To define the spatiotemporal development of and simultaneously select for oligodendrocytes (OLs) and Schwann cells (SCs), transgenic mice were generated that expressed a bacterial beta-galactosidase ...(beta-gal) and neomycin phosphotransferase fusion protein (betageo) under the control of murine 2'3'-cyclic nucleotide 3'-phosphodiesterase (muCNP) promoters I and II. Transgenic beta-gal activity was detected at embryonic day 12.5 in the ventral region of the rhombencephalon and spinal cord and in the neural crest. When cells from the rhombencephalon were cultured in the presence of G418, surviving cells differentiated into OLs, indicating that during development this brain region provides one source of OL progenitors. Postnatally, robust beta-gal activity was localized to OLs throughout the brain and was absent from astrocytes, neurons, and microglia or monocytes. In the sciatic nerve beta-gal activity was localized exclusively to SCs. Cultures from postnatal day 10 brain or sciatic nerve were grown in the presence of G418, and within 8-9 d exposure to antibiotic, 99% of all surviving cells were beta-gal-positive OLs or SCs. These studies demonstrate that the muCNP-betageo transgenic mice are useful for identifying OLs and SCs beginning at early stages of the glial cell lineage and throughout their development. This novel approach definitively establishes that the beta-gal-positive cells identified in vivo are glial progenitors, as defined by their ability to survive antibiotic selection and differentiate into OLs or SCs in vitro. Moreover, this experimental paradigm facilitates the rapid and efficient selection of pure populations of mouse OLs and SCs and further underscores the use of cell-specific promoters in the purification of distinct cell types.
To facilitate the study of the molecular events underlying the development of optic-nerve-derived oligodendrocytes and their growth-factor-related signal transduction events, we immortalized ...perinatal rat optic nerve cells with a temperature-sensitive simian virus 40 large T-antigen, carrying the tsA58 and U19 mutations, via a retrovirus vector. The line, tsU19-9, was selected on the basis of the expression of the neural precursor marker nestin. At the permissive temperature, 33 degreesC, tsU19-9 cells had a flat epithelial morphology. In contrast, following exposure to platelet-derived growth factor (PDGF), a factor important in the lineage progression of oligodendrocytes, or in the presence of dibutyryl cyclic AMP at 39 degreesC (the non-permissive temperature), the cells underwent morphological and antigenic differentiation to cells characteristic of the oligodendrocyte lineage. We used this cell line to investigate the binding characteristics of PDGF and related signalling cascades. Competition binding, phosphoinositide hydrolysis and intracellular Ca2+ mobilization assays all demonstrated that the three different isoforms of PDGF (AA, AB and BB) bound to and acted on the cell line. Overnight exposure to forskolin, a treatment that initiated morphological and phenotypic progression into an oligodendrocyte lineage, decreased PDGF-BB-induced intracellular Ca2+ mobilization and inhibited basal and PDGF-stimulated 3Hthymidine incorporation. Our results demonstrate that tsU19-9 may serve as a resource to study early optic-nerve oligodendrocyte development.
To determine if muscarinic receptor-activation plays a role in oligodendrocyte development, the effect of carbachol, a stable acetylcholine analog, on gene expression and proliferation was ...investigated. Using Northern blot analysis we showed that carbachol caused a time and concentration-dependent increase in c-
fos mRNA. This effect was blocked by atropine, a non-selective muscarinic antagonist. In addition, the muscarinic-stimulated c-
fos increase was inhibited by 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine (H-7), a potent inhibitor of protein kinase C (PKC), but not by
N-2-(
p-bromocinnamylamino)-ethyl-5-isoquinoline-sulfonamide (H-89), a potent inhibitor of protein kinase A, suggesting the involvement of PKC in mediating the response. Down-regulation of PKC by overnight pre-treatment with 12-
O-tetradecanoylphorbol 13-acetate (TPA) blocked only the phorbol ester-stimulated c-
fos accumulation while no effect was observed in the carbachol-induced response. These results suggested that carbachol stimulated an H-7 sensitive PKC pathway which may be different than that activated by TPA. Further evidence for two separate mechanisms of proto-oncogene induction was provided by the additive effect of carbachol and TPA. Induction of c-
fos mRNA by carbachol was dependent on both influx of extracellular Ca
2+ and release from intracellular stores, as both EDTA and BAPTA blocked the response. Since activation of muscarinic receptors can affect cell division in other cellular systems, the effect of carbachol on
3
H
thymidine and bromodeoxyuridine incorporation into oligodendrocyte DNA was measured. Carbachol stimulated DNA synthesis in oligodendrocyte progenitors. This effect was mediated by muscarinic receptors as
3
H
thymidine incorporation was prevented or significantly reduced by the addition of atropine. In conclusion, the present findings suggest that, the neurotransmitter, acetylcholine may act as a trophic factor in developing oligodendrocytes, regulating their growth and development in the central nervous system.
