| 1. |
- Adori, Csaba, et al.
(författare)
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Exploring the role of neuropeptide S in the regulation of arousal : a functional anatomical study
- 2016
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Ingår i: Brain Structure and Function. - : Springer. - 1863-2653 .- 1863-2661. ; 221:7, s. 3521-3546
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Tidskriftsartikel (refereegranskat)abstract
- Neuropeptide S (NPS) is a regulatory peptide expressed by limited number of neurons in the brainstem. The simultaneous anxiolytic and arousal-promoting effect of NPS suggests an involvement in mood control and vigilance, making the NPS-NPS receptor system an interesting potential drug target. Here we examined, in detail, the distribution of NPS-immunoreactive (IR) fiber arborizations in brain regions of rat known to be involved in the regulation of sleep and arousal. Such nerve terminals were frequently apposed to GABAergic/galaninergic neurons in the ventro-lateral preoptic area (VLPO) and to tyrosine hydroxylase-IR neurons in all hypothalamic/thalamic dopamine cell groups. Then we applied the single platform-on-water (mainly REM) sleep deprivation method to study the functional role of NPS in the regulation of arousal. Of the three pontine NPS cell clusters, the NPS transcript levels were increased only in the peri-coerulear group in sleep-deprived animals, but not in stress controls. The density of NPS-IR fibers was significantly decreased in the median preoptic nucleus-VLPO region after the sleep deprivation, while radioimmunoassay and mass spectrometry measurements showed a parallel increase of NPS in the anterior hypothalamus. The expression of the NPS receptor was, however, not altered in the VLPO-region. The present results suggest a selective activation of one of the three NPS-expressing neuron clusters as well as release of NPS in distinct forebrain regions after sleep deprivation. Taken together, our results emphasize a role of the peri-coerulear cluster in the modulation of arousal, and the importance of preoptic area for the action of NPS on arousal and sleep.
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| 2. |
- Attems, Johannes, et al.
(författare)
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Clusters of secretagogin-expressing neurons in the aged human olfactory tract lack terminal differentiation
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:16, s. 6259-6264
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Tidskriftsartikel (refereegranskat)abstract
- Expanding the repertoire of molecularly diverse neurons in the human nervous system is paramount to characterizing the neuronal networks that underpin sensory processing. Defining neuronal identities is particularly timely in the human olfactory system, whose structural differences from nonprimate macrosmatic species have recently gained momentum. Here, we identify clusters of bipolar neurons in a previously unknown outer "shell" domain of the human olfactory tract, which express secretagogin, a cytosolic Ca2+ binding protein. These "shell" neurons are wired into the olfactory circuitry because they can receive mixed synaptic inputs. Unexpectedly, secretagogin is often coexpressed with polysialylated-neural cell adhesion molecule, beta-III-tubulin, and calretinin, suggesting that these neurons represent a cell pool that might have escaped terminal differentiation into the olfactory circuitry. We hypothesized that secretagogin-containing "shell" cells may be eliminated from the olfactory axis under neurodegenerative conditions. Indeed, the density, but not the morphological or neurochemical integrity, of secretagogin-positive neurons selectively decreases in the olfactory tract in Alzheimer's disease. In conclusion, secretagogin identifies a previously undescribed cell pool whose cytoarchitectonic arrangements and synaptic connectivity are poised to modulate olfactory processing in humans.
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| 3. |
- Bensing, Sophie, et al.
(författare)
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Pituitary autoantibodies in autoimmune polyendocrine syndrome type 1
- 2007
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:3, s. 949-954
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies (Aabs) toward intracellular enzymes are a hallmark for APS1 and serve as diagnostic markers and predictors for disease manifestations. In this study, we aimed to identify pituitary autoantigens in patients with APS1. A pituitary cDNA expression library was screened with APS1 sera and a tudor domain containing protein 6 (TDRD6) cDNA clone was isolated. Positive immunoreactivity against in vitro translated TDRD6 fragments was shown in 42/86 (49%) APS1 patients but not in patients with other autoimmune diseases or in healthy controls. By using immunohistochemistry, sera from 3/6 APS1 patients with growth hormone (GH) deficiency showed immunostaining of a small number of guinea pig anterior pituitary cells, and 40-50% of these cells were GH-positive. No such immunostaining was seen with sera from healthy controls. The APS1 Aab-positive, GH-negative cells may represent a novel subpopulation of anterior pituitary cells. In addition, 4/6 patient sera showed staining of a fiber-plexus in the pituitary intermediate lobe recognizing enzymes of monoamine and GABA synthesis. Thus, we have identified TDRD6 as a major autoantigen in APS1 patients and shown that several sera from GH-deficient patients stain specific cell populations and nerves in the pituitary gland.
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| 4. |
- Bergman, Peter, et al.
