Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator

Rationale: Current first-line treatments for stress related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "alpha 5-PAM"), a positive allosteric modulator selective for (alpha 5-subunit containing GABA(A) receptors found predominantly on cortical pyramidal cell dendrites, has anti stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with alpha 5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic alpha 5-PAM treatments produce a pattern of decreased stress induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic alpha 5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to alpha 5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with alpha 5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of alpha 5 subunit containing GABA(A) receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities

Involvement of microRNA Lethal-7a in the Regulation of Embryo Implantation in Mice

MicroRNAs interact with multiple mRNAs resulting in their degradation and/or translational repression. This report used the delayed implantation model to determine the role of miRNAs in blastocysts. Dormant blastocysts in delayed implanting mice were activated by estradiol. Differential expression of 45 out of 238 miRNAs examined was found between the dormant and the activated blastocysts. Five of the nine members of the microRNA lethal-7 (let-7) family were down-regulated after activation. Human blastocysts also had a low expression of let-7 family. Forced-expression of a family member, let-7a in mouse blastocysts decreased the number of implantation sites (let-7a: 1.1±0.4; control: 3.8±0.4) in vivo, and reduced the percentages of blastocyst that attached (let-7a: 42.0±8.3%; control: 79.0±5.1%) and spreaded (let-7a: 33.5±2.9%; control: 67.3±3.8%) on fibronectin in vitro. Integrin-β3, a known implantation-related molecule, was demonstrated to be a target of let-7a by 3′-untranslated region reporter assay in cervical cancer cells HeLa, and Western blotting in mouse blastocysts. The inhibitory effect of forced-expression of let-7a on blastocyst attachment and outgrowth was partially nullified in vitro and in vivo by forced-expression of integrin-β3. This study provides the first direct evidence that let-7a is involved in regulating the implantation process partly via modulation of the expression of integrin-β3. (200 words)

Women’s Action Committees and Local Services in Nigeria (Metaketa V)

This study is part of Metaketa V, and will test whether training interventions designed to strengthen women’s sense of collective efficacy improve their voice and agency in local political engagement via a randomized control trial to be implemented in three southwestern states of Nigeria (Ogun, Osun, and Oyo) in 2023. In both treatment and control communities (i.e., wards), we will recruit previously unaffiliated women to join women’s action committees (WACs) to be trained by ActionAid Nigeria: 1/3 of WACs (control group) will receive basic training in civic education; 1/3 (treatment group 1) will receive civic education training in addition to intensive training in leadership, organizing, and advocacy, intended to build women’s collective agency and improve their articulation of demands to policymakers and policymakers’ responsiveness to them; and 1/3 (treatment group 2) will receive the same training as treatment group 1 and their husbands will be invited to participate in a parallel men’s training focused on men’s allyship in women’s empowerment and gender equality. We will examine the effects of the treatments on both attitudinal and behavioral outcomes focused on the level and quality of women’s political participation and on policy responsiveness, including whether women apply for a small grant opportunity to be allocated by local representatives in their community and the quality of their application. We will also examine potential mechanisms for these effects, which include levels of perceived injustice, group identity, group efficacy, and informedness, as well as the size of political networks and the closeness of policy priorities and preferences among participating women