Neuronal responses support a role for orbitofrontal cortex in cognitive set reconfiguration

We are often faced with the need to abandon no‐longer beneficial rules and adopt new ones. This process, known as cognitive set reconfiguration, is a hallmark of executive control. Although cognitive functions like reconfiguration are most often associated with dorsal prefrontal structures, recent evidence suggests that the orbitofrontal cortex (OFC) may play an important role as well. We recorded the activity of OFC neurons while rhesus macaques performed an analogue of the Wisconsin Card Sorting Task that involved a trial and error stage. The OFC neurons demonstrated two types of switch‐related activity, an early (switch‐away) signal and a late (switch‐to) signal, when the new task set was established. We also found a pattern of match modulation: a significant change in activity for the stimulus that matched the current perceptual rule (and would therefore be selected). These results extend our understanding of the executive functions of the OFC. They also allow us to directly compare the OFC with the complementary datasets we previously collected in the ventral (VS) and dorsal (DS) striatum. Although both effects are observed in all three areas, the timing of responses aligns the OFC more closely with DS than with VS.     

Berkeleyones and related meroterpenes from a deep water acid mine waste fungus that inhibit the production of interleukin 1-β from induced inflammasomes

The Berkeley Pit, an acid mine waste lake, is a source of extremophilic microorganisms that produce interesting bioactive compounds. We have previously reported the isolation of berkeleydione (1), berkeleytrione (2), the berkeleyacetals, and the berkeleyamides from the Pit Lake fungus Penicillium rubrum. In this paper we report the isolation and characterization of berkeleyones A-C (4, 5, and 7) as well as previously described preaustinoid A (3) and A1(6) from this same fungus. These compounds were evaluated as inhibitors of the signaling enzyme caspase-1 and as potential inhibitors of interleukin 1-β production by inflammasomes in induced THP-1 cell line assays.     

Impact of type 1 diabetes and body weight status on cardiovascular risk factors in adolescent children

Type 1 diabetes (T1D) is a risk factor for cardiovascular disease. However, it is unclear whether increased body weight amplifies that risk in T1D patients. This is a cross-sectional study examining the presence of cardiovascular risk factors in normal and overweight children, both with and without T1D. Sixty-six children (aged 16±2.2 years) were included in one of the following groups: (T1D and normal weight, T1D and overweight, healthy and normal weight, and healthy and overweight). A fasting blood sample was analyzed for lipid profile (triglyceride, cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), apolipoprotein B (apoB), and apolipoprotein C-III (apoC-III) levels. Body composition was determined by dual energy x-ray absorptiometry and vascular elasticity by HDI/Pulsewave CR-2000 (Hypertension Diagnostics, Eagan, MN). Statistical analyses examined the effect of T1D and body weight status and their interactions on cardiovascular risk parameters. In this study, the authors were unable to demonstrate an additive effect of body weight status and T1D on cardiovascular risk profile. However, subgroup analysis of patients with T1D revealed higher apoC-III levels in overweight patients with T1D (P=.0453) compared with normal-weight diabetic children. Most notably, there was a direct relationship of small artery elasticity to body weight status. This seemingly paradoxical observation supports recent data and warrants further investigation.     

PDGFRβ-P2A-CreER<Superscript>T2</Superscript> mice: a genetic tool to target pericytes in angiogenesis

Pericytes are essential mural cells distinguished by their association with small caliber blood vessels and the presence of a basement membrane shared with endothelial cells. Pericyte interaction with the endothelium plays an important role in angiogenesis; however, very few tools are currently available that allow for the targeting of pericytes in mouse models, limiting our ability to understand their biology. We have generated a novel mouse line expressing tamoxifen-inducible Cre-recombinase under the control of the platelet-derived growth factor receptor β promoter: PDGFRβ-P2A-CreER ^T2 . We evaluated the expression of the PDGFRβ-P2A-CreER ^T2 line by crossing it with fluorescent reporter lines and analyzed reporter signal in the angiogenic retina and brain at different time points after tamoxifen administration. Reporter lines showed labeling of NG2⁺, desmin⁺, PDGFRβ⁺ perivascular cells in the retina and the brain, indicating successful targeting of pericytes; however, signal from reporter lines was also observed in a small subset of glial cells both in the retina and the brain. We also evaluated recombination in tumors and found efficient recombination in perivascular cells associated with tumor vasculature. As a proof of principle, we used our newly generated driver to delete Notch signaling in perivascular cells and observed a loss of smooth muscle cells in retinal arteries, consistent with previously published studies evaluating Notch3 null mice. We conclude that the PDGFRβ-P2A-CreER ^T2 line is a powerful new tool to target pericytes and will aid the field in gaining a deeper understanding of the role of these cells in physiological and pathological settings.     

