Depression is one of the most disabling medical conditions in the world today, yet its etiologies remain unclear and current treatments are not wholly effective. Animal models are a powerful tool to ...investigate possible causes and treatments for human diseases. We describe an animal model of social defeat as a possible model for human depression. We discuss the paradigm, behavioral correlates to depression, and potential underlying neurobiological mechanisms with an eye toward possible future therapies.
Benzodiazepines can ameliorate social disturbances and increase social competition, particularly in high-anxious individuals. However, the neural circuits and mechanisms underlying benzodiazepines' ...effects in social competition are not understood. Converging evidence points to the mesolimbic system as a potential site of action for at least some benzodiazepine-mediated effects. Furthermore, mitochondrial function in the nucleus accumbens (NAc) has been causally implicated in the link between anxiety and social competitiveness. Here, we show that diazepam facilitates social dominance, ameliorating both the competitive disadvantage and low NAc mitochondrial function displayed by high-anxious rats, and identify the ventral tegmental area (VTA) as a key site of action for direct diazepam effects. We also show that intra-VTA diazepam infusion increases accumbal dopamine and DOPAC, as well as activity of dopamine D1- but not D2-containing cells. In addition, intra-NAc infusion of a D1-, but not D2, receptor agonist facilitates social dominance and mitochondrial respiration. Conversely, intra-VTA diazepam actions on social dominance and NAc mitochondrial respiration are blocked by pharmacological NAc micro-infusion of a mitochondrial complex I inhibitor or an antagonist of D1 receptors. Our data support the view that diazepam disinhibits VTA dopaminergic neurons, leading to the release of dopamine into the NAc where activation of D1-signaling transiently facilitates mitochondrial function, that is, increased respiration and enhanced ATP levels, which ultimately enhances social competitive behavior. Therefore, our findings critically involve the mesolimbic system in the facilitating effects of diazepam on social competition and highlight mitochondrial function as a potential therapeutic target for anxiety-related social dysfunctions.
Potentially morally injurious experiences (PMIEs) are events that may violate deeply held values or belief systems. Combat engagement places service members at a heightened risk for PMIE exposure. ...Exposure to PMIEs may elicit internal conflict between moral beliefs and experiences and, if unresolved, conflict may manifest as feelings of guilt, shame, and spiritual or existential crisis. Further, distress caused by these experiences may promote harmful behaviors (e.g., excessive alcohol use), which may serve as attempts to cope with PMIEs veterans have witnessed or participated in. The present study examined a sequential mediation model in which combat exposure was associated with alcohol use (i.e., alcohol consumption, dependence symptoms, and alcohol‐related problems) via PMIE exposure and spiritual injury (e.g., alienation from and/or anger towards respective higher power) in a community sample of 380 recent‐era combat veterans. Multiple‐group sequential mediation was then used to examine whether the model fit similarly across men and women. Exposure to PMIEs and spiritual injury sequentially mediated the association between combat and alcohol; higher levels of PMIE exposure and spiritual injury were associated with increased alcohol use, R2 = .17, f2 = 0.07. The multiple‐group model showed that these associations significantly varied between genders such that the mediation was only significant among men. The results indicated that PMIEs and spiritual injury were associated with increased alcohol use, but these associations differed as a function of gender. Future research is needed to refine our understanding of moral and spiritual injury and explore possible risk and protective factors.
