Differential regulation of NMDA receptors by D-serine and glycine in mammalian spinal locomotor networks

This work was supported by an Institutional Strategic Support Fund grant from the Wellcome Trust.Activation of N-methyl-d-aspartate receptors (NMDARs) requires the binding of a coagonist, either d-serine or glycine, in addition to glutamate. Changes in occupancy of the coagonist binding site are proposed to modulate neural networks including those controlling swimming in frog tadpoles. Here, we characterize regulation of the NMDAR coagonist binding site in mammalian spinal locomotor networks. Blockade of NMDARs by d(−)-2-amino-5-phosphonopentanoic acid (d-APV) or 5,7-dichlorokynurenic acid reduced the frequency and amplitude of pharmacologically induced locomotor-related activity recorded from the ventral roots of spinal-cord preparations from neonatal mice. Furthermore, d-APV abolished synchronous activity induced by blockade of inhibitory transmission. These results demonstrate an important role for NMDARs in murine locomotor networks. Bath-applied d-serine enhanced the frequency of locomotor-related but not disinhibited bursting, indicating that coagonist binding sites are saturated during the latter but not the former mode of activity. Depletion of endogenous d-serine by d-amino acid oxidase or the serine-racemase inhibitor erythro-β-hydroxy-l-aspartic acid (HOAsp) increased the frequency of locomotor-related activity, whereas application of l-serine to enhance endogenous d-serine synthesis reduced burst frequency, suggesting a requirement for d-serine at a subset of synapses onto inhibitory interneurons. Consistent with this, HOAsp was ineffective during disinhibited activity. Bath-applied glycine (1–100 µM) failed to alter locomotor-related activity, whereas ALX 5407, a selective inhibitor of glycine transporter-1 (GlyT1), enhanced burst frequency, supporting a role for GlyT1 in NMDAR regulation. Together these findings indicate activity-dependent and synapse-specific regulation of the coagonist binding site within spinal locomotor networks, illustrating the importance of NMDAR regulation in shaping motor output.Publisher PDFPeer reviewe

Influence of front-of-package nutrition labels on beverage healthiness perceptions: Results from a randomized experiment

The final publication is available at Elsevier via https://dx.doi.org/10.1016/j.ypmed.2018.08.022 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/The current study explored the influence of three summary indicator front-of-pack (FOP) nutrition labels on consumer perceptions of the healthiness of different beverage products. In 2016, a total of 675 respondents in southwestern Ontario aged 16 and over viewed images of soda, unflavoured milk and chocolate milk displaying one of four FOP label conditions (no FOP label, numeric rating, health star rating (HSR), or simplified traffic light (STL)), and rated the products' healthiness. Participants also indicated their preference for summary indicator versus nutrient-specific FOP labels. Logistic regression models comparing correct responses across label conditions found no differences across label conditions for unflavoured milk or soda. Consumers in the HSR and STL conditions were more likely to correctly perceive a chocolate milk beverage as ‘moderately healthy’ (p = 0.004, p = 0.016). No differences in responses were identified across sociodemographic groups. Most respondents (93%) indicated that they would like to see a health rating or nutrient-specific information on the front of food products. Results of this study suggest that the influence of FOP labels may vary based on the nutritional quality of food products, and may have the greatest influence on consumer perceptions of ‘nutritionally ambiguous’ foods. Consumers indicated almost unanimous support for implementing FOP nutrition labelling systems.Public Health Agency of CanadaCanadian Institutes of Health ResearchQueen Elizabeth II Graduate Scholarship in Science and Technolog

Influence of front-of-package nutrition labels on beverage healthiness perceptions: Results from a randomized experiment

The final publication is available at Elsevier via https://dx.doi.org/10.1016/j.ypmed.2018.08.022 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/The current study explored the influence of three summary indicator front-of-pack (FOP) nutrition labels on consumer perceptions of the healthiness of different beverage products. In 2016, a total of 675 respondents in southwestern Ontario aged 16 and over viewed images of soda, unflavoured milk and chocolate milk displaying one of four FOP label conditions (no FOP label, numeric rating, health star rating (HSR), or simplified traffic light (STL)), and rated the products' healthiness. Participants also indicated their preference for summary indicator versus nutrient-specific FOP labels. Logistic regression models comparing correct responses across label conditions found no differences across label conditions for unflavoured milk or soda. Consumers in the HSR and STL conditions were more likely to correctly perceive a chocolate milk beverage as ‘moderately healthy’ (p = 0.004, p = 0.016). No differences in responses were identified across sociodemographic groups. Most respondents (93%) indicated that they would like to see a health rating or nutrient-specific information on the front of food products. Results of this study suggest that the influence of FOP labels may vary based on the nutritional quality of food products, and may have the greatest influence on consumer perceptions of ‘nutritionally ambiguous’ foods. Consumers indicated almost unanimous support for implementing FOP nutrition labelling systems.Public Health Agency of CanadaCanadian Institutes of Health ResearchQueen Elizabeth II Graduate Scholarship in Science and Technolog