(författare)
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Induction of the antimicrobial peptide CRAMP in the blood-brain barrier and meninges after meningococcal infection
- 2006
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Ingår i: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 74:12, s. 6982-6991
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Tidskriftsartikel (refereegranskat)abstract
- Antimicrobial peptides are present in most living species and constitute important effector molecules of innate immunity. Recently, we and others have detected antimicrobial peptides in the brain. This is an organ that is rarely infected, which has mainly been ascribed to the protective functions of the blood-brain barrier (BBB) and meninges. Since the bactericidal properties of the BBB and meninges are not known, we hypothesized that antimicrobial peptides could play a role in these barriers. We addressed this hypothesis by infecting mice with the neuropathogenic bacterium Neisseria meningitidis. Brains were analyzed for expression of the antimicrobial peptide CRAMP by immunohistochemistry in combination with confocal microscopy. After infection, we observed induction of CRAMP in endothelial cells of the BBB and in cells of the meninges. To explore the functional role of CRAMP in meningococcal disease, we infected mice deficient of the CRAMP gene. Even though CRAMP did not appear to protect the brain from invasion of meningococci, CRAMP knockout mice were more susceptible to meningococcal infection than wild-type mice and exhibited increased meningococcal growth in blood, liver, and spleen. Moreover, we could demonstrate that carbonate, a compound that accumulates in the circulation during metabolic acidosis, makes meningococci more susceptible to CRAMP.
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| 5. |
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| 6. |
- Broberger, Christian, et al.
(författare)
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Differential effects of intrastriatally infused fully and endcap phosphorothioate antisense oligonucleotides on morphology, histochemistry and prodynorphin expression in rat brain
- 2000
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Ingår i: Brain Research. Molecular Brain Research. - : Elsevier BV. - 0169-328X .- 1872-6941. ; 75:1, s. 25-45
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, we investigated the selectivity and specificity associated with continuous intrastriatal treatment with antisense oligonucleotides. Rats were given intrastriatal infusions for 72 h with phosphodiester, and fully and endcap phosphorothioated oligonucleotide probes complementary to prodynorphin mRNA. Dynorphin (Dyn) peptide levels were measured by radioimmunoassay. The integrity of three other striatal transmitter systems, the neuropeptide Y (NPY)-ergic interneurons, the cholinergic interneurons and the dopaminergic afferent innervation, was assessed histochemically. The gross morphology of the striatum and the distribution of fluorescently labelled antisense probes were also investigated. Brains infused with phosphodiester probes had tissue Dyn levels not different from control. They also showed little or no change in staining for NPY, acetylcholinesterase (AChE) and tyrosine hydroxylase (TH) and essentially normal striatal gross morphology. In contrast, brains treated with fully phosphorothioated oligonucleotides showed significant decreases in striatal Dyn levels but also severe tissue damage accompanied by massive cell infiltration and decreases in immunoreactivities for the striatal neurochemical markers. Fluorescently labelled phosphorothioate probes were observed widely in the striatum and adjacent structures and, presumably retrogradely transported, in the dopamine cell bodies in the substantia nigra, also revealing the presence of abnormal cellular structures within the striatum. By comparison, endcap probes significantly reduced striatal Dyn levels and showed good tissue penetration without inducing major changes in tissue morphology or histochemistry of non-dynorphinergic systems, except for cell infiltration. The deleterious tissue effects of fully phosphorothioated oligonucleotides and the ineffectiveness of phosphodiester oligonucleotides in inhibiting protein synthesis suggest that, of the probes examined in this study, endcap oligonucleotides are the most useful for in vivo studies in the central nervous system.
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| 7. |
- Ekström, Per A R, et al.
(författare)
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Leukemia inhibitory factor null mice : Unhampered in vitro outgrowth of sensory axons but reduced stimulatory potential by nerve segments
- 2000
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Ingår i: Neuroscience Letters. - 0304-3940. ; 281:2-3, s. 107-110
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Tidskriftsartikel (refereegranskat)abstract
- Leukemia inhibitory factor (LIF) is locally up-regulated after peripheral nerve injury and may be involved in the subsequent regeneration. Here, adult mice with or without LIF gene deletions were used to study the role of LIF in regeneration. The results show that axonal regeneration in vitro from dorsal root ganglia (DRGs) was unaffected by LIF deletion. However, segments from wild type mice promoted DRG axonal outgrowth better than segments from LIF deleted animals when in vivo-injured sciatic nerve segments were co-cultured with DRGs from normal adult mice. Addition of LIF could not restore the deficit. This suggests that LIF is engaged in the local regulation of regeneration but not in the regenerative events occuring at the cell body level. (C) 2000 Elsevier Science Ireland Ltd.