Resumen
Spanish s by Asociación Chilena de Estrés Traumático (ACET)
Las Asociaciones entre la Exposición a Experiencias Potencialmente Dañinas Moralmente, Daño Espiritual, y el Uso de Alcohol Entre Combatientes Veteranos
EXPOSICION, DAÑO ESPIRITUAL, Y USO DE ALCOHOL
Las experiencias potencialmente dañinas moralmente (PMIEs en su sigla en inglés) son eventos que pueden transgredir los valores profundamente arraigados o los sistemas de creencias. La participación en combates posiciona a los miembros en servicio en un más alto riesgo de exposición a las PMIEs. La exposición a las PMIEs puede provocar conflictos internos entre las creencias morales y las experiencias y, si no son resueltos, el conflicto puede manifestarse como sentimientos de culpa, vergüenza, y crisis espirituales o existenciales. Además, el malestar causado por estas experiencias puede promover conductas dañinas (por ej., uso excesivo de alcohol), las cuales pueden servir como intentos para lidiar con las PMIEs que los veteranos han observado o en las que ellos han participado. En el presente estudio, en una muestra comunitaria de 380 combatientes veteranos de la era reciente, se examinó un modelo de mediación secuencial en el cual la exposición al combate fue asociada con el uso de alcohol (por ej., consumo de alcohol, síntomas de dependencia, y problemas asociados al alcohol) por medio de la exposición a las PMIEs y el daño espiritual (por ej., alienación y enojo contra una deidad). Una mediación secuencial de grupos múltiples fue luego usada para examinar si el modelo se ajustaba similarmente entre hombres y mujeres. La exposición a las PMIEs y el daño espiritual mediaron secuencialmente la asociación entre el combate y el alcohol; niveles más altos de exposición a las PMIEs y el daño espiritual se asociaron con mayor uso de alcohol, R2 = .17, f2 = 0.07. El modelo de grupos múltiples mostró que estas asociaciones variaron significativamente entre los géneros, de manera tal que la mediación fue solamente significativa entre los hombres. Los resultados indican que las PMIEs y el daño espiritual se encuentran asociados con un mayor uso de alcohol, pero estas asociaciones son diferentes dependiendo del género. Las futuras investigaciones son necesarias para mejorar nuestro entendimiento del daño moral y espiritual y explorar posibles factores de riesgo y protectores.
抽象
Traditional and Simplified Chinese s by the Asian Society for Traumatic Stress Studies (AsianSTSS)
簡體及繁體中文撮要由亞洲創傷心理研究學會翻譯
Associations between Exposure to Potentially Morally Injurious Experiences, Spiritual Injury, and Alcohol Use among Combat Veterans
Traditional Chinese
標題: 退役戰鬥軍人中, 潛在會導致道德創傷的事件經歷、精神創傷和酒精使用的關連
撮要: 潛在會導致道德創傷的事件經歷(PMIEs)即可能違反個人根深蒂固的價值或信念系統的事件。戰鬥行為使軍人有較高風險取得PMIEs。PMIEs可導致
道德信念和經驗的內在衝突。假若這種衝突未被解決, 便會形成內疚感、羞愧感, 以及精神或存在方面的危機。而且, 退役軍人的這些經歷帶來的悲痛, 可能會導致他們作出傷害行為 (如濫用酒精) 以作為面對目擊或親身經歷PMIEs的方法。本研究檢視一個序列中介模型。當中, 戰鬥經歷透過PMIEs與精神創傷 (如遠離神和/或對神感到憤怒) , 跟酒精使用 (即喝酒、依賴症狀、酒精相關問題) 相關。研究的社區樣本由380名現代的退役戰鬥軍人組成。我們採用多組別序列中介分析, 以檢視模型是否對男女同等合適使用。PMIEs與精神創傷對戰鬥經歷與酒精使用的關連有序列中介作用;PMIEs與精神創傷水平較高, 與酒精使用提升有關(R2 = .17, f2 = 0.07)。多組別模型反映, 這些關連在不同性別間有顯著差異, 中介作用只在男性中顯著。結果反映, PMIEs與精神創傷跟酒精使用提升有關, 但這些關連因性別而生異。未來研究需進一步提升對道德及精神創傷的理解, 並探索可能存在的風險和保護因素。
Simplified Chinese
标题: 退役战斗军人中, 潜在会导致道德创伤的事件经历、精神创伤和酒精使用的关连
撮要: 潜在会导致道德创伤的事件经历(PMIEs)即可能违反个人根深蒂固的价值或信念系统的事件。战斗行为使军人有较高风险取得PMIEs。PMIEs可导致
道德信念和经验的内在冲突。假若这种冲突未被解决, 便会形成内疚感、羞愧感, 以及精神或存在方面的危机。而且, 退役军人的这些经历带来的悲痛, 可能会导致他们作出伤害行为 (如滥用酒精) 以作为面对目击或亲身经历PMIEs的方法。本研究检视一个序列中介模型。当中, 战斗经历透过PMIEs与精神创伤 (如远离神和/或对神感到愤怒) , 跟酒精使用 (即喝酒、依赖症状、酒精相关问题) 相关。研究的小区样本由380名现代的退役战斗军人组成。我们采用多组别序列中介分析, 以检视模型是否对男女同等合适使用。PMIEs与精神创伤对战斗经历与酒精使用的关连有序列中介作用;PMIEs与精神创伤水平较高, 与酒精使用提升有关(R2 = .17, f2 = 0.07)。多组别模型反映, 这些关连在不同性别间有显著差异, 中介作用只在男性中显著。结果反映, PMIEs与精神创伤跟酒精使用提升有关, 但这些关连因性别而生异。未来研究需进一步提升对道德及精神创伤的理解, 并探索可能存在的风险和保护因素。
