We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and identify a role for the astroglial xCT in ventral dentate gyrus (vDG) in stress and antidepressant responses. We provide an RNA-seq roadmap for the stress-sensitive vDG. The transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27ac to regulate expression of xCT, which is also reduced in a genetic mouse model of inherent susceptibility to depressive-like behavior. Pharmacologically, modulating histone acetylation with acetyl-L-carnitine (LAC) or acetyl-N-cysteine (NAC) rapidly increases xCT and activates a network with mGlu2 receptors to prime an enhanced glutamate homeostasis that promotes both pro-resilient and antidepressant-like responses. Pharmacological xCT blockage counteracts NAC prophylactic effects. GFAP-Cre-dependent overexpression of xCT in vDG mimics pharmacological actions in promoting resilience. This work establishes a mechanism by which vDG protection leads to stress resilience and antidepressant responses via epigenetic programming of an xCT-mGlu2 network.

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Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in-vivo molecular mechanisms of brain IR until recently has proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared to age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM + exosomes in subjects with MDD as compared to age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM + exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM + exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM + exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.

Major depressive disorder (MDD) is a primary psychiatric illness worldwide; there is a dearth of new mechanistic models for the development of better therapeutic strategies. Although we continue to discover individual biological factors, a major challenge is the identification of integrated, multidimensional traits underlying the complex heterogeneity of depression and treatment outcomes. Here, we set out to ascertain the emergence of the novel mitochondrial mediator of epigenetic function acetyl-L-carnitine (LAC) in relation to previously described individual predictors of antidepressant responses to the insulin-sensitizing agent pioglitazone. Herein, we report that i) subjects with MDD and shorter leukocyte telomere length (LTL) show decreased levels of LAC, increased BMI, and a history of specific types of childhood trauma; and that ii) these multidimensional factors spanning mitochondrial metabolism, cellular aging, metabolic function, and childhood trauma provide more detailed signatures to predict longitudinal changes in depression severity in response to pioglitazone than individual factors. The findings of multidimensional signatures involved in the pathophysiology of depression and their role in predicting treatment outcomes provide a starting point for the development of a mechanistic framework linking biological networks and environmental factors to clinical outcomes in pursuit of personalized medicine strategies to effectively treat MDD.

Objective: Sinus of Valsalva (SOV) aneurysms are rare and data on operative management are limited. They can cause right ventricular outflow tract or pulmonary artery compression, and rupture may be fatal. In this study, we describe our experience with the repair of 13 SOV aneurysms. Methods: All patients who underwent SOV aneurysm repair from May 2001 toDecember 2017 at our single tertiary referral center were reviewed retrospectively.Results: Thirteen patients (92% male) with a mean age of 60 years underwent repair of an SOV aneurysm; mean aneurysm diameter was 5.9 ± 0.8 cm and four patients (30.7%) presented with rupture into another cardiac chamber. Operative interventions included six Bentall procedures, five patch repairs (one with aortic valve replacement [AVR]), and two primary aneurysm closures both with concomitant AVR. There were no strokes, myocardial infarctions, re-explorations, or deaths in the postoperative period. After an average of 2.25 years, computed tomographic imaging in five patients demonstrated no aneurysm recurrence. Conclusions: Surgery is a safe option for both ruptured and nonruptured SOV aneurysms. A variety of repair strategies may be used. Larger studies are needed. K E Y W O R D S aneurysm repair, operative technique, sinus of Valsalva, valve repair/replacement J Card Surg. 2019;34:400-403. wileyonlinelibrary.com/journal/jocs 400 |