Neural computations underlying action-based decision making in the human brain

Action-based decision making involves choices between different physical actions to obtain rewards. To make such decisions the brain needs to assign a value to each action and then compare them to make a choice. Using fMRI in human subjects, we found evidence for action-value signals in supplementary motor cortex. Separate brain regions, most prominently ventromedial prefrontal cortex, were involved in encoding the expected value of the action that was ultimately taken. These findings differentiate two main forms of value signals in the human brain: those relating to the value of each available action, likely reflecting signals that are a precursor of choice, and those corresponding to the expected value of the action that is subsequently chosen, and therefore reflecting the consequence of the decision process. Furthermore, we also found signals in the dorsomedial frontal cortex that resemble the output of a decision comparator, which implicates this region in the computation of the decision itself

A Screening Pipeline for Antiparasitic Agents Targeting Cryptosporidium Inosine Monophosphate Dehydrogenase

Persistent diarrhea is a leading cause of illness and death among impoverished children, and a growing share of this disease burden can be attributed to the parasite Cryptosporidium. There are no vaccines to prevent Cryptosporidium infection, and the treatment options are limited and unreliable. Critically, no effective treatment exists for children or adults suffering from AIDS. Cryptosporidium presents many technical obstacles for drug discovery; perhaps the most important roadblock is the difficulty of monitoring drug action. Here we have developed a set of methods to accelerate the drug discovery process for cryptosporidiosis. We exploit the opportunities for experimental manipulation in the related parasite Toxoplasma to genetically engineer a Cryptosporidium model. This new model parasite mirrors the metabolism of Cryptosporidium for a particularly promising drug target that supplies the building blocks for DNA and RNA. Drug effectiveness can be assayed through simple fluorescence measurements for many candidates. Using this assay as an initial filter, and adapting other assays to a high throughput format, we identify several novel chemical compounds that exhibit markedly improved anti-cryptosporidial activity and excellent selectivity

Involvement of the endocannabinoid system in reward processing in the human brain

Rationale Disturbed reward processing in humans has been associated with a number of disorders, such as depression, addiction, and attention-deficit hyperactivity disorder. The endocannabinoid (eCB) system has been implicated in reward processing in animals, but in humans, the relation between eCB functioning and reward is less clear. Objectives The current study uses functional magnetic resonance imaging (fMRI) to investigate the role of the eCB system in reward processing in humans by examining the effect of the eCB agonist Δ9-tetrahydrocannabinol (THC) on reward-related brain activity. Methods Eleven healthy males participated in a randomized placebo-controlled pharmacological fMRI study with administration of THC to challenge the eCB system. We compared anticipatory and feedback-related brain activity after placebo and THC, using a monetary incentive delay task. In this task, subjects are notified before each trial whether a correct response is rewarded (“reward trial”) or not (“neutral trial”). Results Subjects showed faster reaction times during reward trials compared to neutral trials, and this effect was not altered by THC. THC induced a widespread attenuation of the brain response to feedback in reward trials but not in neutral trials. Anticipatory brain activity was not affected. Conclusions These results suggest a role for the eCB system in the appreciation of rewards. The involvement of the eCB system in feedback processing may be relevant for disorders in which appreciation of natural rewards may be affected such as addiction

Advanced paternal age effects in neurodevelopmental disorders?review of potential underlying mechanisms

Multiple epidemiological studies suggest a relationship between advanced paternal age (APA) at conception and adverse neurodevelopmental outcomes in offspring, particularly with regard to increased risk for autism and schizophrenia. Conclusive evidence about how age-related changes in paternal gametes, or age-independent behavioral traits affect neural development is still lacking. Recent evidence suggests that the origins of APA effects are likely to be multidimensional, involving both inherited predisposition and de novo events. Here we provide a review of the epidemiological and molecular findings to date. Focusing on the latter, we present the evidence for genetic and epigenetic mechanisms underpinning the association between late fatherhood and disorder in offspring. We also discuss the limitations of the APA literature. We propose that different hypotheses relating to the origins of the APA effects are not mutually exclusive. Instead, multiple mechanisms likely contribute, reflecting the etiological complexity of neurodevelopmental disorders

Reward-Related Dorsal Striatal Activity Differences between Former and Current Cocaine Dependent Individuals during an Interactive Competitive Game

Cocaine addiction is characterized by impulsivity, impaired social relationships, and abnormal mesocorticolimbic reward processing, but their interrelationships relative to stages of cocaine addiction are unclear. We assessed blood-oxygenation-level dependent (BOLD) signal in ventral and dorsal striatum during functional magnetic resonance imaging (fMRI) in current (CCD; n = 30) and former (FCD; n = 28) cocaine dependent subjects as well as healthy control (HC; n = 31) subjects while playing an interactive competitive Domino game involving risk-taking and reward/punishment processing. Out-of-scanner impulsivity-related measures were also collected. Although both FCD and CCD subjects scored significantly higher on impulsivity-related measures than did HC subjects, only FCD subjects had differences in striatal activation, specifically showing hypoactivation during their response to gains versus losses in right dorsal caudate, a brain region linked to habituation, cocaine craving and addiction maintenance. Right caudate activity in FCD subjects also correlated negatively with impulsivity-related measures of self-reported compulsivity and sensitivity to reward. These findings suggest that remitted cocaine dependence is associated with striatal dysfunction during social reward processing in a manner linked to compulsivity and reward sensitivity measures. Future research should investigate the extent to which such differences might reflect underlying vulnerabilities linked to cocaine-using propensities (e.g., relapses)