Major depression is a growing problem worldwide with variation in symptoms and response to treatment. Individual differences in response to stress may contribute to such observed individual variation ...in behavior and pathology. Therefore, we investigated depressive-like behavior following exposure to repeated social defeat in a rat model of individual differences in response to novelty. Rats are known to exhibit either high locomotor activity and sustained exploration (high responders, HR) or low activity with minimal exploration (low responders, LR) in a novel environment. We measured anhedonia using the sucrose preference test in HR and LR rats following exposure to social defeat stress or in basal, non-defeated conditions. We then compared histone acetylation in the hippocampus in HR and LR defeat and non-defeated rats and measured mRNA levels of histone deacetylases (HDAC) 3, 4, 5, and Creb binding protein (CBP). We found that basally, HR rats consumed more sucrose solution than LR rats, but reduced consumption after exposure to defeat. LR rats' preference was unaffected by social defeat. We found that HR rats had higher levels of histone acetylation on H3K14 and H2B than LR rats in non-stress conditions. Following defeat, this acetylation pattern changed differentially, with HR rats decreasing acetylation of H3K14 and H2B and LR's increasing acetylation of H3K14. Acetylation on histone H4 decreased following defeat with no individual variation. Basal differences in CBP expression levels may underlie the observed acetylation pattern; however we found no significant effects of defeat in levels of HDACs 3, 4, 5 in the hippocampus.
►There is individual variation in response to stress and in treatment to depression. ►HR rats exhibit anhedonia following exposure to social stress while LR rats do not. ►HR and LR rats have differential histone acetylation following social stress. ►Basal differences in hippocampal CBP mRNA may underlie these individual responses.
Decision‐making processes can be modulated by stress, and the time elapsed from stress induction seems to be a crucial factor in determining the direction of the effects. Although current approaches ...consider the first post‐stress hour a uniform period, the dynamic pattern of activation of the physiological stress systems (i.e., the sympathetic nervous system and hypothalamic‐pituitary‐adrenal axis) suggests that its neurobehavioural impact might be heterogeneous. Here, we evaluate economic risk preferences on the gain domain (i.e., risk aversion) at three time points following exposure to psychosocial stress (immediately after, and 20 and 45 min from onset). Using lottery games, we examine decisions at both the individual and social levels. We find that risk aversion shows a time‐dependent change across the first post‐stress hour, evolving from less risk aversion shortly after stress to more risk averse behaviour at the last testing time. When risk implied an antisocial outcome to a third party, stressed individuals showed less regard for this person in their decisions. Participants’ cortisol levels explained their behaviour in the risk, but not the antisocial, game. Our findings reveal differential stress effects in self‐ and other‐regarding decision‐making and highlight the multidimensional nature of the immediate aftermath of stress for cognition.
Participants take more risks immediately after exposure to social stress. However, over time, they become more risk averse than even unstressed controls. When risks carry a negative financial consequence to another person, all participants adjust their behaviour to take less risk, but stressed participants adjust less.
Highlights ► We review the consequences of adolescent chronic unpredictable stress exposure on stress and addiction. ► We review the consequences of adolescent physical and social chronic ...unpredictable stress exposure on stress and addiction. ► We review the consequences of adolescent physical and social chronic unpredictable on the adolescent and adult brain.
Aims/hypothesis
Insulin resistance (IR) improves with weight loss, but this response is heterogeneous. We hypothesised that metabolomic profiling would identify biomarkers predicting changes in IR ...with weight loss.
