Purpose: Changes in systemic circulatory dynamics and choroidal thickness are poorly understood. This study aimed to investigate the time course of changes in choroidal morphology during normal ...menstrual cycles in healthy women using enhanced depth imaging optical coherence tomography (EDI-OCT).Materials and Methods: This prospective study included 15 left eyes of 15 healthy Japanese women (mean age, 20.2 ± 0.8 years) with a normal menstrual cycle. Using EDI-OCT, the subfoveal choroidal thickness (SCT) was manually measured during the late follicular and mid-luteal phases. Intraocular pressure (IOP), systolic, diastolic, and mean blood pressure (SBP, DBP, and MBP), and heart rate (HR) were also evaluated during these phases.Results: SBP, DBP, and MBP were significantly elevated in the mid-luteal phase. The average SCT was significantly decreased in the mid-luteal phase. In contrast, there were no significant changes in IOP or HR.Conclusion: These findings indicate that choroidal thickness decreases during the mid-luteal phase in healthy Japanese women with normal menstrual cycles depending on systemic circulatory dynamics. However, since the difference in the SCT values between the late follicular and the mid-luteal phase is not large (7 μm), the menstrual cycle may have little influence on the interpretation of choroidal thickness data in clinical practice.
In the present study, we investigated the role of orexinergic systems in the activation of midbrain dopamine neurons. In an in vitro study, exposure to either orexin A or orexin B under superfusion ...conditions produced a transient increase in the intracellular Ca2+ concentration through the phospholipase C (PLC)/protein kinase C (PKC) pathway via Gq11α or Gβγ subunits in midbrain cultured neurons, which were shown to be tyrosine hydroxylase (TH)‐positive cells, but not in purified midbrain astrocytes. Here we show that in vivo injection with a selective PKC inhibitor chelerythrine chloride or 2‐{8‐(dimethylamino)methyl‐6,7,8,9‐tetrahydropyrido1,2‐aindol‐3‐yl}‐3‐1‐methyl‐1H‐indol‐3‐ylmaleimide HCl (Ro‐32–0432) into the ventral tegmental area (VTA) significantly suppressed the place preference and increased levels of dopamine in the nucleus accumbens (NAcc) induced by intra‐VTA injection of orexins. These results strongly support the idea that activation of the orexin‐containing neuron in the VTA leads to the direct activation of mesolimbic dopamine neurons through the activation of the PLC/PKC pathway via Gq11α or Gβγ‐subunit activation, which could be associated with the development of its rewarding effect.
Evidence suggests that cytokines may be one of the major factors influencing cognitive development in those with autism spectrum disorder (ASD). To shed light on the neural and cognitive mechanisms ...of ASD, we investigated the association between peripheral cytokine levels and cognitive profiles in children with ASD. The serum levels of 10 cytokines (granulocyte macrophage colony-stimulating factor, interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and tumor necrosis factor-α) were examined in 14 children with ASD using the Human Ultrasensitive Cytokine Magnetic 10-Plex Panel for the Luminex platform. The Wechsler Intelligence Scale for Children (WISC) was administered to each subject, and the relationships between WISC scores and serum levels of the cytokines were examined. The full-scale intelligence quotient (IQ) was significantly negatively correlated with the levels of IL-6 (Spearman's rank,
< 0.0001, false discovery rate
< 0.01). The levels of IL-6 and IFN-γ showed significant negative correlations with the verbal comprehension index (
< 0.001,
< 0.01) and working memory index (
< 0.01,
< 0.05), respectively. No other cytokines were significantly correlated with full-scale IQ or with any of the subscale scores of the WISC. The present results suggest negative correlations of IL-6 and IFN-γ levels with cognitive development of children with ASD. Our preliminary findings add to the evidence that cytokines may play a role in the neural development in ASD.
Recent clinical studies have demonstrated that when opioids are used to control pain, psychological dependence is not a major problem. In this study, we further investigated the mechanisms that ...underlie the suppression of opioid reward under neuropathic pain in rodents. Sciatic nerve ligation suppressed a place preference induced by the selective μ-opioid receptor agonist d-Ala2, N-MePhe4, Gly-ol5 enkephalin (DAMGO) and reduced both the increase in the level of extracellular dopamine by s.c. morphine in the nucleus accumbens and guanosine-5′-o-(3-35Sthio) triphosphate (35SGTPγS) binding to membranes of the ventral tegmental area (VTA) induced by DAMGO. These effects were eliminated in mice that lacked the β-endorphin gene. Furthermore, intra-VTA injection of a specific antibody to the endogenous μ-opioid peptide β-endorphin reversed the suppression of the DAMGO-induced rewarding effect by sciatic nerve ligation in rats. These results provide molecular evidence that nerve injury results in the continuous release of endogenous β-endorphin to cause the dysfunction of μ-opioid receptors in the VTA. This phenomenon could explain the mechanism that underlies the suppression of opioid reward under a neuropathic pain-like state.
