Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep-layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models-in utero valproic acid (VPA) exposure, CNTNAP2 knockout and FMR1 knockout-layer 5 subcortically projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing. To explore how altered SC neuron physiology might impact behavior, we took advantage of the fact that in deep layers of the mPFC, dopamine D2 receptors (D2Rs) are mainly expressed by SC neurons, and used D2-Cre mice to label D2R+ neurons for calcium imaging or optogenetics. We found that social exploration preferentially recruits mPFC D2R+ cells, but that this recruitment is attenuated in VPA-exposed mice. Stimulating mPFC D2R+ neurons disrupts normal social interaction. Conversely, inhibiting these cells enhances social behavior in VPA-exposed mice. Importantly, this effect was not reproduced by nonspecifically inhibiting mPFC neurons in VPA-exposed mice, or by inhibiting D2R+ neurons in wild-type mice. These findings suggest that multiple forms of autism may alter the physiology of specific deep-layer prefrontal neurons that project to subcortical targets. Furthermore, a highly overlapping population-prefrontal D2R+ neurons-plays an important role in both normal and abnormal social behavior, such that targeting these cells can elicit potentially therapeutic effects.
Isotherms for the adsorption of poly(vinylpyrrolidone) (PVP) and bovine serum albumin (BSA) onto silica have been determined. The adsorption capacity for PVP increased with increasing molecular mass but was independent of pH and ionic strength. The adsorbed layer thickness, δ, was determined from ζ potential measurements. δ was found to increase with increasing surface coverage but was significantly less than the polymer radius of gyration even at the adsorption plateau, indicating that the polymer coils flattened at the surface. BSA did not adsorb onto silica from water at pH 7 because of electrostatic repulsions, but adsorption did occur in the presence of electrolyte. The amount of BSA adsorbed at plateau coverage increased from ∼0.1 mg/m 2 in 0.001 M NaCl to ∼1.0 mg/m 2 in 0.5 M NaCl. BSA adsorption was significantly inhibited but not completely prevented, by precoating the silica particles with PVP. Even at low PVP surface coverages, where δ had very low values, some inhibition occurred. Furthermore, PVP was able to desorb most but not all BSA molecules from the silica particles.
Suspended sediments are a natural component of aquatic ecosystems, but anthropogenic activity such as land development can result in significant increases, especially after rain events. Continuous exposures of suspended clay and silt have been shown to affect growth and reproduction of Cladocera, leading to a decrease in population growth rate. The mechanism of clay toxicity in these filter-feeding organisms is clogging of the gut tract, resulting in decreased food uptake and assimilation. When placed in clean water, daphnids can purge clay from their gut and recover. In many surface waters, aquatic organisms experience episodic exposures of high concentrations of suspended solids driven by rain events. However, little is known about the consequences of pulsed exposures on individuals and populations. The objective of the present study was to characterize the effects of continuous and pulsed exposures of natural and defined clays on survival, growth, and reproduction of Daphnia magna. Two defined clays, montmorillonite and kaolinite, as well as clay isolated from the Piedmont region of South Carolina, USA, were used. Continuous exposures of clays elicited a dose dependent decrease in survival. Toxicity varied depending on clay source with montmorillonite > natural clay > kaolinite. Pulsed exposures caused a decrease in survival in a 24 h exposure of 734 mg/L kaolinite. Exposure to 73.9 mg/L also caused an increase in the time to gravidity, although there was not a corresponding decrease in neonate production over 21 d. No significant effects resulted from 12 h exposures even at 730 mg/L, almost 10 times the 24-h reproductive effects concentration. This suggests that exposure duration impacted toxicity more than exposure concentration in these pulsed exposures.
SUMMARY Both the medial prefrontal cortex (mPFC) and serotonin play key roles in anxiety, however, specific mechanisms through which serotonin might act on the mPFC to modulate anxiety-related behavior remain unknown. Here, we use a combination of optogenetics and synaptic physiology to show that serotonin acts presynaptically via 5-HT1B receptors to selectively suppress inputs from the contralateral mPFC and ventral hippocampus (vHPC), while sparing those from mediodorsal thalamus. To elucidate how these actions could potentially regulate prefrontal circuit function, we infused a 5-HT1B agonist into the mPFC of freely behaving mice. Consistent with previous studies that have optogenetically inhibited vHPC-mPFC projections, activating prefrontal 5-HT1B receptors suppressed theta-frequency (4–12 Hz) mPFC activity, and also reduced avoidance of anxiogenic regions in the elevated plus maze. These findings suggest a potential mechanism, linking specific receptors, synapses, patterns of circuit activity, and behavior, through which serotonin may regulate prefrontal circuit function including anxiety-related behaviors.
