Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal rictor null mice

Abstract The mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is a multimeric signaling unit that phosphorylates protein kinase B/Akt following hormonal and growth factor stimulation. Defective Akt phosphorylation at the mTORC2-catalyzed Ser473 site has been linked to schizophrenia. While human imaging and animal studies implicate a fundamental role for Akt signaling in prefrontal dopaminergic networks, the molecular mechanisms linking Akt phosphorylation to specific schizophrenia-related neurotransmission abnormalities have not yet been described. Importantly, current understanding of schizophrenia suggests that cortical decreases in DA neurotransmission and content, defined here as cortical hypodopaminergia, contribute to both the cognitive deficits and the negative symptoms characteristic of this disorder. We sought to identify a mechanism linking aberrant Akt signaling to these hallmarks of schizophrenia. We used conditional gene targeting in mice to eliminate the mTORC2 regulatory protein rictor in neurons, leading to impairments in neuronal Akt Ser473 phosphorylation. Rictor-null (KO) mice exhibit prepulse inhibition (PPI) deficits, a schizophrenia-associated behavior. In addition, they show reduced prefrontal dopamine (DA) content, elevated cortical norepinephrine (NE), unaltered cortical serotonin (5-HT), and enhanced expression of the NE transporter (NET). In the cortex, NET takes up both extracellular NE and DA. Thus, we propose that amplified NET function in rictor KO mice enhances accumulation of both NE and DA within the noradrenergic neuron. This phenomenon leads to conversion of DA to NE and ultimately supports both increased NE tissue content as well as a decrease in DA. In support of this hypothesis, NET blockade in rictor KO mice reversed cortical deficits in DA content and PPI, suggesting that dysregulation of DA homeostasis is driven by alteration in NET expression, which we show is ultimately influenced by Akt phosphorylation status. These data illuminate a molecular link, Akt regulation of NET, between the recognized association of Akt signaling deficits in schizophrenia with a specific mechanism for cortical hypodopaminergia and hypofunction. Additionally, our findings identify Akt as a novel modulator of monoamine homeostasis in the cortex

Dysregulation of the Norepinephrine Transporter Sustains Cortical Hypodopaminergia and Schizophrenia-Like Behaviors in Neuronal Rictor Null Mice

A novel animal model highlights the link between Akt dysfunction, reduced cortical dopamine function, norepinephrine transporters, and schizophrenia-like behaviors

Badania eksperymentalne i teoretyczne strat ciepła zasobnika ciepłej wody

Efektywność magazynowania ciepła ma wpływ na efektywność energetyczną instalacji ciepłej wody. Do jej zwiększenia przyczynia się utrzymanie rozwarstwienia termicznego w zasobniku ciepłej wody. Zaburzenie stratyfikacji termicznej może być spowodowane między innymi stratami ciepła ze zbiornika do otoczenia. W pracy przedstawiono dynamikę zmian temperatury wody w zasobniku o pojemności 350 dm3, podczas jego wychładzania w godzinach nocnych, na podstawie przeprowadzonych pomiarów temperatury wody magazynowanej na 15 wyróżnionych poziomach. Dla zasobnika obliczono współczynniki strat ciepła dla części górnej, bocznej oraz dolnej, jak również dla całego zasobnika. Uzyskane wyniki odniesiono do wyników badań innych autorów

Analysis of the Influence of a Glazed Surface Type and Solar Shading Devices on the Building Energy Balance

A detailed analysis of the influence of a glazed surface type with a diversified thermal transmittance on the energy balance of a detached house boasting the volume of 445.10 m3, was carried out on the basis of the Passive House Planning Program (PHPP). Average monthly transmission heat losses and solar gains by windows with five different U-Values were determined. A part of heat losses by windows in the total building energy balance was compared. It was pointed out, that the use of windows with thermal transmittance equals 0.80 W/(m2×K) enables to reduce transmission heat losses by 34% and to decrease the energy need for heating by circa 18% in comparison with the windows with thermal transmittance equals 1.20 W/(m2×K). The annual primary energy demand in this building was reduced by 2.9%. For all analyzed cases, the use of external solar shading devices contributes to reduction of the transmission heat losses and the energy demand ratio for the heating system. The solar control devices allowed to decrease of solar heat gains at the average by 41.3% during the months from May to September. The application of energy-saving windows with external solar shading devices influenced the increase of the building energy efficiency

