Functional α7β2 Nicotinic Acetylcholine Receptors Expressed In Hippocampal Interneurons Exhibit High Sensitivity To Pathological Level Of Amyloid β Peptides

Background: β-amyloid (Aβ) accumulation is described as a hallmark of Alzheimer\u27s disease (AD). Aβ perturbs a number of synaptic components including nicotinic acetylcholine receptors containing α7 subunits (α7-nAChRs), which are abundantly expressed in the hippocampus and found on GABAergic interneurons. We have previously demonstrated the existence of a novel, heteromeric α7β2-nAChR in basal forebrain cholinergic neurons that exhibits high sensitivity to acute Aβ exposure. To extend our previous work, we evaluated the expression and pharmacology of α7β2-nAChRs in hippocampal interneurons and their sensitivity to Aβ.Results: GABAergic interneurons in the CA1 subregion of the hippocampus expressed functional α7β2-nAChRs, which were characterized by relatively slow whole-cell current kinetics, pharmacological sensitivity to dihydro-β-erythroidine (DHβE), a nAChR β2* subunit selective blocker, and α7 and β2 subunit interaction using immunoprecipitation assay. In addition, α7β2-nAChRs were sensitive to 1 nM oligomeric Aβ. Similar effects were observed in identified hippocampal interneurons prepared from GFP-GAD mice.Conclusion: These findings suggest that Aβ modulation of cholinergic signaling in hippocampal GABAergic interneurons via α7β2-nAChRs could be an early and critical event in Aβ-induced functional abnormalities of hippocampal function, which may be relevant to learning and memory deficits in AD. © 2012 Liu et al.; licensee BioMed Central Ltd

Whole-Body Vibration Alleviates Symptoms of Morphine Withdrawal

Whole-body vibration at 80 Hz has previously been shown to blunt neuropathological markers and behavioral symptoms of alcohol dependence. Here, we evaluate its ability to ameliorate symptoms of morphine use and withdrawal. Behavioral and neurophysiological symptoms of withdrawal were reduced significantly by whole-body vibration treatment

BDNF signaling in the VTA links the drug-dependent state to drug withdrawal aversions

Drug administration to avoid unpleasant drug withdrawal symptoms has been hypothesized to be a crucial factor that leads to compulsive drug-taking behavior. However, the neural relationship between the aversive motivational state produced by drug withdrawal and the development of the drug-dependent state still remains elusive. It has been observed that chronic exposure to drugs of abuse increases brain-derived neurotrophic factor (BDNF) levels in ventral tegmental area (VTA) neurons. In particular, BDNF expression is dramatically increased during drug withdrawal, which would suggest a direct connection between the aversive state of withdrawal and BDNF-induced neuronal plasticity. Using lentivirus-mediated gene transfer to locally knock down the expression of the BDNF receptor tropomyosin-receptor-kinase type B in rats and mice, we observed that chronic opiate administration activates BDNF-related neuronal plasticity in the VTA that is necessary for both the establishment of an opiate-dependent state and aversive withdrawal motivation. Our findings highlight the importance of a bivalent, plastic mechanism that drives the negative reinforcement underlying addiction

Coronaridine congeners attenuate fentanyl seeking during prolonged abstinence

Background: The prevalence of opioid use disorder (OUD) has reached epidemic proportions with a record-breaking number of overdose deaths. Over 70% of the record-breaking number of overdose deaths are caused by synthetic opioids, including fentanyl. Fentanyl is commonly administered intravenously or by inhalation (smoking/vaping), which results in rapid drug bioavailability in the brain. There is a current need to identify a novel pharmacologic therapy to treat OUD, and there is increasing evidence to support the use of novel compounds referred to as coronaridine congeners to treat OUD and other psychiatric illnesses. In preclinical models, coronaridine congeners have been shown to decrease self-administration of drugs of abuse and induce antidepressant and anxiolytic effects. Here we used a preclinical fentanyl vapor self-administration model and fast-scan cyclic voltammetry (FSCV) to study the anti-addictive effects of two coronaridine congeners, 18-methoxycoronaridine (18-MC) and catharanthine (Cath).Methods: C57BL/6J mice were trained to self-administer vaporized fentanyl (5 mg/mL) or vehicle in airtight operant chambers. Mice self-administered vapor for 1 hour per day for 10 days (sessions were conducted for 5 consecutive days, followed by 2 days off). Chambers were equipped with two nosepokes, one active and one inactive. A successful response in the active nosepoke resulted in a vapor delivery that coincided with the presentation of a cue light, followed by a 1-minute timeout period. Mice learned to self-administer vapor with 3-second vapor deliveries for the first 3 days of training, which was then reduced to 1.5-second vapor deliveries the remaining 7 days. After training, mice were returned to their home cages for a forced abstinence period. Cue-induced drug seeking tests were conducted on abstinence days (AD) 20 and 25. During cue-induced seeking tests, successful responses in the active nosepoke resulted in presentation of the drug-associated cue, but no vapor was delivered (i.e. extinction conditions). Cue-induced drug seeking tests were conducted using a crossover design where half of subjects received coronaridine treatment (18-MC or Cath), while the other half received vehicle (ddH2O), on AD20. On AD25, subjects received the opposite treatment compared to AD20. Mice were injected (i.p.) with either vehicle or coronaridine treatment 1 hour before seeking tests. To examine the molecular mechanism of coronaridine congeners, FSCV was conducted on dopaminergic pre-synaptic terminals in the nucleus accumbens (NAc) neurons to measure dopamine (DA) release in the presence of 18-MC and Cath with or without nicotinic acetylcholine receptor antagonists.Results: We found that both 18-MC and Cath significantly reduced fentanylseeking during prolonged abstinence with no effect on mice that had previously self-administered vehicle. Furthermore, FSCV revealed that 18-MC and Cath significantly reduced DA release onto NAc neurons.Conclusion: In this study, we report that both 18-MC and Cath decrease fentanyl seeking during prolonged abstinence. DA release is important for opioid-related behaviors, and we found that 18-MC and Cath reduce DA release in the NAc, a mechanism that may underlie the effect of coronaridine congeners on fentanyl seeking. Together, these results provide evidence that coronaridine congeners may be promising novel compounds for the pharmacotherapeutic treatment of OUD

