Brain mechanisms of self-control: A neurocognitive investigation of reward-based action control and error awareness

Motivation and the ability to detect errors are critical for the interaction with our environment. They provide us with the opportunity to engage in purposive, persistent and corrective behavior, and to take the consequences of our actions into account. Diminished motivation and error awareness have been linked to decreased goal directed behavior and reduced insight in certain types of brain injury and particular psychiatric syndromes. How the brain processes motivation and awareness is still largely unknown. This dissertation used behavioral and neuroimaging methods to examine how cognitive control is shaped by what we expect (motivational incentive) and what we are aware of (insight in our actions). The findings emphasize, that the positive impact of motivational incentive on cognitive control appears intact with advancing age and in Parkinson’s disease. Individual differences in white matter pathways between cortex and striatum translated into individual differences in the efficacy which with older adults improved their behavior by motivational incentive. The findings on error awareness suggest that local fluctuations in brain activation during awareness are interacting globally with distant brain areas, and that these fluctuations and interactions are related to physiological arousal, indexed by pupil dilation. The value of the current approach lies in the fact that it provides a framework to embed the local activity of brain structures into larger functional systems, and that it sheds light on factors that help to improve decline in cognitive control among healthy older adults and in older adults with Parkinson’s disease

A subset of yeast vacuolar protein sorting mutants is blocked in one branch of the exocytic pathway

Exocytic vesicles that accumulate in a temperature-sensitive sec6 mutant at a restrictive temperature can be separated into at least two populations with different buoyant densities and unique cargo molecules. Using a sec6 mutant background to isolate vesicles, we have found that vacuolar protein sorting mutants that block an endosome-mediated route to the vacuole, including vps1, pep12, vps4, and a temperature-sensitive clathrin mutant, missort cargo normally transported by dense exocytic vesicles, such as invertase, into light exocytic vesicles, whereas transport of cargo specific to the light exocytic vesicles appears unaffected. Immunoisolation experiments confirm that missorting, rather than a changed property of the normally dense vesicles, is responsible for the altered density gradient fractionation profile. The vps41Δ and apl6Δ mutants, which block transport of only the subset of vacuolar proteins that bypasses endosomes, sort exocytic cargo normally. Furthermore, a vps10Δ sec6 mutant, which lacks the sorting receptor for carboxypeptidase Y (CPY), accumulates both invertase and CPY in dense vesicles. These results suggest that at least one branch of the yeast exocytic pathway transits through endosomes before reaching the cell surface. Consistent with this possibility, we show that immunoisolated clathrin-coated vesicles contain invertase

Short-term and long-term effects of United Nations peace operations

Earlier studies have shown that United Nations peace operations make a positive contribution to peacebuilding efforts after civil wars. But do these effects carry over to the period after the peacekeepers leave? And how do the effects of UN peace operations interact with other determinants of peacebuilding in the long run? The author addresses these questions using a revised version of the Doyle and Sambanis dataset and applying different estimation methods to estimate the short-term and long-term effects of UN peace missions. He finds that UN missions have robust, positive effects on peacebuilding in the short term. UN missions can help parties implement peace agreements but the UN cannot fight wars, and UN operations contribute more to the quality of the peace where peace is based on participation, than to the longevity of the peace, where peace is simply the absence of war. The effects of UN missions are also felt in the long run, but they dissipate over time. What is missing in UN peacebuilding is a strategy to foster the self-sustaining economic growth that could connect increased participation with sustainable peace.Post Conflict Reintegration,Peace&Peacekeeping,International Affairs,Post Conflict Reconstruction,Politics and Government

