Motivational valence is determined by striatal melanocortin 4 receptors

It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and κ opioid receptor- induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli

Testing of the functional mathematical model of analysis of mechanisms of linkage of universal energy tools and general purpose tractor

Представлено формализованное описание проверки функциональной математической модели процесса перевода в транспортное положение косилки-плющилки прицепной КПП-4,2, агрегатируемой с универсальным энергетическим средством УЭС-2-280А и трактором общего назначения БЕЛАРУС 2022. Расчет выходных параметров механизмов навески УЭС-2-280А и БЕЛАРУС 2022 выполнен с помощью различных аналитических выражений. Идентичность сравниваемых результатов расчета выходных параметров механизмов навески УЭС-2-280А и БЕЛАРУС 2022 позволяет сделать вывод о правильности разработанной функциональной математической модели механизма навески, эффективной для мобильных энергетических средств.The article presents a formalized description of the checking of the functional mathematical model of the process of transferring to transport position of pull-type mower conditioners PTMC-4,2, aggregated with universal power tool UPT-2-280А and general-purpose tractor BELARUS 2022. Calculation of the output parameters of linkage mechanisms UPT-2-280А and BELARUS 2022 is performed using various analytical expressions. The identity of the compared results of calculating the output parameters of the linkage mechanisms UPT-2-280А and BELARUS 2022 allows to make a conclusion about the correctness of the developed functional mathematical model of the linkage mechanism, effective for mobile power equipment

Immune-to-Brain Signaling in Fever : The Brain Endothelium as Interface

Fever is a brain-regulated elevation of body temperature that occurs in response to infectious and non-infectious stimuli. During inflammatory episodes, circulating cytokines that are released by activated immune cells, trigger the induction of cyclooxygenase (COX)-2 in the ventromedial preoptic area of the hypothalamus (the thermoregulation center). COX-2-dependent-prostaglandin (PG)E2 synthesis is essential for the generation of fever and upon an immune challenge, it is induced in several cells within the brain including the brain endothelial cells and perivascular macrophages. However, due to lack of experimental models with cell type-specific modulation of PGE2 synthesizing enzymes, the cellular source of pyrogenic PGE2 and its induction mechanism(s) remained obscure. Using such technology, we showed that the brain endothelium is the cellular source of pyrogenic PGE2 and that activation of brain endothelial IL-6 receptors by circulating IL-6 is critical for the PGE2 induction. Inhibition of PGE2 synthesis is assumed to be the mode of action of many antipyretic drugs, possibly including paracetamol. Given that paracetamol at a high dose has been shown to induce hypothermia by activation of the transient receptor potential ankyrin 1 (TRPA1) ion channel, we examined whether the antipyretic effect of paracetamol is also TRPA1 dependent. Our findings revealed that the antipyretic effect of paracetamol is independent of TRPA1 and associated with inhibition of the PGE2 synthesis in the brain. This thesis provides new insight into the molecular mechanism behind the febrile response in which the peripheral circulating IL-6 communicates with the brain by induction of pyrogenic PGE2 in the brain endothelium. It also demonstrates that the antipyretic effect of paracetamol is exerted by inhibition of the PGE2 synthesis in the brain.Minor corrections are made in the electronic version of the thesis (Page 10).</p

Cyclooxygenase Isoform Exchange Blocks Brain-Mediated Inflammatory Symptoms

Cyclooxygenase-2 (COX-2) is the main source of inducible prostaglandin E-2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. COX-1 is dispensable for fever, anorexia and hyperalgesia but is important for several other functions both under basal conditions and during inflammation. The differential functionality of the COX isoforms could be due to differences in the regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, resulting in distinct functional properties of the proteins. To study the molecular underpinnings of the functional differences between the two isoforms in the context of inflammatory symptoms, we used mice in which the coding sequence of COX-2 was replaced by the corresponding sequence of COX-1. In these mice, COX-1 mRNA was induced by inflammation but COX-1 protein expression did not fully mimic inflammation-induced COX-2 expression. Just like mice globally lacking COX-2, these mice showed a complete lack of fever and inflammation-induced anorexia as well as an impaired response to inflammatory pain. However, as previously reported, they displayed close to normal survival rates, which contrasts to the high fetal mortality in COX-2 knockout mice. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate the inflammatory symptoms studied, making the line an interesting alternative to COX-2 knockouts for the study of inflammation. Our results also show that the functional differences between COX-1 and COX-2 in the context of inflammatory symptoms are not only dependent on the features of the promoter regions. Instead they indicate that there are fundamental differences between the isoforms at translational or posttranslational levels.Funding Agencies|European Research Council [260820]; Swedish Medical Research Council [25084, 25052, 77044]; Knut och Alice Wallenbergs Stiftelse; Hjarnfonden; County Council of Ostergotland</p

Immune-Induced Fever Is Mediated by IL-6 Receptors on Brain Endothelial Cells Coupled to STAT3-Dependent Induction of Brain Endothelial Prostaglandin Synthesis

