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

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

Aberrant neurodevelopment in human iPS cell-derived models of Alexander disease

23 p.-6 fig.Alexander disease (AxD) is a rare and severe neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP). While the exact disease mechanism remains unknown, previous studies suggest that mutant GFAP influences many cellular processes, including cytoskeleton stability, mechanosensing, metabolism, and proteasome function. While most studies have primarily focused on GFAP-expressing astrocytes, GFAP is also expressed by radial glia and neural progenitor cells, prompting questions about the impact of GFAP mutations on central nervous system (CNS) development. In this study, we observed impaired differentiation of astrocytes and neurons in co-cultures of astrocytes and neurons, as well as in neural organoids, both generated from AxD patient-derived induced pluripotent stem (iPS) cells with a GFAPR239C mutation. Leveraging single-cell RNA sequencing (scRNA-seq), we identified distinct cell populations and transcriptomic differences between the mutant GFAP cultures and a corrected isogenic control. These findings were supported by results obtained with immunocytochemistry and proteomics. In co-cultures, the GFAPR239C mutation resulted in an increased abundance of immature cells, while in unguided neural organoids and cortical organoids, we observed altered lineage commitment and reduced abundance of astrocytes. Gene expression analysis revealed increased stress susceptibility, cytoskeletal abnormalities, and altered extracellular matrix and cell–cell communication patterns in the AxD cultures, which also exhibited higher cell death after stress. Overall, our results point to altered cell differentiation in AxD patient-derived iPS-cell models, opening new avenues for AxD research. © 2024 The Author(s). GLIA published by Wiley Periodicals LLC.This work was supported by grants from EJP RD COFUND-EJP Nº825575 Alexander to EMH, MP, MK, HA, and DPS and from la Caixa Foundation, Grant Agreement LCF/PR/HR21/52410002 to DPS,MP and EMH; grants from the Swedish Research Council (2017-02255, 2020-01148, and 2019-00284), ALF Gothenburg (146051), The Swedish Society for Medical Research, Hjärnfonden (FO02021-0082), ALF (965939), Söderberg's Foundations, Hagströmer's Foundation Millennium, Amlöv's Foundation, and E. Jacobson's Donation Fund to MP, and a mobility grant from the Swedish Foundation for Strategic Research (SM23-0033) to MK; grants from the Czech Science Foundation (24-11364S, 24-12028S) to LV, and Institutional support (RVO 86652036) to MK; grant from ZonMw 463002004 to EMH; grants from The Swedish Research Council, Hjärnfonden and Petrus och Augusta Hedlunds stiftelse to HA,grants from MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe” (PID2021-126827OB-I00) to DPS, and grants from X-Omics initiative (184.034.019) the Oncode Institute to CAGHVG and HRV; grants from the Swedish Society for Medical Research to IC.Peer reviewe

Activation of lumbosacral 5-HT2C receptors induces bursts of rhythmic activity in sympathetic nerves to the vas deferens in male rats

1. We previously demonstrated that p-chloroamphetamine (PCA) intravenously (i.v.) evokes a specific patterned bursting response in the vas deferens nerve (VDN) of anaesthetised male rats that is associated with contraction of the vas deferens, and ejaculation and contraction of the bulbospongiosus muscles. The present study used selective 5-HT agonists to induce similar rhythmic bursting responses in the VDN in order to reveal the 5-HT receptor subtypes involved. 2. The 5-HT(2C) receptor agonist (1.0 mg kg(−1) Ro600175 i.v.) evoked the characteristic bursting pattern responses in the VDN. The 5-HT(1A) receptor agonist (1.0 mg kg(−1) 8-OH-DPAT i.v.) failed to elicit any responses. However, 8-OH-DPAT coadministered in combination with Ro600175 induced a potentiation of the responses. 3. Responses were also evoked in rats with a mid-thoracic spinalisation, with a more predictable response being observed following the combination of agonists. This suggests an action of both agonists in the lumbosacral spinal cord. 4. Responses were blocked by 0.5 mg kg(−1) SB206553 i.v. (5-HT(2B/C) receptor antagonist) or 0.5 mg kg(−1) WAY100635 i.v. (5-HT(1A) receptor antagonist), but not 0.1 or 1.0 mg kg(−1) SB269970 i.v. (5-HT(7) receptor antagonist). 5. We suggest that activation of 5-HT(2C) and 5-HT(1A) receptor subtypes synergistically elicits contraction of the vas deferens through the activation of sympathetic preganglionic neurones in the spinal cord. 6. These data support the idea of a proejaculatory action of 5-HT(2C) receptors in the lumbosacral spinal cord, suggesting a descending 5-HT excitatory pathway in addition to a 5-HT inhibitory pathway. An excitatory action of 8-OH-DPAT at lumbosacral sites is also evident

The effects of 5HT1agonists on erection in rats in vivo and rabbit corpus cavernosum in vitro

10.1038/sj.ijir.3900848International Journal of Impotence Research144205-212IJIR