BackgroundSex differences in idiopathic pulmonary fibrosis (IPF) suggest a protective role for estrogen (E2); however, mechanistic studies in animal models have produced mixed results. Reports using cell lines have investigated molecular interactions between transforming growth factor beta1 (TGF-β1) and estrogen receptor (ESR) pathways in breast, prostate, and skin cells, but no such interactions have been described in human lung cells. To address this gap in the literature, we investigated a role for E2 in modulating TGF-β1-induced signaling mechanisms and identified novel pathways impacted by estrogen in bronchial epithelial cells.MethodsWe investigated a role for E2 in modulating TGF-β1-induced epithelial to mesenchymal transition (EMT) in bronchial epithelial cells (BEAS-2Bs) and characterized the effect of TGF-β1 on ESR mRNA and protein expression in BEAS-2Bs. We also quantified mRNA expression of ESRs in lung tissue from individuals with IPF and identified potential downstream targets of E2 signaling in BEAS-2Bs using RNA-Seq and gene set enrichment analysis.ResultsE2 negligibly modulated TGF-β1-induced EMT; however, we report the novel observation that TGF-β1 repressed ESR expression, most notably estrogen receptor alpha (ESR1). Results of the RNA-Seq analysis showed that TGF-β1 and E2 inversely modulated the expression of several genes involved in processes such as extracellular matrix (ECM) turnover, airway smooth muscle cell contraction, and calcium flux regulation. We also report that E2 specifically modulated the expression of genes involved in chromatin remodeling pathways and that this regulation was absent in the presence of TGF-β1.ConclusionsCollectively, these results suggest that E2 influences unexplored pathways that may be relevant to pulmonary disease and highlights potential roles for E2 in the lung that may contribute to sex-specific differences.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0861-5) contains supplementary material, which is available to authorized users.
This study explores students' experiences of group working in an internationalising MBA context using the research perspectives of postcolonialism (Spivak 1993;Prasad 2003) and critical management education (Reynolds 1997(Reynolds , 1999Currie & Knights 2003). Data are drawn from interviews with 30 full-time MBA students at two leading UK business schools. Students' perceived gains from the international group working experience are identified, as are areas of concern, such as practices of exclusion and domination that occur in the group working process and a reluctance to talk about and reflect on their group work experiences, are identified. By comparing international group working experiences at the two case-study institutions helpful practices concerning organisation of group work and induction are identified. The paper considers ways in which group work could be made more inclusive and how students can make the most of being in an international environment. Recommendations are made for future course design, including more induction focusing on modes of participation and cultural differences, specific induction to group working including the examination of language and behaviours and the use of critical dialogue and debriefing in making sense of the experience. The paper concludes that assumptions around the benefits of group working need re-visiting within the international context and training is needed of students and staff alike on how to make group work a more beneficial and enjoyable experience for all concerned.
Dopaminergic modulation of prefrontal cortex (PFC) is thought to play key roles in many cognitive functions and to be disrupted in pathological conditions, such as schizophrenia. We have previously described a phenomenon whereby dopamine D2 receptor (D2R) activation elicits afterdepolarizations (ADPs) in subcortically projecting (SC) pyramidal neurons within L5 of the PFC. These D2R-induced ADPs only occur following synaptic input, which activates NMDARs, even when the delay between the synaptic input and ADPs is relatively long (e.g., several hundred milliseconds). Here, we use a combination of electrophysiological, optogenetic, pharmacological, transgenic, and chemogenetic approaches to elucidate cellular mechanisms underlying this phenomenon in male and female mice. We find that knocking out D2Rs eliminates the ADP in a cell-autonomous fashion, confirming that this ADP depends on D2Rs. Hyperpolarizing current injection, but not AMPA receptor blockade, prevents synaptic stimulation from facilitating D2R-induced ADPs, suggesting that this phenomenon depends on the recruitment of voltage-dependent currents (e.g., NMDAR-mediated Ca 2ϩ influx) by synaptic input. Finally, the D2R-induced ADP is blocked by inhibitors of cAMP/PKA signaling, insensitive to pertussis toxin or -arrestin knockout, and mimicked by G s -DREADD stimulation, suggesting that D2R activation elicits the ADP by stimulating cAMP/PKA signaling. These results show that this unusual physiological phenomenon, in which D2Rs enhance cellular excitability in a manner that depends on synaptic input, is mediated at the cellular level through the recruitment of signaling pathways associated with G s , rather than the G i/o -associated mechanisms that have classically been ascribed to D2Rs.
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