Anatomy and Neuroscience - Journal Articles

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    Increased amygdalar metabotropic glutamate receptor 7 mRNA in a genetic mouse model of impaired fear extinction
    (Springer Nature, 2018-09-13) O’Connor, Richard M.; McCafferty, Cian P.; Bravo, Javier A.; Singewald, Nicolas; Holmes, Andrew; Cryan, John F.; Science Foundation Ireland; Health Research Board; Irish Research Council for Science, Engineering and Technology; National Institute on Alcohol Abuse and Alcoholism; Austrian Science Fund
    Rationale: Post-traumatic stress disorder (PTSD) is a devastating anxiety-related disorder which develops subsequent to a severe psychologically traumatic event. Only ~ 9% of people who experience such a trauma develop PTSD. It is clear that a number of factors, including genetics, influence whether an individual will develop PTSD subsequent to a trauma. The 129S1/SvImJ (S1) inbred mouse strain displays poor fear extinction and may be useful to model this specific aspect of PTSD. The metabotropic glutamate receptor 7 (mGlu7 receptor) has previously been shown to be involved in cognitive processes and anxiety-like behaviour placing it in a key position to regulate fear extinction processes. We sought to compare mGlu7 receptor mRNA levels in the S1 strain with those in the robustly extinguishing C57BL/6J (B6) inbred strain using in situ hybridisation (ISH) in three brain regions associated with fear extinction: the amygdala, hippocampus and prefrontal cortex (PFC). Results: Compared to the B6 strain, S1 mice had increased mGlu7 receptor mRNA levels in the lateral amygdala (LA) and basolateral amygdala (BLA) subdivisions. An increase was also seen in the hippocampal CA1 and CA3 subregions of S1 mice. No difference in mGlu7 receptor levels were seen in the central nucleus (CeA) of the amygdala, dentate gyrus (DG) of the hippocampus or prefrontal cortex. Conclusions: These data show altered mGlu7 receptor expression in key brain regions associated with fear extinction in two different inbred mouse strains which differ markedly in their fear extinction behaviour. Altered mGlu7 receptor levels may contribute to the deficit fear extinction processes seen in fear extinction in the S1 strain.
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    Maternal hypertensive disorders of pregnancy and depression or anxiety in adolescence: Findings from the Millennium Cohort Study - a reply
    (Elsevier, 2024-03-19) Keenan, Martin; Khashan, Ali S.; O'Byrne, Laura J.; O'Keeffe, Gerard W.; Al Khalaf, Sukainah; Maher, Gillian M.
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    Maternal hypertensive disorders of pregnancy and depression or anxiety in adolescence: Findings from the Millennium Cohort Study
    (Elsevier, 2023-11-18) Keenan, Martin; Khashan, Ali S.; O'Byrne, Laura J.; O'Keeffe, Gerard W.; Al Khalaf, Sukainah; Maher, Gillian M.
    Background: The short-term effects of hypertensive disorders of pregnancy (HDP) on the health of the fetus are well known; however, their impacts on the risk of mental health in the exposed offspring are not fully understood. Our aim was to examine the association between HDP and depression/anxiety at age 17 years. Methods: We used data from The Millennium Cohort Study, a nationally representative longitudinal study of children born in the United Kingdom. Data on HDP and potential confounders were collected when children were 9-months. Data on depression and anxiety were collected as one variable when children were aged 17 years using self-reported doctor diagnosis, and reclassified as depression/anxiety (overall), depression/anxiety with treatment, and depression/anxiety without treatment. Crude and adjusted logistic regression models were performed to examine the association between HDP and depression/anxiety, adjusting for several maternal and socio-economic factors. Results: There were 9517 singleton mother-child pairs included in the analyses. Adjusted logistic regression suggested an association between HDP and depression/anxiety (adjusted odds ratio, (aOR):1.30 [95 % CI, 1.02–1.66]) at age 17 years. A similar association was observed for HDP and depression/anxiety with treatment (aOR:1.33 [95 % CI, 1.01–1.73]) and HDP and depression/anxiety without treatment (aOR: 1.30 [95 % CI, 0.80–2.12]), although the latter did not reach statistical significance. Limitations: Data on severity and classifications of HDP were not available. Conclusion: Exposure to HDP may be associated with an increased likelihood of depression or anxiety at age 17 years. Future research should consider severity and different classifications of HDP.
