Autistic women’s experiences of self-compassion and receiving their diagnosis in adulthood.

Knowledge of autistic individuals’ experiences of self-compassion is very limited. This study investigated autistic women’s experiences of self-compassion after receiving their diagnosis in adulthood. Eleven autistic women completed semi-structured interviews analysed using interpretative phenomenological analysis. Three super-ordinate themes were identified: ‘Disconnect between the autistic self and experience of societal expectations’ (the burden of conformity; autism is misunderstood; social challenges; mental health impact); ‘Unmasking: the process of self-understanding’ (autonomy and self-compassion; validation and grief) and ‘Impact on relationships’ (diagnosis disclosure dilemmas; connection and understanding). Frustration with society’s misconceptions of autism and unhelpful thinking styles were presented as barriers to self-compassion. Most participants reported that their diagnosis had led to the development of a greater sense of self-understanding, which facilitated self-compassion. Some participants suggested their own increased understanding of autism facilitated their compassion towards others. Findings from this study have clinical implications for increasing understanding about autistic women’s experiences of self-compassion and possibly ways to facilitate its development, to enhance well-being

MicroRNA-31 is required for astrocyte specification

Previously, we determined microRNA-31 (miR-31) is a noncoding tumor suppressive gene frequently deleted in glioblastoma (GBM); miR-31 suppresses tumor growth, in part, by limiting the activity of NF-κB. Herein, we expand our previous studies by characterizing the role of miR-31 during neural precursor cell (NPC) to astrocyte differentiation. We demonstrate that miR-31 expression and activity is suppressed in NPCs by stem cell factors such as Lin28, c-Myc, SOX2 and Oct4. However, during astrocytogenesis, miR-31 is induced by STAT3 and SMAD1/5/8, which mediate astrocyte differentiation. We determined miR-31 is required for terminal astrocyte differentiation, and that the loss of miR-31 impairs this process and/or prevents astrocyte maturation. We demonstrate that miR-31 promotes astrocyte development, in part, by reducing the levels of Lin28, a stem cell factor implicated in NPC renewal. These data suggest that miR-31 deletions may disrupt astrocyte development and/or homeostasis

Equal but Opposite: Acute Anxiolytic versus Chronic Anxiogenic Effects Following Adolescent Fluoxetine Use

Fluoxetine (FIx) is cunently one the most commonly prescribed antidepressant medications for adolescents suffering from various emotional disorders. FIx has been approved by the United States Food and Drug Administration (FDA) for the treatment of adolescent major depressive disorder (MDD) and obsessive compulsive disorder (OeD), despite limited research into the possible long-term effects of this psychoactive substance on the developing adolescent brain. The cunent study aimed to investigate the effects of adolescent FIx exposure on later anxietylike behaviour in rats. The current study involved the oral administration of FIx hydrochloride, via drinking water, to Inale and female adolescent PVG/C Hooded rats. There were three treatment conditions with differing FIx treatment periods (early, late or early plus late), and a control group. Immediately following FIx treatment, all groups were tested on an acute open-field test. The rats were then tested on two later occasions during adulthood on a battery of anxiety-related tests: the light-dark box test, the responsiveness to brightness change Y -maze and the social interaction test (SIT). On the acute open-field test, the FIx-treated rats displayed greater ambulation and possibly lower corner square occupancy, suggestive of an acute anxiolytic effect of FIx. The chronic effects testing suggested that rats treated during the late phase of adolescence, either alone or in combination with early treatlnent, were the Inost affected by FIx. The late FIx-treated group spent less time in the light during the light-dark box test, and defecated more than other groups during the SIT. In addition, the males within the late FIx-treated group spent significantly more time within the comer squares and less time within the centre squares of the SIT apparatus than males from the early FIx-treated group. Overall this study suggests that the long-term effects of adolescent FIx use are anxiogenic

Lithium controls central nervous system autoimmunity through modulation of IFN-γ signaling.

Inhibitors of glycogen synthase kinase 3 (GSK3) are being explored as therapy for chronic inflammatory diseases. We previously demonstrated that the GSK inhibitor lithium is beneficial in experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. In this study we report that lithium suppresses EAE induced by encephalitogenic interferon-γ (IFN-γ)-producing T helper (Th1) cells but not by interleukin (IL)-17-producing T helper (Th17) cells. The therapeutic activity of lithium required functional IFN-γ-signaling, but not the receptor for type I IFN (IFNAR). Inhibitor/s of GSK3 attenuated IFN-γ dependent activation of the transcription factor STAT1 in naïve T cells as well as in encephalitogenic T cells and Th1 cells. The inhibition of STAT1 activation was associated with reduced IFN-γ production and decreased expansion of encephalitogenic Th1 cells. Furthermore, lithium treatment induced Il27 expression within the spinal cords of mice with EAE. In contrast, such treatment of Ifngr(-/-) mice did not induce Il27 and was associated with lack of therapeutic response. Our study reveals a novel mechanism for the efficacy of GSK3 targeting in EAE, through the IFN-γ-STAT1 axis that is independent IFNAR-STAT1 axis. Overall our findings set the framework for the use of GSK3 inhibitors as therapeutic agents in autoimmune neuroinflammation

IFN-γ-signaling is required for attenuation of EAE by lithium.