Effect of probiotics on growing performance and health of calves

The study was conducted to determine the effect of probiotics based on Lactobacillus spp. on the performance and health status of Holstein male calves. Twelve three-day old calves, with mean initial live weight of 35 kg were assigned to the control and the probiotics groups. All calves were weaned at the 60th day. They consumed 228 L of whole milk twice daily until weaning. The calves from the probiotics group received daily 2 g of probiotics with the morning milk. The results obtained in the experiment showed that there were no differences in daily gain, roughage, concentrate or total feed intake, feed/gain ratio and weaning weight. Calves fed probiotics were healthier than those from the control group. Three calves from the control group and one calf from the probioticss group died from scour and/or bloat. In respect to diarrhea and bloat cases, the probioticss group was superior to the control. It would be concluded that the probioticss administration before weaning could improve calf health and decrease mortality and medication cost

Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology

The mammalian target of rapamycin (mTOR) assembles into two distinct multi-protein complexes called mTORC1 and mTORC2. Whereas mTORC1 is known to regulate cell and organismal growth, the role of mTORC2 is less understood. We describe two mouse lines that are devoid of the mTORC2 component rictor in the entire central nervous system or in Purkinje cells. In both lines neurons were smaller and their morphology and function were strongly affected. The phenotypes were accompanied by loss of activation of Akt, PKC, and SGK1 without effects on mTORC1 activity. The striking decrease in the activation and expression of several PKC isoforms, the subsequent loss of activation of GAP-43 and MARCKS, and the established role of PKCs in spinocerebellar ataxia and in shaping the actin cytoskeleton strongly suggest that the morphological deficits observed in rictor-deficient neurons are mediated by PKCs. Together our experiments show that mTORC2 has a particularly important role in the brain and that it affects size, morphology, and function of neurons

Improved proliferation of antigen-specific cytolytic T lymphocytes using a multimodal nanovaccine

Bo Li,1,2 Michael Siuta,1 Vanessa Bright,1,2 Dmitry Koktysh,3,4 Brittany K Matlock,5 Megan E Dumas,1 Meiying Zhu,1 Alex Holt,1 Donald Stec,3,6 Shenglou Deng,7 Paul B Savage,7 Sebastian Joyce,8,9 Wellington Pham1,2,6,10–12 1Institute of Imaging Science, Vanderbilt University School of Medicine, 2Department of Radiology and Radiological Sciences, 3Department of Chemistry, Vanderbilt University, 4Vanderbilt Institute of Nanoscale Science and Engineering, 5Vanderbilt Flow Cytometry Shared Resource, Vanderbilt University, 6Vanderbilt Institute of Chemical Biology, 7Department of Chemistry and Biochemistry, Brigham Young University, 8Department of Pathology, Microbiology and Immunology, Vanderbilt University, 9Veterans Administration Tennessee Valley Healthcare System, 10Department of Biomedical Engineering, 11Vanderbilt Ingram Cancer Center, 12Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA Abstract: The present study investigated the immunoenhancing property of our newly designed nanovaccine, that is, its ability to induce antigen-specific immunity. This study also evaluated the synergistic effect of a novel compound PBS-44, an α-galactosylceramide analog, in boosting the immune response induced by our nanovaccine. The nanovaccine was prepared by encapsulating ovalbumin (ova) and an adjuvant within the poly(lactic-co-glycolic acid) nanoparticles. Quantitative analysis of our study data showed that the encapsulated vaccine was physically and biologically stable; the core content of our nanovaccine was found to be released steadily and slowly, and nearly 90% of the core content was slowly released over the course of 25 days. The in vivo immunization studies exhibited that the nanovaccine induced stronger and longer immune responses compared to its soluble counterpart. Similarly, intranasal inhalation of the nanovaccine induced more robust antigen-specific CD8+ T cell response than intraperitoneal injection of nanovaccine. Keywords: nanovaccine, dendritic cells, GalCer, inhalable vaccin

Brief exposure to obesogenic diet disrupts brain dopamine networks.

OBJECTIVE:We have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH). METHODS:We examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3α in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [18F]fallypride positron emission tomography (PET). RESULTS:We found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens-anterior cingulate) and sensorimotor circuits (caudate/putamen-thalamus-sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals. CONCLUSION:These studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding