Do non-philosophers think epistemic consequentialism is counterintuitive?

Direct epistemic consequentialism is the idea that X is epistemically permissible iff X maximizes epistemic value. It has received lots of attention in recent years and is widely accepted by philosophers to have counterintuitive implications. There are various reasons one might suspect that the relevant intuitions will not be widely shared among non-philosophers. This paper presents an initial empirical study of ordinary intuitions. The results of two experiments demonstrate that the counterintuitiveness of epistemic consequentialism is more than a philosophers' worry---the folk seem to agree

Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates

Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs(1,2). In reprogramming, the same factors are often used to reprogram many different donor cell types3. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors(4,5), it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l)(6) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.Non peer reviewe

Role of Dopamine D2 Receptors in Human Reinforcement Learning

Influential neurocomputational models emphasize dopamine (DA) as an electrophysiological and neurochemical correlate of reinforcement learning. However, evidence of a specific causal role of DA receptors in learning has been less forthcoming, especially in humans. Here we combine, in a between-subjects design, administration of a high dose of the selective DA D2/3-receptor antagonist sulpiride with genetic analysis of the DA D2 receptor in a behavioral study of reinforcement learning in a sample of 78 healthy male volunteers. In contrast to predictions of prevailing models emphasizing DA's pivotal role in learning via prediction errors, we found that sulpiride did not disrupt learning, but rather induced profound impairments in choice performance. The disruption was selective for stimuli indicating reward, while loss avoidance performance was unaffected. Effects were driven by volunteers with higher serum levels of the drug, and in those with genetically-determined lower density of striatal DA D2 receptors. This is the clearest demonstration to date for a causal modulatory role of the DA D2 receptor in choice performance that might be distinct from learning. Our findings challenge current reward prediction error models of reinforcement learning, and suggest that classical animal models emphasizing a role of postsynaptic DA D2 receptors in motivational aspects of reinforcement learning may apply to humans as well.Neuropsychopharmacology accepted article peview online, 09 April 2014; doi:10.1038/npp.2014.84

Functional Integration of Grafted Neural Stem Cell-Derived Dopaminergic Neurons Monitored by Optogenetics in an In Vitro Parkinson Model

Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson's disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D2 autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD

Sedative effects of the dopamine D1 receptor agonist A 68930 on rat open-field behavior

The present results demonstrate sedative effects of the DA D1 receptor agonist A 68930 (0.9-15 micromol kg(-1), s.c.) on rat spontaneous locomotor activity in an open field. The effects were particularly strong, and dose-dependent, for the ambulatory activity in the open-field arena (forward locomotion) and for rearing activity, whereas the suppression of locomotor activity (i.e. total horizontal activity in the open field) was less conspicuous. The distribution of activity within the open field (activity in center vs periphery) was not consistently affected by the A 68930 treatment. In support for DA D1 receptor mediated effects of A 68930, the effects on locomotor activity, forward locomotion, and on rearing behavior, were partially antagonized by the DA D1 receptor antagonist SCH 23390 (15 nmol kg(-1) s.c.). SCH 23390 by itself produced a modest, but statistically significant, suppression of these different items of open-field behavior. The atypical antipsychotic agent clozapine has previously, in this laboratory, been shown to stimulate DA D1 receptors in vivo. There are a number of clinical and laboratory observations, consistent with the notion of a beneficial role for such effects in schizophrenia. Thus, the sedation, apparently not related to extrapyramidal motor functions, produced by DA D1 receptor agonist A 68930 could reflect an important aspect of the mechanism of action for atypical antipsychotic drugs