Functional and genetic analysis in type 2 diabetes of Liver X receptor alleles – a cohort study

<p>Abstract</p> <p>Background</p> <p>Liver X receptor alpha <it>(LXRA</it>) and beta (<it>LXRB</it>) regulate glucose and lipid homeostasis in model systems but their importance in human physiology is poorly understood. This project aimed to determine whether common genetic variations in <it>LXRA </it>and <it>LXRB </it>associate with type 2 diabetes (T2D) and quantitative measures of glucose homeostasis, and, if so, reveal the underlying mechanisms.</p> <p>Methods</p> <p>Eight common single nucleotide polymorphisms in <it>LXRA </it>and <it>LXRB </it>were analyzed for association with T2D in one French cohort (N = 988 cases and 941 controls), and for association with quantitative measures reflecting glucose homeostasis in two non-diabetic population-based samples comprising N = 697 and N = 1344 adults. Investigated quantitative phenotypes included fasting plasma glucose, serum insulin, and HOMA_IRas measure of overall insulin resistance. An oral glucose tolerance test was performed in N = 1344 of adults. The two alleles of the proximal <it>LXRB </it>promoter, differing only at the SNP rs17373080, were cloned into reporter vectors and transiently transfected, whereupon allele-specific luciferase activity was measured. rs17373080 overlapped, according to <it>in silico </it>analysis, with a binding site for Nuclear factor 1 (NF1). Promoter alleles were tested for interaction with NF1 using direct DNA binding and transactivation assays.</p> <p>Results</p> <p>Genotypes at two <it>LXRB </it>promoter SNPs, rs35463555 and rs17373080, associated nominally with T2D (P values 0.047 and 0.026). No <it>LXRA </it>or <it>LXRB </it>SNP associated with quantitative measures reflecting glucose homeostasis. The rs17373080 C allele displayed higher basal transcription activity (P value < 0.05). The DNA-mobility shift assay indicated that oligonucleotides corresponding to either rs17373080 allele bound NF1 transcription factors in whole cell extracts to the same extent. Different NF1 family members showed different capacity to transactivate the <it>LXRB </it>gene promoter, but there was no difference between promoter alleles in NF1 induced transactivation activity.</p> <p>Conclusion</p> <p>Variations in the <it>LXRB </it>gene promoter may be part of the aetiology of T2D. However, the association between <it>LXRB </it>rs35463555 and rs17373080, and T2D are preliminary and needs to be investigated in additional larger cohorts. Common genetic variation in <it>LXRA </it>is unlikely to affect the risk of developing T2D or quantitative phenotypes related to glucose homeostasis.</p

SHANK3 controls maturation of social reward circuits in the VTA.

Haploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of autism spectrum disorder. How SHANK3 insufficiency affects specific neural circuits and how this is related to specific symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the ventral tegmental area of mice. We identified dopamine (DA) and GABA cell-type-specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors mGluR1 during the first postnatal week restored DA neuron excitatory synapse transmission and partially rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired ventral tegmental area function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy

Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial.

Background: The evidence base regarding the safety of intravenous (IV) iron therapy in patients with chronic kidney disease (CKD) is incomplete and largely based on small studies of relatively short duration. Methods: FIND-CKD (ClinicalTrials.gov number NCT00994318) was a 1-year, open-label, multicenter, prospective study of patients with nondialysis-dependent CKD, anemia and iron deficiency randomized (1:1:2) to IV ferric carboxymaltose (FCM), targeting higher (400-600 µg/L) or lower (100-200 µg/L) ferritin, or oral iron. A post hoc analysis of adverse event rates per 100 patient-years was performed to assess the safety of FCM versus oral iron over an extended period. Results: The safety population included 616 patients. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin FCM, low ferritin FCM and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient-years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups. At least one ferritin level ≥800 µg/L occurred in 26.6% of high ferritin FCM patients, with no associated increase in adverse events. No patient with ferritin ≥800 µg/L discontinued the study drug due to adverse events. Estimated glomerular filtration rate remained the stable in all groups. Conclusions: These results further support the conclusion that correction of iron deficiency anemia with IV FCM is safe in patients with nondialysis-dependent CKD

Discourse and religion in educational practice

Despite the existence of long-held binaries between secular and sacred, private and public spaces, school and religious literacies in many contemporary societies, the significance of religion and its relationship to education and society more broadly has become increasingly topical. Yet, it is only recently that the investigation of the nexus of discourse and religion in educational practice has started to receive some scholarly attention. In this chapter, religion is understood as a cultural practice, historically situated and embedded in specific local and global contexts. This view of religion stresses the social alongside the subjective or experiential dimensions. It explores how through active participation and apprenticeship in culturally appropriate practices and behaviors often mediated intergenerationally and the mobilisation of linguistic and other semiotic resources but also affective, social and material resources, membership in religious communities is constructed and affirmed. The chapter reviews research strands that have explored different aspects of discourse and religion in educational practice as a growing interdisciplinary field. Research strands have examined the place and purpose of religion in general and evangelical Christianity in particular in English Language Teaching (ELT) programmes and the interplay of religion and teaching and learning in a wide range of religious and increasingly secular educational contexts. They provide useful insights for scholars of discourse studies to issues of identity, socialisation, pedagogy and language policy