Male and female variability in response to chronic stress and morphine in C57BL/6J, DBA/2J, and their BXD progeny.

Drug addiction is a multifactorial syndrome in which genetic predispositions and exposure to environmental stressors constitute major risk factors for the early onset, escalation, and relapse of addictive behaviors. While it is well known that stress plays a key role in drug addiction, the genetic factors that make certain individuals particularly sensitive to stress and thereby more vulnerable to becoming addicted are unknown. In an effort to test a complex set of gene x environment interactions-specifically gene x chronic stress -here we leveraged a systems genetics resource: BXD recombinant inbred mice (BXD5, BXD8, BXD14, BXD22, BXD29, and BXD32) and their parental mouse lines, C57BL/6J and DBA/2J. Utilizing the chronic social defeat stress (CSDS) and chronic variable stress (CVS) paradigms, we first showed sexual dimorphism in the behavioral stress response between the mouse strains. Further, we observed an interaction between genetic background and vulnerability to prolonged exposure to non-social stressors. Finally, we found that DBA/2J and C57BL/6J mice pre-exposed to stress displayed differences in morphine sensitivity. Our results support the hypothesis that genetic variation in predisposition to stress responses influences morphine sensitivity and is likely to modulate the development of drug addiction.

A Novel Role for Hypothalamic AgRP Neurons in Mediating Depressive Behavior.

A recent paper by Fang et al. examined the role of Agouti-Related Peptide (AgRP)-expressing neurons in the arcuate nucleus of the hypothalamus in mediating depressive-like behavior in mice. Chronic, but not acute stress, led to changes in neuronal excitability in AgRP neurons concomitant with the display of depressive-like behaviors, which were bidirectionally modulated using AgRP-selective chemogenetic manipulations. Together, these findings broaden our understanding of the diverse roles AgRP neurons play in driving motivational states, aside from their influence on hunger and feeding behaviors.

Predictors of Gleason score upgrading in a large African-American population.

PURPOSE: Gleason score from biopsy specimens is important for prostate cancer (PCa) risk stratification and influences treatment decisions. Gleason score upgrading (GSU) between biopsy and surgical pathology specimens has been reported as high as 50 % and presents a challenge in counseling low-risk patients. While recent studies have investigated predictors of GSU, populations in these studies have been largely Caucasian. We report our analysis of predictors of GSU in a large urban African-American population. METHODS: A total of 959 patients with D'Amico low-risk prostate cancer underwent radical prostatectomy at Georgetown University or Washington Hospital Center between January 2005 and July 2012. Race, age, PSA, body mass index (BMI), cancer of the prostate risk assessment (CAPRA) score, and transrectal ultrasound (TRUS) biopsy characteristics (percent of biopsy cores showing adenocarcinoma, highest percent of biopsy core involved with cancer, and measured TRUS prostate volume) were analyzed with both univariate and multivariate analyses to identify significant predictors of GSU while controlling for clinical parameters. RESULTS: Of the 959 cases, 288 (30.0 %) were upgraded on final pathologic specimen with approximately 38 % (133/355) of African-American patients experiencing GSU. BMI (P = 0.02), percent positive biopsy cores (P < 0.01) and percent of core involved with cancer (P < 0.01), increasing CAPRA score, and serum PSA were independent predictors of GSU on both uni- and multivariate regression analyses. African Americans had a 73 % increase in the incidence of GSU over other races. CONCLUSION: More than a quarter of low-risk prostate cancer patients were upgraded on final pathology in our series. Higher BMI, serum PSA, CAPRA score, percent of cores positive, and percent of cores involved were independent predictors of GSU. Individuals with those clinical parameters may harbor occult high-grade disease and should be carefully counseled on treatment decisions.