A high-throughput screen for chemical inhibitors of exocytic transport in yeast

This is the peer reviewed version of the following article: Zhang, L., Nebane, N. M., Wennerberg, K., Li, Y., Neubauer, V., Hobrath, J. V., … Harsay, E. (2010). A high-throughput screen for chemical inhibitors of exocytic transport in yeast. Chembiochem : A European Journal of Chemical Biology, 11(9), 1291–1301. http://doi.org/10.1002/cbic.200900681, which has been published in final form at doi.org/10.1002/cbic.200900681. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Most of the components of the membrane and protein traffic machinery were discovered by perturbing their functions, either with bioactive compounds or by mutations. However, the mechanisms responsible for exocytic transport vesicle formation at the Golgi and endosomes are still largely unknown. Both the exocytic traffic routes and the signaling pathways that regulate these routes are highly complex and robust, so that defects can be overcome by alternate pathways or mechanisms. A classical yeast genetic screen designed to account for the robustness of the exocytic pathway identified a novel conserved gene, AVL9, that functions in late exocytic transport. We now describe a chemical-genetic version of the mutant screen, in which we performed a high-throughput phenotypic screen of a large compound library and identified novel small molecule secretory inhibitors. In order to maximize the number and diversity of our hits, the screen was performed in a pdr5Δ snq2Δ mutant background, which lacks two transporters responsible for pleiotropic drug resistance. However, we found that deletion of both transporters reduced the fitness of our screen strain, whereas the pdr5Δ mutation had relatively small effect on growth and was also the more important transporter mutation for conferring sensitivity to our hits. In this and similar chemical-genetic yeast screens, using just a single pump mutation may be sufficient for increasing hit diversity while minimizing the physiological effects of transporter mutations

Error blindness and motivational significance: Shifts in networks centering on anterior insula co-vary with error awareness and pupil dilation

This investigation aims to further our understanding of the brain mechanisms underlying the awareness of one's erroneous actions. While all errors are registered as such in the rostral cingulate zone, errors enter awareness only when the anterior insula cortex is activated. Aware but not unaware errors elicit autonomic nervous system reactivity. Our aim is to investigate the hypothesis that activation in the insula during error awareness is related to autonomic arousal and to inter-regional interactions with other areas of the brain. To examine the role of the anterior insula in error awareness, we assessed its functional connectivity to other brain regions along with autonomic nervous system reactivity in young healthy participants who underwent simultaneous pupil-diameter and functional magnetic resonance imaging measurements while performing a complex and error-prone task. Error blindness was associated with failures to engage sufficient autonomic reactivity. During aware errors increased pupil-diameter along with increased task-related activation within, and increased connectivity between anterior insula and task-related networks suggested an increased capacity for action-control information transfer. Increased pupil-diameter during aware errors was furthermore associated with decreased activation of the default-mode network along with decreased insular connectivity with regions of the default mode system, possibly reflecting decreased task-irrelevant information processing. This shifting mechanism may be relevant to a better understanding of how the brain and the autonomic nervous system interact to enable efficient adaptive behavior during cognitive challenge

Frontostriatal anatomical connections predict age- and difficulty-related differences in reinforcement learning

Contains fulltext : 167812.pdf (Publisher’s version ) (Closed access)Reinforcement learning (RL) is supported by a network of striatal and frontal cortical structures that are connected through white-matter fiber bundles. With age, the integrity of these white-matter connections declines. The role of structural frontostriatal connectivity in individual and age-related differences in RL is unclear, although local white-matter density and diffusivity have been linked to individual differences in RL. Here we show that frontostriatal tract counts in young human adults (aged 18-28), as assessed noninvasively with diffusion-weighted magnetic resonance imaging and probabilistic tractography, positively predicted individual differences in RL when learning was difficult (70% valid feedback). In older adults (aged 63-87), in contrast, learning under both easy (90% valid feedback) and difficult conditions was predicted by tract counts in the same frontostriatal network. Furthermore, network-level analyses showed a double dissociation between the task-relevant networks in young and older adults, suggesting that older adults relied on different frontostriatal networks than young adults to obtain the same task performance. These results highlight the importance of successful information integration across striatal and frontal regions during RL, especially with variable outcomes.12 p

Remedial Effects of Motivational Incentive on Declining Cognitive Control In Healthy Aging and Parkinson's Disease

The prospect of reward may provide a motivational incentive for optimizing goal-directed behavior. Animal work demonstrates that reward-processing networks and oculomotor-control networks in the brain are connected through the dorsal striatum, and that reward anticipation can improve oculomotor control via this nexus. Due perhaps to deterioration in dopaminergic striatal circuitry, goal-directed oculomotor control is subject to decline in healthy seniors, and even more in individuals with Parkinson's disease (PD). Here we examine whether healthy seniors and PD patients are able to utilize reward prospects to improve their impaired antisaccade performance. Results confirmed that oculomotor control declined in PD patients compared to healthy seniors, and in healthy seniors compared to young adults. However, the motivational incentive of reward expectation resulted in benefits in antisaccade performance in all groups alike. These findings speak against structural and non-modifiable decline in cognitive control functions, and emphasize the remedial potential of motivational incentive mechanisms in healthy as well as pathological aging