Regulation of mammalian spinal locomotor networks by glial cells

Networks of interneurons within the spinal cord coordinate the rhythmic activation of muscles during locomotion. These networks are subject to extensive neuromodulation, ensuring appropriate behavioural output. Astrocytes are proposed to detect neuronal activity via Gαq-linked G-protein coupled receptors and to secrete neuromodulators in response. However, there is currently a paucity of evidence that astrocytic information processing of this kind is important in behaviour. Here, it is shown that protease-activated receptor-1 (PAR1), a Gαq-linked receptor, is preferentially expressed by glia in the spinal cords of postnatal mice. During ongoing locomotor-related network activity in isolated spinal cords, PAR1 activation stimulates release of adenosine triphosphate (ATP), which is hydrolysed to adenosine extracellularly. Adenosine then activates A1 receptors to reduce the frequency of locomotor-related bursting recorded from ventral roots. This entails inhibition of D1 dopamine receptors, activation of which enhances burst frequency. The effect of A1 blockade scales with network activity, consistent with activity-dependent production of adenosine by glia. Astrocytes also regulate activity by controlling the availability of D-serine or glycine, both of which act as co-agonists of glutamate at N-methyl-D-aspartate receptors (NMDARs). The importance of NMDAR regulation for locomotor-related activity is demonstrated by blockade of NMDARs, which reduces burst frequency and amplitude. Bath-applied D-serine increases the frequency of locomotor-related bursting but not intense synchronous bursting produced by blockade of inhibitory transmission, implying activity-dependent regulation of co-agonist availability. Depletion of endogenous D-serine increases the frequency of locomotor-related but not synchronous bursting, indicating that D-serine is required at a subset of NMDARs expressed by inhibitory interneurons. Blockade of the astrocytic glycine transporter GlyT1 increases the frequency of locomotor-related activity, but application of glycine has no effect, indicating that GlyT1 regulates glycine at excitatory synapses. These results indicate that glia play an important role in regulating the output of spinal locomotor networks

Probabilistic Standards of Proof, Their Complements and the Errors that that are Expected to Flow from Them

Probability theory provides insights into the levels at which standards of proof are set. An analysis is provided of the rates of errors that flow from different standards, a necessary element of which is an assumption as to the level of certainty achieved in the flow of cases. Where one party is required to satisfy a standard of proof, a complementary standard is imposed on the other party

The impact of price and nutrition labelling on sugary drink purchases: Results from an experimental marketplace study

The final publication is available at Elsevier via http://dx.doi.org/10.1016/j.appet.2017.11.089 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/To examine the effect of front-of-package (FOP) nutrition labelling and sugary drink taxation on consumer beverage purchases. A total of 675 respondents aged 16 years and older participated in an experimental marketplace study using a 4 × 5 within-between group design. Participants were randomised to one of four labelling conditions (no label; star rating; high sugar symbol; health warning) and completed five within-subject purchase tasks. Beverage prices in each task corresponded to ‘tax’ conditions: 0%, 10%, 20%, 30% and a variable tax proportional to free sugar level. In each task, participants selected from 20 commercially available beverages; upon conclusion, one of five selections was randomly chosen for purchase. As price increased, participants were significantly less likely to select a sugary drink, and selected drinks with fewer calories and less free sugar (p < 0.001 for all). The overall effect of labelling was not statistically significant, although there was a trend for the ‘high sugar’ label to reduce the likelihood of selecting a sugary drink (p = 0.11) and encouraging participants to select drinks with less free sugar (p = 0.11). Increasing price was associated with reduced sugary drink purchases. Enhanced FOP labelling results highlight the need for further research to investigate their potential impact. The study adds empirical support for taxation to reduce sugary drink consumption.his study was supported by a Chair in Applied Public Health funded by the Public Health Agency of Canada (PHAC) in partnership with the Canadian Institutes of Health Research (CIHR)

Gliotransmission and adenosinergic modulation : insights from mammalian spinal motor networks