Methods
Targeted mass spectrometry-based profiling of 60 metabolites, plus biochemical assays of NEFA, β-hydroxybutyrate, ketones, insulin and glucose were performed in baseline and 6 month plasma samples from 500 participants who had lost ≥4 kg during Phase I of the Weight Loss Maintenance (WLM) trial. Homeostatic model assessment of insulin resistance (HOMA-IR) and change in HOMA-IR with weight loss (∆HOMA-IR) were calculated. Principal components analysis (PCA) and mixed models adjusted for race, sex, baseline weight, and amount of weight loss were used; findings were validated in an independent cohort of patients (
n
= 22).
Results
Mean weight loss was 8.67 ± 4.28 kg; mean ∆HOMA-IR was −0.80 ± 1.73, range −28.9 to 4.82). Baseline PCA-derived factor 3 (branched chain amino acids BCAAs and associated catabolites) correlated with baseline HOMA-IR (
r
= 0.50,
p
< 0.0001) and independently associated with ∆HOMA-IR (
p
< 0.0001). ∆HOMA-IR increased in a linear fashion with increasing baseline factor 3 quartiles. Amount of weight loss was only modestly correlated with ∆HOMA-IR (
r
= 0.24). These findings were validated in the independent cohort, with a factor composed of BCAAs and related metabolites predicting ∆HOMA-IR (
p
= 0.007).
Conclusions/interpretation
A cluster of metabolites comprising BCAAs and related analytes predicts improvement in HOMA-IR independent of the amount of weight lost. These results may help identify individuals most likely to benefit from moderate weight loss and elucidate novel mechanisms of IR in obesity.
We purified, cloned, and expressed aggrecanase, a protease that is thought to be responsible for the degradation of cartilage aggrecan in arthritic diseases. Aggrecanase-1 a disintegrin and ...metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) is a member of the ADAMTS protein family that cleaves aggrecan at the glutamic acid-373-alanine-374 bond. The identification of this protease provides a specific target for the development of therapeutics to prevent cartilage degradation in arthritis.
Background To improve methods for long-term weight management, the Weight Loss Maintenance (WLM) trial, a four-center randomized trial, was conducted to compare alternative strategies for maintaining ...weight loss over a 30-month period. This paper describes methods and results for the initial 6-month weight-loss program (Phase I). Methods Eligible adults were aged ≥25, overweight or obese (BMI=25–45 kg/m2 ), and on medications for hypertension and/or dyslipidemia. Anthropomorphic, demographic, and psychosocial measures were collected at baseline and 6 months. Participants ( n =1685) attended 20 weekly group sessions to encourage calorie restriction, moderate-intensity physical activity, and the DASH (dietary approaches to stop hypertension) dietary pattern. Weight-loss predictors with missing data were replaced by multiple imputation. Results Participants were 44% African American and 67% women; 79% were obese (BMI≥30), 87% were taking anti-hypertensive medications, and 38% were taking antidyslipidemia medications. Participants attended an average of 72% of 20 group sessions. They self-reported 117 minutes of moderate-intensity physical activity per week, kept 3.7 daily food records per week, and consumed 2.9 servings of fruits and vegetables per day. The Phase-I follow-up rate was 92%. Mean (SD) weight change was −5.8 kg (4.4), and 69% lost at least 4 kg. All race–gender subgroups lost substantial weight: African-American men (−5.4 kg ± 7.7); African-American women (−4.1 kg ± 2.9); non–African-American men (−8.5 kg ± 12.9); and non–African-American women (−5.8 kg ± 6.1). Behavioral measures (e.g., diet records and physical activity) accounted for most of the weight-loss variation, although the association between behavioral measures and weight loss differed by race and gender groups. Conclusions The WLM behavioral intervention successfully achieved clinically significant short-term weight loss in a diverse population of high-risk patients.
The explosion of cable networks, cinema distributors, and mobile media companies explicitly designed for sexual minorities in the contemporary moment has made media culture a major factor in what it ...feels like to be a queer person. F. Hollis Griffin demonstrates how cities offer a way of thinking about that phenomenon. By examining urban centers in tandem with advertiser-supported newspapers, New Queer Cinema and B-movies, queer-targeted television, and mobile apps, Griffin illustrates how new forms of LGBT media are less "new" than we often believe. He connects cities and LGBT media through the experiences they can make available to people, which Griffin articulates as feelings, emotions, and affects. He illuminates how the limitations of these experiences-while not universally accessible, nor necessarily empowering-are often the very reasons why people find them compelling and desirable.
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