The identification of connexin32 (Cx32) in myelinating Schwann cells and the association of Cx32 mutations with peripheral neuropathies suggest a functional role for gap junction proteins in the ...nerve. However, after nerve crush injury, Cx32 expression dramatically decreases in Schwann cells in the degenerating region, returning to control levels at newly formed nodes of Ranvier and Schmidt–Lantermann incisures by 30 days. The present study examined increases in expression of other connexins that occur after peripheral nerve injury. A 56/58-kDa connexin46 (Cx46) protein species was detected in adult rat sciatic nerve, along with very low levels of Cx46 mRNA. However, by 3 days after crush injury, coincident with changes in Schwann cell phenotype, Cx46 mRNA rapidly increased in the degenerating regions. Additionally, the 56/58-kDa Cx46 protein species present in adult nerve decreased and a 53-kDa Cx46 species, which was also present in cultured Schwann cells, became apparent. Connexin43 (Cx43) mRNA and protein, which was localized to perineurial cells in adult nerve, dramatically increased in endoneurial fibroblasts in the crush and distal regions by 3 days, coincident with macrophage infiltration. By 12 days after injury, Cx43 decreased and was comparable to normal nerve. These results suggest that enhanced expression of Cx46 and Cx43, by nonneuronal cells, may be important for the injury and regenerative responses of peripheral nerves.
Schwann cell responses to nerve injury are stimulated, in part, by inflammatory cytokines. This study compares changes in the phenotype of cultured Schwann cells after exposure to the cytokine tumor ...necrosis factor (TNF)-α or the mitogen neu differentiation factor (NDF)-β. TNFα inhibited proliferation in a dose-dependent manner without altering Schwann cell survival. TNFα also reduced both gap junctional conductance and Lucifer yellow dye coupling between Schwann cells. Moreover, both P0and glial fibrillary acidic protein (GFAP) immunoreactivity were reduced. By contrast, NDFβ initially had little effect on cell division although it reduced junctional coupling within 8h. However, by 48 h, NDFβ stimulated proliferation with a concomitant increase in coupling. Dividing Schwann cells (BrdU+) were preferentially dye coupled compared to nondividing cells, indicating an association between proliferation and coupling. Moreover, cultured Schwann cells expressed connexin46 mRNA and protein, and changes in the levels of the protein correlated with the degree of proliferation and coupling. The data thus provide evidence for cytokine-induced modulation of Schwann cell antigenic phenotype, proliferation, and gap junction properties. These observations suggest that enhanced gap junctional communication among Schwann cells after nerve injury could help to coordinate cellular responses to the injury, and that TNFα may be a signal which terminates proliferation as well as junctional communication.
Neuroeconomics Loewenstein, George; Rick, Scott; Cohen, Jonathan D
Annual review of psychology,
2008, Volume:
59
Journal Article
Peer reviewed
Neuroeconomics has further bridged the once disparate fields of economics and psychology. Such convergence is almost exclusively attributable to changes within economics. Neuroeconomics has inspired ...more change within economics than within psychology because the most important findings in neuroeconomics have posed more of a challenge to the standard economic perspective. Neuroeconomics has primarily challenged the standard economic assumption that decision making is a unitary process--a simple matter of integrated and coherent utility maximization--suggesting instead that it is driven by the interaction between automatic and controlled processes. This article reviews neuroeconomic research in three domains of interest to both economists and psychologists: decision making under risk and uncertainty, intertemporal choice, and social decision making. In addition to reviewing new economic models inspired by this research, we also discuss how neuroeconomics may influence future work in psychology.
Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite ...Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine’s activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy.
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•HpARI is a suppressor of IL-33 release and consequent allergic sensitization•HpARI binds active IL-33 and nuclear DNA, tethering IL-33 within necrotic cells•HpARI is active against both human and murine IL-33
Osbourn et al identified HpARI, a protein secreted by a helminth parasite that is capable of suppressing allergic responses. HpARI binds to IL-33 (a critical inducer of allergy) and nuclear DNA, preventing the release of IL-33 from necrotic epithelial cells.
Acute lower respiratory infections (ALRI) account for nearly one fifth of mortality in young children worldwide and have been associated with exposures to indoor and outdoor sources of ...combustion-derived air pollution. A systematic review was conducted to identify relevant articles on air pollution and ALRI in children. Using a Bayesian approach to meta-analysis, a summary estimate of 1.12 (1.03, 1.30) increased risk in ALRI occurrence per 10 μg/m
3
increase in annual average PM
2.5
concentration was derived from the longer-term (subchronic and chronic) effects studies. This analysis strengthens the evidence for a causal relationship between exposure to PM
2.5
and the occurrence of ALRI and provides a basis for estimating the global attributable burden of mortality due to ALRI that is not influenced by the wide variation in regional case fatality rates. Most studies, however, have been conducted in settings with relatively low levels of PM
2.5
. Extrapolating their results to other, more polluted, regions will require a model that is informed by evidence from studies of the effects on ALRI of exposure to PM
2.5
from other combustion sources, such as secondhand smoke and household solid fuel use.