The cytokine IL-6, which is released upon peripheral immune challenge, is critical for the febrile response, but the mechanism by which IL-6 is pyrogenic has remained obscure. Herewegenerated mice with deletion of themembranebound IL-6 receptor alpha (IL-6R alpha) onneural cells, on peripheral nerves, on fine sensory afferent fibers, and on brain endothelial cells, respectively, and examined its role for the febrile response to peripherally injected lipopolysaccharide. We show that IL-6R alpha on neural cells, peripheral nerves, and fine sensory afferents are dispensable for the lipopolysaccharide-induced fever, whereas IL-6R alpha in the brain endothelium plays an important role. Hence deletion of IL-6R alpha on brain endothelial cells strongly attenuated the febrile response, and also led to reduced induction of the prostaglandin synthesizing enzyme Cox-2 in the hypothalamus, the temperature-regulating center in the brain, as well as reduced expression of SOCS3, suggesting involvement of the STAT signaling pathway. Furthermore, deletion of STAT3 in the brain endothelium also resulted in attenuated fever. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6R alpha on brain endothelial cells to induce prostaglandin synthesis in these cells, probably in concerted action with other peripherally released cytokines.Funding Agencies|Swedish Medical Research Council; Swedish Cancer Foundation; European Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain foundation; County CouncilO Ostergotland</p

Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.

Systemic inflammation evokes an array of brain-mediated responses including fever, anorexia and taste aversion. Both fever and anorexia are prostaglandin dependent but it has been unclear if the cell-type that synthesizes the critical prostaglandins is the same. Here we show that pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not of COX-1, attenuates inflammation-induced anorexia. Mice with deletions of COX-2 selectively in brain endothelial cells displayed attenuated fever, as demonstrated previously, but intact anorexia in response to peripherally injected lipopolysaccharide (10μg/kg). Whereas intracerebroventricular injection of a cyclooxygenase inhibitor markedly reduced anorexia, deletion of COX-2 selectively in neural cells, in myeloid cells or in both brain endothelial and neural cells had no effect on LPS-induced anorexia. In addition, COX-2 in myeloid and neural cells was dispensable for the fever response. Inflammation-induced conditioned taste aversion did not involve prostaglandin signaling at all. These findings collectively show that anorexia, fever and taste aversion are triggered by distinct routes of immune-to-brain signaling.Funding agencies: Swedish Medical Research Council [20725, 07879]; European Research Council; Knut and Alice Wallenberg foundation; Swedish Brain Foundation; Swedish Cancer Foundation [213/692]; County Council of Ostergotland</p

Immune-Induced Fever Is Dependent on Local But Not Generalized Prostaglandin E-2 Synthesis in the Brain

Fever occurs upon binding of prostaglandin E-2 (PGE(2)) to EP3 receptors in the median preoptic nucleus of the hypothalamus, but the origin of the pyrogenic PGE(2) has not been clearly determined. Here, using mice of both sexes, we examined the role of local versus generalized PGE(2) production in the brain for the febrile response. In wild-type mice and in mice with genetic deletion of the prostaglandin synthesizing enzyme cyclooxygenase-2 in the brain endothelium, generated with an inducible CreER(T2) under the Slco1c1 promoter, PGE(2) levels in the CSF were only weakly related to the magnitude of the febrile response, whereas the PGE(2) synthesizing capacity in the hypothalamus, as reflected in the levels of cyclooxygenase-2 mRNA, showed strong correlation with the immune-induced fever. Histological analysis showed that the deletion of cyclooxygenase-2 in brain endothelial cells occurred preferentially in small-and medium-sized vessels deep in the brain parenchyma, such as in the hypothalamus, whereas larger vessels, and particularly those close to the neocortical surface and in the meninges, were left unaffected, hence leaving PGE(2) synthesis largely intact in major parts of the brain while significantly reducing it in the region critical for the febrile response. Furthermore, injection of a virus vector expressing microsomal prostaglandin E synthase-1 (mPGES-1) into the median preoptic nucleus of fever-refractive mPGES-1 knock-out mice, resulted in a temperature elevation in response to LPS. We conclude that the febrile response is dependent on local release of PGE(2) onto its target neurons and not on the overall PGE(2) production in the brain.Funding Agencies|Swedish Medical Research Council; Swedish Cancer Foundation; European Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain foundation; County Council of Ostergotland</p

Attenuated febrile response in COX-1>COX-2 animals after administration of LPS.

<p>A. Telemetric recordings in freely moving animals showing the deep body temperature of COX-1>COX-2 animals or WT littermates after the administration of LPS (100 μg/kg) or vehicle intraperitoneally. B Average body temperature after LPS administration is completely normalized in COX-1>COX-2 animals compared to WT animals for the duration of the febrile response (2.5-8h post LPS). ***p<0,001</p

Cumulative food intake in COX-1>COX-2 and WT littermates during the first 3 hours after LPS injection (10μg/kg).

<p>The COX-1>COX-2 animals are significantly protected from the acute, anorexigenic effects of LPS (***p<0.001).</p