LRRK2 mutation alters behavioral, synaptic, and nonsynaptic adaptations to acute social stress.

Parkinson's disease (PD) risk is increased by stress and certain gene mutations, including the most prevalent PD-linked mutation LRRK2-G2019S. Both PD and stress increase risk for psychiatric symptoms, yet it is unclear how PD-risk genes alter neural circuitry in response to stress that may promote psychopathology. Here we show significant differences between adult G2019S knockin and wild-type (wt) mice in stress-induced behaviors, with an unexpected uncoupling of depression-like and hedonia-like responses in G2019S mice. Moreover, mutant spiny projection neurons in nucleus accumbens (NAc) lack an adaptive, stress-induced change in excitability displayed by wt neurons, and instead show stress-induced changes in synaptic properties that wt neurons lack. Some synaptic alterations in NAc are already evident early in postnatal life. Thus G2019S alters the magnitude and direction of behavioral responses to stress that may reflect unique modifications of adaptive plasticity in cells and circuits implicated in psychopathology in humans.NEW & NOTEWORTHY Depression is associated with Parkinson's disease (PD), and environmental stress is a risk factor for both. We investigated how LRRK2-G2019S PD mutation affects depression-like behaviors, synaptic function, and intrinsic neuronal excitability following stress. In response to stress, the mutation drives abnormal synaptic changes, prevents adaptive changes in intrinsic excitability, and leads to aberrant behaviors, thus defining new ways in which PD mutations derail adaptive plasticity in response to stress that may contribute to disease onset.

Screening for Pancreatic Ductal Adenocarcinoma: Are We Asking the Impossible?

Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. Because of this, significant interest and research funding has been devoted to development of a screening test to identify individuals during a prolonged asymptomatic period; however, to date, no such test has been developed. We evaluated current NIH spending and clinical trials to determine the focus of research on pancreatic cancer screening as compared with other cancer subtypes. Using statistical methodology, we determined the effects of population-based pancreatic cancer screening on overall population morbidity and mortality. Population-based pancreatic cancer screening would result in significant harm to non-diseased individuals, even in cases where a near-perfect test was developed. Despite this mathematical improbability, NIH funding for pancreatic cancer demonstrates bias toward screening test development not seen in other cancer subtypes. Focusing research energy on development of pancreatic screening tests is unlikely to result in overall survival benefits. Efforts to increase the number of patients who are candidates for surgery and improving surgical outcomes would result in greater population benefit.Prevention Relevance: For patients with pancreatic cancer, early stage detection offers the greatest survival benefit. However, the incidence of pancreatic cancer and associated mortality of pancreatic resections make development of a screening test a difficult, if not impossible, challenge.