a single-channel direct current-Superconducting Quantum Interference Device second-order gradiometer. The topographic maps were consistent on the same subjects recorded 2 months apart. The half-field responses produced the strongest signals in the contralateral hemisphere and were consistent with the cruciform model of the calcarine fissure. Right half fields produced upper-left-quadrant outgoing fields and lower-left-quadrant ingoing fields, while the left half field produced the opposite response. The topographic maps also varied with check size, with the larger checks producing positive or negative maximum position more anteriorly than small checks. In addition, with large checks the full-field responses could be explained as the summation of the two half fields, whereas full-field responses to smaller checks were more unpredictable and may be due to sources located at the occipital pole or lateral surface. In addition, dipole sources were located as appropriate with the use of inverse problem solutions. Topographic data will be vital to the clinical use of the visual evoked field but, in addition, provides complementary information to visual evoked potentials, allowing detailed studies of the visual cortex. © 1992 Kluwer Academic Publishers.

Investigating central mechanisms underlying the effects of action observation and imagery through transcranial magnetic stimulation

Sport and exercise psychologists provide some interventions for clients based on limited direct evidence and partial understanding of the mechanisms that underpin their efficacy. The authors review a recent technique, transcranial magnetic stimulation (TMS), which offers a tested procedure for investigating cortical activity during observation and imagery processes. They provide a detailed description of the TMS protocol and highlight some of the key studies that inform sport and exercise psychology research. Finally, the authors offer some thoughts on the direct application to practice.

PARTNERSHIP, SOCIOCULTURAL INFORMATION AND STIMULATION IN SMALL BRAZILIAN MUNICIPALITIES: CONCRETE EXAMPLES

The text came from the UNESP-Project in Partnership with the Public Administration: City of Echaporã ‖, a multidisciplinary project, interdepartmental and that results from a term partnership signed between the State University / Campus Marilia, the Regional Office of Articulation Planning and the Municipality of Echaporã.Given the serious social problems diagnosed in this county Administrative Region of Marilia, somaramse forces and, since April 2002, Echaporã account with the performance of a design matrix that involves the community in six (6) subprojects, among which a which emphasizes the dissemination of information (the public library as a center of information and knowledge irradiator for urban and rural areas, seeking to enter the Society daInformação). By their nature, the project-matrix is considered open and can accommodate new subprojects, where they concern the problems identified in the initial diagnosis. For its validity, each subproject has its own methodology, some innovative and will be subject to further systematization and dissemination, however, after a few months of deployment, the results show the correctness of community involvement (being representative) in all discussions and steps of research, and activities developed, widely disseminated to the target audience. The membership of the community, the leaders and the authorities can be considered a good barometer of the actions carried out in Echaporã and evidence of change in information culture that is already noticeable in the city, setting the socio-cultural dynamics of the same, in terms a new public policy to be strengthened with the participation of specialists in this specific area, in direct work with local managers, in this case, specific examples relating to the strength of information in the process of change in small municipalities.