ABSTRACT
Despite the importance of prefrontal cortical dopamine in modulating reward, little is known about the implication of the specific subregion of prefrontal cortex in opioid reward. We ...investigated the role of neurons projecting from the ventral tegmental area (VTA) to the anterior cingulate cortex (ACG) in opioid reward. Microinjection of the retrograde tracer fluorogold (FG) into the ACG revealed several retrogradely labelled cells in the VTA. The FG‐positive reactions were noted in both tyrosine hydroxylase (TH)‐positive and ‐negative VTA neurons. The released levels of dopamine and its major metabolites in the ACG were increased by either the electrical stimulation of VTA neurons or microinjection of a selective μ‐opioid receptor (MOR) agonist, (D‐Ala2,N‐MePhe4,Gly‐ol5) enkephalin (DAMGO), into the VTA. MOR‐like immunoreactivity was seen in both TH‐positive and ‐negative VTA neurons projecting to the ACG. The conditioned place preference induced by intra‐VTA injection of DAMGO was significantly attenuated by chemical lesion of dopaminergic terminals in the ACG. The depletion of dopamine in the ACG induced early extinction of μ‐opioid‐induced place preference. The levels of phosphorylated DARPP32 (Thr34) and phosphorylated CREB (Ser133) were increased in the ACG of rats that had maintained the morphine‐induced place preference, whereas the increases of these levels induced by morphine were blocked by pre‐treatment of a selective dopamine D1 receptor antagonist SCH23390. These findings suggest that VTA‐ACG transmission may play a crucial role in the acquisition and maintenance of μ‐opioid‐induced place preference. The activation of DARPP32 and CREB through dopamine D1 receptors in the ACG could be implicated in the maintenance of μ‐opioid‐induced place preference.
It has often been proposed that opioid addiction does not arise as a consequence of opioid treatment for pain. Recently, we demonstrated that activated protein kinase C (PKC) in the spinal cord ...associated with chronic pain-like hyperalgesia suppressed the morphine-induced rewarding effect in mice. In the present study, we investigated whether a gene deletion for an endogenous μ-opioid peptide β-endorphin could affect pain-like behavior and the suppression of the morphine-induced rewarding effect by the direct activation of PKC in the spinal cord. We found that activation of spinal PKC by intrathecal (i.t.) treatment with phorbol 12,13-dibutyrate (PDBu), a specific PKC activator, caused thermal hyperalgesia, pain-like behaviors and suppression of the morphine-induced rewarding effect. This suppression of morphine reward was eliminated in mice that lacked β-endorphin. In contrast, thermal hyperalgesia and pain-like behaviors were not affected in β-endorphin knockout mice. These results suggest that the activation of PKC in the spinal cord may play an essential role in the suppression of the morphine-induced rewarding effect in mice with neuropathic pain through the constant release of β-endorphin.
Abstract
Fukuyama congenital muscular dystrophy (FCMD) is an autosomal recessive disorder caused by fukutin (FKTN) gene mutations. FCMD is the second most common form of childhood muscular ...dystrophy in Japan, and the most patients possess a homozygous retrotransposal SINE-VNTR-Alu insertion in the 3′-untranslated region of FKTN. A deep-intronic variant (DIV) was previously identified as the second most prevalent loss-of-function mutation in Japanese patients with FCMD. The DIV creates a new splicing donor site in intron 5 that causes aberrant splicing and the formation of a 64-base pair pseudoexon in the mature mRNA, resulting in a truncated nonfunctional protein. Patients with FCMD carrying the DIV present a more severe symptoms, and currently, there is no radical therapy available for this disorder. In the present study, we describe in vitro evaluation of antisense oligonucleotide mediated skipping of pseudoexon inclusion and restoration of functional FKTN protein. A total of 16 19–26-mer antisense oligonucleotide sequences were designed with a 2’-O-methyl backbone and were screened in patient-derived fibroblasts, lymphoblast cells and minigene splice assays. One antisense oligonucleotide targeting the exonic splice enhancer region significantly induced pseudoexon skipping and increased the expression of normal mRNA. It also rescued FKTN protein production in lymphoblast cells and restored functional O-mannosyl glycosylation of alpha-dystroglycan in patient-derived myotubes. Based on our results, antisense oligonucleotide-based splicing correction should be investigated further as a potential treatment for patients with FCMD carrying the DIV.
One Sentence Summary Antisense oligonucleotide treatment restored normal FKTN protein production and functional O-mannosyl glycosylation of alpha-dystroglycan via pseudoexon skipping in patient-derived cells carrying the compound heterozygous deep-intronic variant of Fukuyama muscular dystrophy.
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