186 research outputs found
STATA code for article in PLOS ONE: Socio-cultural disparities in GDM burden differ by maternal age at first delivery
No full text<p>This is a pdf file of the STATA code used to produce the results in the article <em>Socio-cultural disparities in GDM burden differ by maternal age at first delivery </em>accepted for publication in PLOS ONE. The authors are Marian Abouzeid, Vincent L. Versace, Edward D. Janus, Mary-Ann Davey, Benjamin Philpot, Jeremy Oats and James A Dunbar.</p
Identification of depression in diabetes the efficacy of PHQ-9 and HADS-D
No full textBackground Clinical guidelines advise screening for depression in patients with diabetes. The Patient Health Questionnaire (PHQ-9) and the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) are commonly used in primary care. Aim To compare the efficacy of HADS-D and PHQ-9 in identifying moderate to severe depression among primary care patients with type 2 diabetes. Design of study Self-report postal survey, clinical records assessed by GPs. Setting Seven metropolitan and rural general practices in Victoria, Australia. Method Postal questionnaires were sent to all patients with diabetes on the registers of seven practices in Victoria. A total of 561 completed postal questionnaires were returned, giving a response rate 47%. Surveys included demographic information, and history of diabetes and depression. Participants completed both the PHQ-9 and HADS-D. Clinical data from patient records included glycosylated hemoglobin (HbA1c) levels and medications. Results The proportion of the total sample completing HADS-D was 96.8% compared with 82.4% for PHQ-9. Level of education was unrelated to responses on the HADS-D but was related to completion of the PHQ-9. Using complete data (n = 456) from both measures, 40 responders showed HADS-D scores in the moderate to severe range, compared with 103 cases identified by PHQ-9. Only 35 cases were classified in the moderate to severe category by both the PHQ-9 and HADS-D. Items with the highest proportions of positive responses on the PHQ-9 were related to tiredness and sleeping problems and, on the HADS-D, feeling slowed down. Conclusion It may be that the items contributing to the higher prevalence of moderate to severe depression using the PHQ-9 are due to diabetes-related symptoms or sleep disorders. <br
Synaptic plasticity and morphogenesis in the developing postnatal cerebral cortex
No full textLearning how neurons interact, to create functional circuits, is crucial for understanding the basis of cognition and for shedding insight into the underpinnings of neurological disorders. This work will describe how changes in (1) postsynaptic N-methyl D-aspartate receptor (NMDAR) subunit composition and (2) dendritic spine morphology, influence synaptic transmission and synaptic plasticity in the developing cerebral cortex. Synaptic NMDARs undergo a dramatic activity-dependent change in subunit composition, going from being primarily NR2B-containing, to being increasingly NR2A-containing. Interestingly, this change in synaptic subunit composition correlates with developmental changes in the properties of synaptic plasticity. Using pharmacology, I have elucidated how NR2A- and NR2B-type NMDARs contribute to synaptic plasticity at distinct developmental time points. Using this approach, I demonstrate that the degree of NMDAR activation required for the induction of long term potentiation (LTP) increases with age. This work also focuses on the role of slit-robo GTPase activating protein 2 (srGAP2) on shaping the morphology of postsynaptic specializations, called dendritic spines. While the significance of dendritic spines is highly contentious, it has been shown that they play an important role in modulating the efficacy of glutamatergic synapses. This work demonstrates that srGAP2 is expressed at the synapse and that it has the ability to induce an elongation of dendritic spine shape, through the synergistic action of both its FBAR and RhoGAP domains. From a physiological perspective, srGAP2 also influences synaptic transmission, by altering the shape and the complement of receptors at the postsynaptic membrane. As a whole, this doctoral work highlights the importance of changes in postsynaptic receptor composition and dendritic spine morphology, in shaping neural circuitry
Neuron