Illuminating the life of GPCRs

The investigation of biological systems highly depends on the possibilities that allow scientists to visualize and quantify biomolecules and their related activities in real-time and non-invasively. G-protein coupled receptors represent a family of very dynamic and highly regulated transmembrane proteins that are involved in various important physiological processes. Since their localization is not confined to the cell surface they have been a very attractive "moving target" and the understanding of their intracellular pathways as well as the identified protein-protein-interactions has had implications for therapeutic interventions. Recent and ongoing advances in both the establishment of a variety of labeling methods and the improvement of measuring and analyzing instrumentation, have made fluorescence techniques to an indispensable tool for GPCR imaging. The illumination of their complex life cycle, which includes receptor biosynthesis, membrane targeting, ligand binding, signaling, internalization, recycling and degradation, will provide new insights into the relationship between spatial receptor distribution and function. This review covers the existing technologies to track GPCRs in living cells. Fluorescent ligands, antibodies, auto-fluorescent proteins as well as the evolving technologies for chemical labeling with peptide- and protein-tags are described and their major applications concerning the GPCR life cycle are presented

Use of Gold Nanoparticles To Enhance Capillary Electrophoresis

We describe here the use of gold nanoparticles to manipulate the selectivity between solutes in capillary electrophoresis. Two different gold-based nanoparticles were added to the run buffer. In one case, the nanoparticles were stabilized with citrate ions, but in another study, the gold nanoparticles were capped with mercaptopropionate ions (thiol-stablized). Citrate-stabilized gold nanoparticles were used in conjunction with capillaries treated with poly(diallyldimethylammonium chloride) (PDADMAC). The positively charged PDADMAC layer on the capillary walls adsorbs the negatively charged gold nanoparticles. The model solutes that were used to study the effect of the presence of the citrate-stabilized gold nanoparticles are structural isomers of aromatic acids and bases. The presence of the PDADMAC layer and the PDADMAC plus the gold nanoparticles changes both the electroosmotic mobility and the observed mobility of the solutes. These changes in the mobilities influence the observed selectivities and the separations of the system. Thiol-stabilized gold nanoparticles were used without PDADMAC in the capillary. The model solutes studied in this part are various aromatic amines. In this case as well, the presence of the gold nanoparticles modifies the electroosmotic mobility and the observed mobility of the solutes. These changes in the mobilities are manifested in selectivity alterations. The largest change in the selectivities occurs at low concentrations of the gold nanoparticles in the run buffer. The presence of nanoparticles improves the precision of the analysis and increases the separation efficiency. Nanodispersions have attracted extensive attention in various fields of physics, biology, and chemistry. [1][2][3][4][5] Physicists and chemists are intrigued by the gradual transition of the nanomaterial properties from molecule-like to those of solid-state properties by a change of a single variable, the particle size. This property has practical and future applications for nonlinear optics and electronics. The large surface area of nanomaterials intrigues chemical engineers and catalysis scientists. Surprisingly, very little research has been devoted to the application of nanoparticles for chemical separation. In this work, we demonstrate the utility and versatility of organically modified gold nanoparticles in capillary electrophoresis (CE) separations. The nanoparticles serve as large surface area platforms for organofunctional groups that interact with the capillary surface, the analytes, or both. Thus, the apparent mobilities of target analytes, as well as the electroosmotic flow, can be altered leading to enhanced selectivities. Separation of various benzene derivatives demonstrates these capabilities. Metallic nanodispersions can be prepared in aqueous and organic solvents using diverse procedures. 1,2,6-9 Nanodispersions can be stabilized in organic solvents by the solvent itself, 10 by the addition of long chain surfactants, 11,12 or by specific ligands. 13 Stabilization of metal nanodispersions in aqueous solutions is somewhat more complicated. Several successful stabilization methods are available that are based on capping of the metal nanoparticles (e.g., citrate, 6 3-mercaptopropionate, 1

A Scoping Review of Quality of Life Questionnaires in Glaucoma Patients

PRECIS: Multiple questionnaires exist to measure glaucoma's impact on quality of life (QoL). Selecting the right questionnaire for the research question is essential, as is patients' acceptability of the questionnaire to enable collection of relevant patient-reported outcomes. PURPOSE: QoL relating to a disease and its treatment is an important dimension to capture. This scoping review sought to identify the questionnaires most appropriate for capturing the impact of glaucoma on QoL. METHODS: A literature search of QoL questionnaires used in glaucoma, including patient-reported outcomes measures, was conducted and the identified questionnaires were analyzed using a developed quality criteria assessment. RESULTS: Forty-one QoL questionnaires were found which were analyzed with the detailed quality criteria assessment leading to a summary score. This identified the top 10 scoring QoL questionnaires rated by a synthesis of the quality criteria grid, considering aspects such as reliability and reproducibility, and the authors' expert clinical opinion. The results were ratified in consultation with an international panel of ophthalmologists (N=49) from the Educational Club of Ocular Surface and Glaucoma representing 23 countries. CONCLUSIONS: Wide variability among questionnaires used to determine vision related QoL in glaucoma and in the responses elicited was identified. In conclusion, no single existing QoL questionnaire design is suitable for all purposes in glaucoma research, rather we have identified the top 10 from which the questionnaire most appropriate to the study objective may be selected. Development of a new questionnaire that could better distinguish between treatments in terms of vision and treatment-related QoL would be useful that includes the patient perspective of treatment effects as well as meeting requirements of regulatory and health authorities. Future work could involve development of a formal weighting system with which to comprehensively assess the quality of QoL questionnaires used in glaucoma