<p>EAE was induced in (A) WT (B), <i>Stat1</i>^−/−, (C) <i>Ifngr1^−/−</i>, and (D) <i>Ifnar1^−/−</i>as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052658#s2" target="_blank">Material and Methods</a>. Arrows indicate first day of administration of lithium. (Mean ± SEM, <i>n</i> = 10–13 mice/group *<i>p</i><0.05, or NS, not significant, from start of treatment until day 30, as determined by Mann-Whitney test). (E) RNA was isolated from spinal cords of WT and <i>Ifngr1^−/−</i> mice on day 20 post-immunization and evaluated for gene expression by real-time PCR, as detailed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052658#s2" target="_blank">Materials and Methods</a>. <i>n</i> = 3 for immunized, <i>n</i> = 1 for unimmunized controls. *<i>p</i><0.05, as determined by one-way ANOVA.</p

Analysis of disease parameters for adoptive transfer of EAE induced by Th1, Th17, and IL-17F-Thy1.1 cells in untreated and lithium-treated animals.

<p>Data are presented as mean ± SEM (<i>n</i> = 8–11 mice).</p>a<p><i>p</i><0.05; Lithium-treated Th1 compared to untreated Th1.</p>b<p><i>p</i><0.05; Lithium-treated Th17 compared to untreated Th17.</p

Lithium attenuates STAT1-Y701 phosphorylation in encephalitogenic CD4⁺ T cells and reduces IFN-γ production.

<p>(A and B) Cells from dLNs and spleen of MOG_35–55 immunized mice (10–21 d post immunization) were either (A) pre-incubated without or with LiCl, and left unstimulated or stimulated for 25 with IFN-γ (5 U/ml) and/or anti-CD3 (1.25 µg/ml) as indicated; or (B) restimulated for 24 h with MOG_35–55 (10 µg/ml) in the absence or presence of LiCl, from onset, or acutely treated for 1 h, as indicated. A subset of cells was stimulated after 24 h with IFN-γ (5 U/ml) for 25 minutes. Cells were gated on CD4⁺ T cells and pSTAT1-Y701 was analyzed as in Fig. 2 and normalized to unstimulated cells from naïve mice. Results are expressed as percent of control, which represent stimulated untreated samples (100%), <i>n</i> = 3. (C) IFN-γ production by 24 h MOG_35–55 restimulated cells (from B). Representative sample shown (<i>n</i> = 3). (D) CD4⁺ T cells from spleens and dLNs of MOG_35–55 immunized mice were polarized under Th1 conditions in the presence or absence of LiCl, from onset or acutely treated for 1 h on day 3. Where indicated cells were stimulated with IFN-γ on day 3. Cells were gated on in CD4⁺, analyzed for pSTAT1-Y701, and normalized to unstimulated cells from naïve mice. Results are expressed as percent of control, which represent stimulated untreated samples (100%), (<i>n</i> = 3) (E), Th1 cells generated by polarization in the absence or presence of LiCl. Dot plots reflect CD4⁺ gated T cells. Representative experiment shown (<i>n</i> = 2). (F) IFN-γ production from Th1 cells (day 3 of polarization) stimulated with anti-CD3 and anti-CD28 (1 µg/ml each) for 8 h in the absence or presence of LiCl was assessed by ELISA. Representative results shown (<i>n</i> = 2). *<i>p</i><0.05, as determined by t-test or one-way ANOVA, as appropriate.</p

GSK3 promotes IFN-γ and IFN-β-induced STAT1-Y701 phosphorylation in CD4⁺ T cells.

<p>(A and B) Splenocytes were pre-incubated for 1 h in the absence or presence of the GSK3 inhibitors LiCl or TDZD-8, and stimulated without or with IFN-γ (5 U/ml; 25 minutes) or IFN-β (100 U/ml; 45 minutes) and/or anti-CD3 (1.25 µg/ml; 25 minutes in (A), and 45 minutes in (B) as indicated. Mononuclear cells were stained for pSTAT1-Y701 and analyzed by flow cytometry. Representative histograms are gated on CD4⁺ T cells. Induction of pSTAT1-Y701 is normalized to unstimulated cells. Fold induction of pSTAT1-Y701 MFI is normalized to unstimulated cells from combined data of 2-4 experiments. *<i>p</i><0.05, as determined by one-way ANOVA. (C) Thioglycollate-elicited macrophages (left histogram) were pre-incubated for 1 h in the absence or presence LiCl. Cells were then stimulated for 25 minutes with IFN-γ (5 U/ml) or left unstimulated, stained and analyzed for pSTAT1-Y701 in CD11b⁺ gated cells as in (A). CD11b⁺ cells (right histogram) were isolated from dLNs and spleens of MOG_35–55-immunized mice, restimulated for 24 h with MOG_35–55 (10 µg/ml) in the absence or presence of LiCl and evaluated for pSTAT1-Y701. (D) Naïve splenocytes from <i>Ifngr1^−/−</i> mice were pre-incubated without or with LiCl, and stimulated for 25 minutes with IFN-γ (5 U/ml) and/or αCD3 (1.25 µg/ml), as indicated, and evaluated for pSTAT1-Y701. Histograms are gated on CD4⁺ T cells.</p