Persuading People with Depression to Seek Help: Respect the Boomerang

People with depression are likely to process information with a negative bias when confronted with self-relevant information. Accordingly, we feared exposing depressed people to a public service announcement (PSA) addressing the stigma of depression would possibly boomerang and result in less intention to seek help and in increased self-stigma. College students (N?=?271; M_age ?=?22.51, SD?=?4.71; 63.1% female; 37.3% White, 31.9% Hispanic, 12.9% Asian, 6.8% multiethnic, 3.4% Black, 7.6% other) were randomly assigned to receive a print ad focused on depression or a nonrelevant comparison ad. A paper-and-pencil survey consisting of the Beck Depression Inventory–II, Self-Stigma of Seeking Help scale, help-seeking intentions, and demographics followed. Regression analysis indicated that viewing a depression ad caused people with greater depressive symptoms to experience greater levels of self-stigma than depressed people exposed to a nonrelevant comparison ad. Bootstrap mediation analysis showed that for individuals who viewed a depression PSA, self-stigma mediated the relationship between depressive symptoms and professional help-seeking intentions. While this current study offers no direct evidence in regard to the utility of current and past depression campaigns, results indicate a definite need for caution when developing materials targeting people with depression to seek help.     

The effect of deafness duration on neurotrophin gene therapy for spiral ganglion neuron protection

A cochlear implant can restore hearing function by electrically exciting spiral ganglion neurons (SGNs) in the deaf cochlea. However, following deafness SGNs undergo progressive degeneration ultimately leading to their death. One significant cause of SGN degeneration is the loss of neurotrophic support that is normally provided by cells within the organ of Corti (OC). The administration of exogenous neurotrophins (NTs) can protect SGNs from degeneration but the effects are short-lived once the source of NTs has been exhausted. NT gene therapy, whereby cells within the cochlea are transfected with genes enabling them to produce NTs, is one strategy for providing a cellular source of NTs that may provide long-term support for SGNs. As the SGNs normally innervate sensory cells within the OC, targeting residual OC cells for gene therapy in the deaf cochlea may provide a source of NTs for SGN protection and targeted regrowth of their peripheral fibers. However, the continual degeneration of the OC over extended periods of deafness may deplete the cellular targets for NT gene therapy and hence limit the effectiveness of this method in preventing SGN loss. This study examined the effects of deafness duration on the efficacy of NT gene therapy in preventing SGN loss in guinea pigs that were systemically deafened with aminoglycosides. Adenoviral vectors containing green fluorescent protein (GFP) with or without genes for Brain Derived Neurotrophic Factor (BDNF) and Neurotrophin-3 (NT3) were injected into the scala media (SM) compartment of cochleae that had been deafened for one, four or eight weeks prior to the viral injection. The results showed that viral transfection of cells within the SM was still possible even after severe degeneration of the OC. Supporting cells (pillar and Deiters' cells), cells within the stria vascularis, the spiral ligament, endosteal cells lining the scala compartments and interdental cells in the spiral limbus were transfected. However, the level of transfection was remarkably lower following longer durations of deafness. There was a significant increase in SGN survival in the entire basal turn for cochleae that received NT gene therapy compared to the untreated contralateral control cochleae for the one week deaf group. In the four week deaf group significant SGN survival was observed in the lower basal turn only. There was no increase in SGN survival for the eight week deaf group in any cochlear region. These findings indicated that the efficacy of NT gene therapy diminished with increasing durations of deafness leading to reduced benefits in terms of SGN protection. Clinically, there remains a window of opportunity in which NT gene therapy can provide ongoing trophic support for SGNs.