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| 8. |
- Engström, Linda, 1976-
(författare)
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Inflammation-Induced Gene Expression in Brain and Adrenal Gland
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The autonomic nervous system serves to maintain a constant inner environment, a process termed homeostasis. Thus, in response to the homeostatic challenge posed by infectious agents, the autonomic nervous system answers to signals from the immune system and elicits adaptive physiological and behavioral reactions. These so called sickness responses include fever, anorexia, hyperalgesia, social avoidance, and the release of stress hormones.Neuropeptides, used in the communication between neurons, are because of their release properties and sustained actions likely mediators of homeostatic responses. The enkephalinergic system constitutes one of the largest neuropeptidergic systems in the brain, but its involvement in inflammatory conditions has been little studied. We first examined the immune-induced activation of the parabrachial nucleus (paper I), an enkephalinergic autonomic relay center in the brain stem. We found that intravenous injection of bacterial endotoxin, lipopolysaccharide (LPS), activated the external lateral parabrachial subnucleus, as measured in terms of Fos expression, but that the enkephalinergic cell population in this subnucleus was largely separated from the LPS-activated neurons. Because Fos may not always be a reliable activity marker, we next examined by in situ hybridization the immune-induced expression of newly transcribed preproenkephalin (ppENK) heteronuclear RNA (hnRNA), which gives a direct indication of the utilization of enkephalin in a particular neuron (paper II). We detected induced expression of ppENK hnRNA in several autonomic structures in the brain, including the paraventricular hypothalamic nucleus (PVH) but not the parabrachial nucleus, indicating increased enkephalinergic signaling activity in the positively labeled structures during inflammatory condition. We then examined the projections of the immune-induced ppENK transcribing PVH neurons by injecting rats intraperitoneally with the retrograde tracer substance Fluoro-Gold, hence labeling neurons with axonal projections outside the blood-brain barrier, followed by systemic injection of LPS (paper III). Dual-labeling histochemical and hybridization techniques showed that the vast majority of the ppENK hnRNA expressing cells were hypophysiotropic cells, hence being involved in neuroendocrine regulation. These findings suggest that centrally produced enkephalin is involved in the coordination of the sickness responses during systemic immune challenge, including the modulation of the release of stress hormones or other hypothalamic hormones during inflammatory conditions.We next turned to the role of prostaglandins in the hypothalamic-pituitary-adrenal (HPA) axis response to inflammation. We injected mice deficient for the terminal prostaglandin (PG) E2 synthesizing enzyme mPGES-1 with LPS and studied their stress hormone release (paper IV). The genetically modified mice displayed attenuated plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone during the later phases of the HPA-axis response compared with wild type mice, and this impairment did not depend on a changed activation pattern in the brain, but instead correlated to an early decrease in corticotropin-releasing hormone mRNA expression in the PVH, hence being the likely cause of the blunted ACTH and corticosterone responses at later time-points. Based on these findings we suggest that a neural, mPGES-1-independent pathway, and a humoral, mPGES-1-dependent pathway act in concert but in distinct temporal patterns to initiate and maintain the HPA-axis response during immune challenge.In addition to activating the central limb of the HPA-axis, inflammatory mediators have been suggested to act directly on the adrenal gland to induce the release of corticosterone, but little is known about the underlying mechanisms. We examined adrenal tissue isolated from rats injected with LPS or interleukin-1β (IL-1β) (paper V), and found that immune stimulation resulted in dynamic changes in the adrenal immune cell population, implying a rapid depletion of dendritic cells in the inner cortical layer and the recruitment of immature cells to the outer layers. These changes were accompanied by an induced production of IL-1β and IL-1 receptor type 1, as well as of cyclo-oxygenase-2 and mPGES-1 in these cells, implying local cytokine-mediated PGE2 production in the adrenals, which also displayed EP1 and EP3 receptors in the cortex and medulla. Additional mechanistic studies using an IL-1 receptor antagonist showed that IL-1β acts locally to affect its own synthesis, as well as that of cyclooxygenase-2. Taken together these data demonstrate a mechanism by which systemic inflammatory agents activate an intrinsically regulated local signaling circuit that may influence the adrenals’ response to immune stress and may help explain the dissociation between plasma levels of ACTH and corticosteroids during chronic immune perturbations.
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| 9. |
- Fetissov, Sergueï O, et al.
(författare)
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Aggressive behavior linked to corticotropin-reactive autoantibodies
- 2006
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 60:8, s. 799-802
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Altered stress response is characteristic for subjects with abnormal aggressive and antisocial behavior, but the underlying biological mechanisms are unclear. We hypothesized that autoantibodies (autoAbs) directed against several stress-related neurohormones may exist in aggressive subjects. METHODS: Using enzyme-linked immunosorbent assay, we studied whether autoAbs directed against corticotropin (ACTH), alpha-melanocyte-stimulating hormone (alpha-MSH), oxytocin, and vasopressin are present in serum of male subjects with conduct disorder and prisoners with history of violence. Healthy blood donors served as control subjects. RESULTS: Both conduct disorder and prisoners groups displayed strongly increased levels of ACTH-reactive immunoglobulin G (IgG) and immunoglobulin M (IgM) autoAbs compared with control subjects. Levels of oxytocin-reactive IgM autoAbs were slightly increased in both groups of aggressive subjects, whereas levels of vasopressin-reactive IgG and IgM autoAbs were lower only in conduct disorder. No differences in the levels of alpha-MSH-reactive autoAbs were found between aggressive and control subjects. CONCLUSIONS: High levels of ACTH-reactive autoAbs as well as altered levels of oxytocin- and vasopressin-reactive autoAbs found in aggressive subjects may interfere with the neuroendocrine mechanisms of stress and motivated behavior. Our data suggest a new biological mechanism of human aggressive behavior that involves autoAbs directed against several stress-related neurohormones.
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| 10. |
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