Cognitive control mechanisms support the deliberate regulation of thought and behavior based on current goals. Recent work suggests that motivational incentives improve cognitive control and has begun to elucidate critical neural substrates. We conducted a quantitative meta-analysis of neuroimaging studies of motivated cognitive control using activation likelihood estimation (ALE) and Neurosynth to delineate the brain regions that are consistently activated across studies. The analysis included studies that investigated changes in brain activation during cognitive control tasks when reward incentives were present versus absent. The ALE analysis revealed consistent recruitment in regions associated with the frontoparietal control network including the inferior frontal sulcus and intraparietal sulcus, as well as regions associated with the salience network including the anterior insula and anterior mid-cingulate cortex. As a complementary analysis, we performed a large-scale exploratory meta-analysis using Neurosynth to identify regions that are recruited in studies using of the terms cognitive control and incentive. This analysis replicated the ALE results and also identified the rostrolateral prefrontal cortex, caudate nucleus, nucleus accumbens, medial thalamus, inferior frontal junction, premotor cortex, and hippocampus. Finally, we separately compared recruitment during cue and target periods, which tap into proactive engagement of rule-outcome associations, and the mobilization of appropriate viscero-motor states to execute a response, respectively. We found that largely distinct sets of brain regions are recruited during cue and target periods. Altogether, these findings suggest that flexible interactions between frontoparietal, salience, and dopaminergic midbrain-striatal networks may allow control demands to be precisely tailored based on expected value.

Mef2 is induced after enrichment in mice, reduces disease-associated hyperexcitability, and is a feature of cognitive resilience in patients with AD.

Cognitive control mechanisms support the deliberate regulation of thought and behavior based on current goals. Recent work suggests that motivational incentives improve cognitive control, and has begun to elucidate the brain regions that may support this effect. Here, we conducted a quantitative meta-analysis of neuroimaging studies of motivated cognitive control using activation likelihood estimation (ALE) and Neurosynth in order to delineate the brain regions that are consistently activated across studies. The analysis included functional neuroimaging studies that investigated changes in brain activation during cognitive control tasks when reward incentives were present versus absent. The ALE analysis revealed consistent recruitment in regions associated with the frontoparietal control network including the inferior frontal sulcus (IFS) and intraparietal sulcus (IPS), as well as consistent recruitment in regions associated with the salience network including the anterior insula and anterior mid-cingulate cortex (aMCC). A large-scale exploratory meta-analysis using Neurosynth replicated the ALE results, and also identified the caudate nucleus, nucleus accumbens, medial thalamus, inferior frontal junction/premotor cortex (IFJ/PMC), and hippocampus. Finally, we conducted separate ALE analyses to compare recruitment during cue and target periods, which tap into proactive engagement of rule-outcome associations, and the mobilization of appropriate viscero-motor states to execute a response, respectively. We found that largely distinct sets of brain regions are recruited during cue and target periods. Altogether, these findings suggest that flexible interactions between frontoparietal, salience, and dopaminergic midbrain-striatal networks may allow control demands to be precisely tailored based on expected value.

apoE is the primary lipid carrier within the CNS and the strongest genetic risk factor for late onset Alzheimer's disease (AD). apoE is primarily lipidated via ABCA1, and both are under transcriptional regulation by the nuclear liver X receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden. However, direct synthetic LXR ligands have hepatotoxic side effects that limit their clinical use. Here, we describe a set of small molecules, previously annotated as antagonists of the purinergic receptor, P2X7, which enhance ABCA1 expression and activity as well as apoE secretion, and are not direct LXR ligands. Furthermore, P2X7 is not required for these molecules to induce ABCA1 upregulation and apoE secretion, demonstrating that the ABCA1 and apoE effects are mechanistically independent of P2X7 inhibition. Hence, we have identified novel dual activity compounds that upregulate ABCA1 across multiple CNS cell types, including human astrocytes, pericytes, and microglia, through an indirect LXR mechanism and that also independently inhibit P2X7 receptor activity.

Introduction: A very brief history of psychedelic substances and scienceHumans have employed an incredible variety of plant--derived substances over the millennia in order to alter consciousness and perception (Schultes, Hofmann, & Rätsch, 2001). Among the innumerable narcotics, analgesics, 'ordeal' drugs, and other psychoactive substances discovered and used in ritualistic contexts by cultures around the world, one class in particular stands out not only for its radical psychological effects, but also for the highly charged political and legal atmosphere that has surrounded it since its widespread adoption about 50 years ago: so--called psychedelic substances.In the 1950's and 1960's, psychedelic substances that had been used for thousands of years in indigenous communities, particularly in Mesoamerica and the Amazon basin, were rediscovered by adventurous foreigners and introduced into Western societies that had been largely ignorant of the use of such substances for centuries, if not millennia