D Acton was supported by funds from a Wellcome Trust Institutional Strategic Support Fund grant. GBM received support from Biotechnology and Biological Science Research Grant BB/M021793/1.Astrocytes are proposed to converse with neurons at tripartite synapses, detecting neurotransmitter release and responding with release of gliotransmitters, which in turn modulate synaptic strength and neuronal excitability. However, a paucity of evidence from behavioral studies calls into question the importance of gliotransmission for the operation of the nervous system in healthy animals. Central pattern generator (CPG) networks in the spinal cord and brainstem coordinate the activation of muscles during stereotyped activities such as locomotion, inspiration and mastication, and may therefore provide tractable models in which to assess the contribution of gliotransmission to behaviorally relevant neural activity. Here, we review evidence for gliotransmission within spinal locomotor networks, including studies indicating that adenosine derived from astrocytes regulates the speed of locomotor activity via metamodulation of dopamine signaling.PostprintPeer reviewe

Prevalence of iron deficiency in 62,685 women of seven race/ethnicity groups: The HEIRS Study.

BackgroundFew cross-sectional studies report iron deficiency (ID) prevalence in women of different race/ethnicity and ages in US or Canada.Materials and methodsWe evaluated screening observations on women who participated between 2001-2003 in a cross-sectional, primary care-based sample of adults ages ≥25 y whose observations were complete: race/ethnicity; age; transferrin saturation; serum ferritin; and HFE p.C282Y and p.H63D alleles. We defined ID using a stringent criterion: combined transferrin saturation &lt;10% and serum ferritin &lt;33.7 pmol/L (&lt;15 μg/L). We compared ID prevalence in women of different race/ethnicity subgrouped by age and determined associations of p.C282Y and p.H63D to ID overall, and to ID in women ages 25-44 y with or without self-reported pregnancy.ResultsThese 62,685 women included 27,079 whites, 17,272 blacks, 8,566 Hispanics, 7,615 Asians, 449 Pacific Islanders, 441 Native Americans, and 1,263 participants of other race/ethnicity. Proportions of women with ID were higher in Hispanics and blacks than whites and Asians. Prevalence of ID was significantly greater in women ages 25-54 y of all race/ethnicity groups than women ages ≥55 y of corresponding race/ethnicity. In women ages ≥55 y, ID prevalence did not differ significantly across race/ethnicity. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy.ConclusionsID prevalence was greater in Hispanic and black than white and Asian women ages 25-54 y. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy

Modulation of spinal motor networks by astrocyte-derived adenosine is dependent on D1-like dopamine receptor signalling

D.A. was supported by funds from a Wellcome Trust Institutional Strategic Support Fund grant. G.B.M. and M.J.B. received support from Biotechnology and Biological Science Research Grant BB/M021793/1.Astrocytes modulate many neuronal networks, including spinal networks responsible for the generation of locomotor behavior. Astrocytic modulation of spinal motor circuits involves release of ATP from astrocytes, hydrolysis of ATP to adenosine, and subsequent activation of neuronal A1 adenosine receptors (A1Rs). The net effect of this pathway is a reduction in the frequency of locomotor-related activity. Recently, it was proposed that A1Rs modulate burst frequency by blocking the D1-like dopamine receptor (D1LR) signaling pathway; however, adenosine also modulates ventral horn circuits by dopamine-independent pathways. Here, we demonstrate that adenosine produced upon astrocytic stimulation modulates locomotor-related activity by counteracting the excitatory effects of D1LR signaling and does not act by previously described dopamine-independent pathways. In spinal cord preparations from postnatal mice, a D1LR agonist, SKF 38393, increased the frequency of locomotor-related bursting induced by 5-hydroxytryptamine and N-methyl-d-aspartate. Bath-applied adenosine reduced burst frequency only in the presence of SKF 38393, as did adenosine produced after activation of protease-activated receptor-1 to stimulate astrocytes. Furthermore, the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine enhanced burst frequency only in the presence of SKF 38393, indicating that endogenous adenosine produced by astrocytes during network activity also acts by modulating D1LR signaling. Finally, modulation of bursting by adenosine released upon stimulation of astrocytes was blocked by protein kinase inhibitor-(14–22) amide, a protein kinase A (PKA) inhibitor, consistent with A1R-mediated antagonism of the D1LR/adenylyl cyclase/PKA pathway. Together, these findings support a novel, astrocytic mechanism of metamodulation within the mammalian spinal cord, highlighting the complexity of the molecular interactions that specify motor output.Publisher PDFPeer reviewe