No full textA recent study by Gabel et al. (2015) found that Mecp2, the gene mutated in Rett syndrome, represses long (> 100 kb) genes associated with neuronal physiology and connectivity by binding to methylated CA sites in DNA. This study adds to a growing body of literature implicating gene length and transcriptional mechanisms in neurodevelopmental and neurodegenerative disorders.DP1 ES024088/ES/NIEHS NIH HHS/United StatesDP1ES024088/DP/NCCDPHP CDC HHS/United StatesP30 NS045892/NS/NINDS NIH HHS/United StatesP30NS045892/NS/NINDS NIH HHS/United StatesR01 MH093372/MH/NIMH NIH HHS/United StatesR01MH093372/MH/NIMH NIH HHS/United StatesU54 HD079124/HD/NICHD NIH HHS/United StatesU54HD079124/HD/NICHD NIH HHS/United State
Identification of depression in diabetes the efficacy of PHQ-9 and HADS-D
No full textBackground Clinical guidelines advise screening for depression in patients with diabetes. The Patient Health Questionnaire (PHQ-9) and the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) are commonly used in primary care. Aim To compare the efficacy of HADS-D and PHQ-9 in identifying moderate to severe depression among primary care patients with type 2 diabetes. Design of study Self-report postal survey, clinical records assessed by GPs. Setting Seven metropolitan and rural general practices In Victoria, Australia. Method Postal questionnaires were sent to all patients with diabetes on the registers of seven practices in Victoria. A total of 561 completed postal questionnaires were returned, giving a response rate 47%. Surveys included demographic information, and history of diabetes and depression. Participants completed both the PHQ-9 and HADS-D. Clinical data from patient records included glycosylated hemoglobin (HbA1c) levels and medications. Results The proportion of the total sample completing HADS-D was 96.8% compared with 82.4% for PHQ-9. Level of education was unrelated to responses on the HADS-D but was related to completion of the PHQ-9. Using complete data (n = 456) from both measures, 40 responders showed HADS-D scores in the moderate to severe range, compared with 103 cases identified by PHQ-9. Only 35 cases were classified in the moderate to severe category by both the PHQ-9 and HADS-D. Items with the highest proportions of positive responses on the PHQ-9 were related to tiredness and sleeping problems and, on the HADS-D, feeling slowed down. Conclusion It may be that the items contributing to the higher prevalence of moderate to severe depression using the PHQ-9 are due to diabetes-related symptoms or sleep disorders. © British Journal of General Practice
Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity
No full textNMDA-type glutamate receptors (NMDARs) mediate many forms of synaptic plasticity. These tetrameric receptors consist of two obligatory NR1 subunits and two regulatory subunits, usually a combination of NR2A and NR2B. In the neonatal neocortex NR2B-containing NMDARs predominate, and sensory experience facilitates a developmental switch in which NR2A levels increase relative to NR2B. In this review, we clarify the roles of NR2 subunits in synaptic plasticity, and argue that a primary role of this shift is to control the threshold, rather than determining the direction, for modifying synaptic strength. We also discuss recent studies that illuminate the mechanisms regulating NR2 subunits, and suggest that the NR2A/NR2B ratio is regulated by multiple means, which may control the ratio both locally at individual synapses and globally in a cell-wide manner. Finally, we use the visual cortex as a model system to illustrate how activity-dependent modifications in the NR2A/NR2B ratio may contribute to the development of cortical functions
Sniffing Out NMDA Receptors in the Olfactory Cortex
No full textSelective olfactory learning is essential for survival in most newborn mammals. Findings by Franks and Isaacson in this issue of Neuron suggest that early olfactory learning might be selective, in part because olfactory experience downregulates NMDA receptors at primary inputs to the olfactory cortex
Preclinical Development of Genetic Normalization Strategies to Treat Pitt-Hopkins Syndrome
No full textNeurodevelopmental disorders (NDDs) are defined as a group of conditions with onset in the developmental period, including intellectual or language impairments, attention-deficit disorders, and autism spectrum disorder. The United States’ National Health Interview Survey has shown that 1 in 6 children have a developmental disability. The current guidelines for NDDs recommend undergoing an evaluation for genetic etiology and receiving general developmental interventions. Despite no approved treatments for NDDs, development of precision treatment strategies for NDDs has been on the rise. Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by monoallelic mutations or deletions of Transcription Factor 4 (TCF4). A decade of basic research has led to an increased understanding of TCF4, including genetic variants and functional roles in brain development. The development of PTHS mouse models has expanded knowledge in molecular and pathophysiological mechanisms underlying PTHS, underpinning the potential therapeutic opportunities to treat the disorder. However, effective therapeutic approaches for PTHS have not been developed yet. The absence of a validated preclinical pipeline has ultimately impeded successful therapeutic development. Here I propose a genetic normalization strategy to treat PTHS and experimentally demonstrate the feasibility of treating PTHS by normalizing TCF4 expression. Furthermore, I address the challenges faced in developing a rational preclinical pipeline by characterizing the cell type-specific distribution of TCF4 and identifying a feasible intervention window. The studies comprising this dissertation provide an important framework for future rational design of genetic normalization clinical treatments for PTHS.Doctor of Philosoph
Visual Deprivation Modifies Both Presynaptic Glutamate Release and the Composition of Perisynaptic/Extrasynaptic NMDA Receptors in Adult Visual Cortex
No full textUse-dependent modifications of synapses have been well described in the developing visual cortex, but the ability for experience to modify synapses in the adult visual cortex is poorly understood. We found that 10 d of late-onset visual deprivation modifies both presynaptic and postsynaptic elements at the layer 4-->2/3 connection in the visual cortex of adult mice, and these changes differ from those observed in juveniles. Although visual deprivation in juvenile mice modifies the subunit composition and increases the current duration of synaptic NMDA receptors (NMDARs), no such effect is observed at synapses between layer 4 and layer 2/3 pyramidal neurons in adult mice. Surprisingly, visual deprivation in adult mice enhances the temporal summation of NMDAR-mediated currents induced by bursts of high-frequency stimulation. The enhanced temporal summation of NMDAR-mediated currents in deprived cortex could not be explained by a reduction in the rate of synaptic depression, because our data indicate that late-onset visual deprivation actually increases the rate of synaptic depression. Biochemical and electrophysiological evidence instead suggest that the enhanced temporal summation in adult mice could be accounted for by a change in the molecular composition of NMDARs at perisynaptic/extrasynaptic sites. Our data demonstrate that the experience-dependent modifications observed in the adult visual cortex are different from those observed during development. These differences may help to explain the unique consequences of sensory deprivation on plasticity in the developing versus mature cortex
Astrocytic Gq-GPCR-Linked IP3R-Dependent Ca2+ Signaling Does Not Mediate Neurovascular Coupling in Mouse Visual Cortex in vivo
No full textLocal blood flow is modulated in response to changing patterns of neuronal activity (Roy and Sherrington, 1890), a process termed neurovascular coupling. It has been proposed that the central cellular pathway driving this process is astrocytic Gq-GPCR-linked IP3R-dependent Ca2+ signaling, though in vivo tests of this hypothesis are largely lacking. We examined the impact of astrocytic Gq-GPCR and IP3R-dependent Ca2+ signaling on cortical blood flow in awake, responsive mice using multiphoton laser-scanning microscopy and novel genetic tools that enable the selective manipulation of astrocytic signaling pathways in vivo. Selective stimulation of astrocytic Gq-GPCR cascades and downstream Ca2+ signaling with the hM3Dq DREADD designer receptor system was insufficient to modulate basal cortical blood flow. We found no evidence of observable astrocyte endfeet Ca2+ elevations following physiological visual stimulation despite robust dilations of adjacent arterioles using cyto-GCaMP3 and Lck-GCaMP6s, the most sensitive Ca2+ indicator available. Astrocytic Ca2+ elevations could be evoked when inducing the startle response with unexpected air puffs. However, startle-induced astrocytic Ca2+ signals did not precede corresponding startle-induced hemodynamic changes. Further, neurovascular coupling was intact in awake, responsive mice genetically lacking astrocytic IP3R-dependent Ca2+ signaling (IP3R2 KO). These data establish that astrocytic Gq-GPCR-linked IP3R-dependent Ca2+ signaling does not mediate neurovascular coupling in visual cortex of awake, responsive mice.Doctor of Philosoph
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