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    Maternal mid-gestation cytokine dysregulation in mothers of children with autism spectrum disorder
    (Springer, 2021-09-09) Casey, Sophie; Carter, Michael; Looney, Ann-Marie; Livingstone, Vicki; Moloney, Gerard M.; O'Keeffe, Gerard W. ; Taylor, Rennae S.; Kenny, Louise C.; McCarthy, Fergus P.; McCowan, Lesley M. E.; Thompson, John M. D.; Murray, Deirdre M.; SCOPE Consortium; Irish Research Council; National Children's Research Centre, Ireland; Health Research Board; Science Foundation Ireland; Health Research Board of Ireland; New Enterprise Research Fund, New Zealand; Foundation for Research, Science and Technology; Health Research Council of New Zealand; Evelyn Bond Fund, New Zealand; Auckland District Health Board Charitable Trust, New Zealand
    Autism spectrum disorder (ASD) is a developmental disorder characterised by deficits in social interactions and communication, with stereotypical and repetitive behaviours. Recent evidence suggests that maternal immune dysregulation may predispose offspring to ASD. Independent samples t-tests revealed downregulation of IL-17A concentrations in cases, when compared to controls, at both 15 weeks (p = 0.02), and 20 weeks (p = 0.02), which persisted at 20 weeks following adjustment for confounding variables. This adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment.
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    Regulator of G-Protein Signalling 4 (RGS4) negatively modulates nociceptin/orphanin FQ opioid receptor signalling: Implication for l-Dopa-induced dyskinesia
    (Wiley; British Pharmacological Society, 2021-11-12) Pisanò, Clarissa A.; Mercatelli, Daniela; Mazzocchi, Martina; Brugnoli, Alberto; Morella, Ilaria; Fasano, Stefania; Zaveri, Nurulain T.; Brambilla, Riccardo; O'Keeffe, Gerard W.; Neubig, Richard R.; Morari, Michele; Università degli Studi di Ferrara
    Background and Purpose: Regulator of G-protein signalling 4 (RGS4) is a signal transduction protein that accelerates intrinsic GTPase activity of Gαi/o and Gαq subunits, suppressing GPCR signalling. Here, we investigate whether RGS4 modulates nociceptin/orphanin FQ (N/OFQ) opioid (NOP) receptor signalling and if this modulation has relevance for l-Dopa-induced dyskinesia. Experimental Approach: HEK293T cells transfected with NOP, NOP/RGS4 or NOP/RGS19 were challenged with N/OFQ and the small-molecule NOP agonist AT-403, using D1-stimulated cAMP levels as a readout. Primary rat striatal neurons and adult mouse striatal slices were challenged with either N/OFQ or AT-403 in the presence of the experimental RGS4 chemical probe, CCG-203920, and D1-stimulated cAMP or phosphorylated extracellular signal regulated kinase 1/2 (pERK) responses were monitored. In vivo, CCG-203920 was co-administered with AT-403 and l-Dopa to 6-hydroxydopamine hemilesioned rats, and dyskinetic movements, striatal biochemical correlates of dyskinesia (pERK and pGluR1 levels) and striatal RGS4 levels were measured. Key Results: RGS4 expression reduced NOFQ and AT-403 potency and efficacy in HEK293T cells. CCG-203920 increased N/OFQ potency in primary rat striatal neurons and potentiated AT-403 response in mouse striatal slices. CCG-203920 enhanced AT-403-mediated inhibition of dyskinesia and its biochemical correlates, without compromising its motor-improving effects. Unilateral dopamine depletion caused bilateral reduction of RGS4 levels, which was reversed by l-Dopa. l-Dopa acutely up-regulated RGS4 in the lesioned striatum. Conclusions and Implications: RGS4 physiologically inhibits NOP receptor signalling. CCG-203920 enhanced NOP responses and improved the antidyskinetic potential of NOP receptor agonists, mitigating the effects of striatal RGS4 up-regulation occurring during dyskinesia expression. Linked articles: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc