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BMJ Open Feb 2016To compare the acute effects of uninterrupted sitting with sitting interrupted by brief bouts of light-intensity walking on self-reported fatigue, cognition,... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To compare the acute effects of uninterrupted sitting with sitting interrupted by brief bouts of light-intensity walking on self-reported fatigue, cognition, neuroendocrine biomarkers and cardiometabolic risk markers in overweight/obese adults.
DESIGN
Randomised two-condition crossover trial.
SETTING
Laboratory study conducted in Melbourne, Australia.
PARTICIPANTS
19 overweight/obese adults (45-75 years).
INTERVENTIONS
After an initial 2 h period seated, participants consumed a meal-replacement beverage and completed (on 2 days separated by a 6-day washout period) each condition over the next 5 h: uninterrupted sitting (sedentary condition) or sitting with 3 min bouts of light-intensity walking every 30 min (active condition).
PRIMARY OUTCOME MEASURES
Self-reported fatigue, executive function and episodic memory at 0 h, 4 h and 7 h.
SECONDARY OUTCOME MEASURES
Neuroendocrine biomarkers and cardiometabolic risk markers (blood collections at 0 h, 4 h and 7 h, blood pressure and heart rate measured hourly and interstitial glucose measured using a continuous glucose monitoring system).
RESULTS
During the active condition, fatigue levels were lower at 4 h (-13.32 (95% CI -23.48 to -3.16)) and at 7 h (-10.73 (95% CI -20.89 to -0.58)) compared to the sedentary condition. Heart rate was higher at 4 h (4.47 (95% CI 8.37 to 0.58)) and at 7 h (4.32 (95% CI 8.21 to 0.42)) during the active condition compared to the sedentary condition. There were no significant differences between conditions by time for other variables. In the sedentary condition, changes in fatigue scores over time correlated with a decrease in heart rate and plasma dihydroxyphenylalanine (DOPA) and an increase in plasma dihydroxyphenylglycol (DHPG).
CONCLUSIONS
Interrupting prolonged sitting with light-intensity walking breaks may be an effective fatigue countermeasure acutely. Fatigue levels corresponded with the heart rate and neuroendocrine biomarker changes in uninterrupted sitting in this pilot study. Further research is needed to identify potential implications, particularly for the occupational health context.
TRIAL REGISTRATION NUMBER
ACTRN12613000137796; Results.
Topics: Aged; Blood Glucose; Blood Pressure; Cognition; Cross-Over Studies; Dihydroxyphenylalanine; Fatigue; Female; Heart Rate; Humans; Male; Methoxyhydroxyphenylglycol; Middle Aged; Obesity; Overweight; Pilot Projects; Sedentary Behavior; Walking
PubMed: 26920441
DOI: 10.1136/bmjopen-2015-009630 -
Journal of Neural Transplantation &... 1993Intravenous administration of 15O-labeled water and 6-[18F]-L-fluorodopa were used to assess abnormal striatal activity in monkeys after long-term recovery of unilateral...
Intravenous administration of 15O-labeled water and 6-[18F]-L-fluorodopa were used to assess abnormal striatal activity in monkeys after long-term recovery of unilateral lesions of the dopaminergic nigro-striatal system induced by the neurotoxin MPTP. PET data were examined in relation to behavioral and biological parameters. Cerebral blood flow and 6-[18F]-L-DOPA uptake were found to be significantly reduced in the lesioned striatum, compared to the unaffected side and to normal controls. There was no correlation between cerebral blood flow and any of the behavioral parameters. The uptake rate constant of 18F-DOPA from blood to striatum and the ratios of striatum to occipital areas were highly correlated to the concentrations of homovanillic acid in the cerebrospinal fluid of the same animals but not to the rotational behavior. This MPTP-induced model of striatal dopamine deficiency in primates presents similarities with idiopathic Parkinson's disease and may be used to evaluate the effects of dopaminergic lesions and transplants on brain function.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Basal Ganglia; Behavior, Animal; Carotid Artery, Internal; Cerebrovascular Circulation; Corpus Striatum; Dihydroxyphenylalanine; Dopamine; Homovanillic Acid; Hydroxyindoleacetic Acid; Injections, Intra-Arterial; MPTP Poisoning; Macaca mulatta; Male; Methoxyhydroxyphenylglycol; Occipital Lobe; Parkinson Disease, Secondary; Tomography, Emission-Computed
PubMed: 7509198
DOI: 10.1155/NP.1993.27 -
Hippocampal protein kinase D1 is necessary for DHPG-induced learning and memory impairments in rats.PloS One 2018Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation...
BACKGROUND
Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of (S)-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs. The knockdown of PKD1 does not affect the DHPG-induced inhibition of AMPA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs) but prevents the DHPG-induced inhibition of NMDAR-mediated mEPSCs in vitro. Thus, we investigated the in vivo effects of bilateral infusions of DHPG into the hippocampal CA1 area of rats in the Morris water maze (MWM) and the novel object discrimination (NOD) tests.
METHODS
A total of 300 adult male Sprague Dawley rats (250-280 g) were used for behavioral tests. One hundred ninety four were used in MWM test and the other 106 rats in the NOD test. Following one week of habituation to the vivarium, rats were bilaterally implanted under deep anesthesia with cannulas aimed at the CA1 area of the hippocampus (CA1 coordinates in mm from Bregma: AP -3.14; lateral +/-2; DV -3.0). Through implanted cannulas artificial cerebrospinal fluid (ACSF), the group1 mGluR antagonist 6-Methyl-2-(phenylethynyl)pyridine (MPEP), the dynamin-dependent internalization inhibitor Dynasore, or the PKD1 inhibitor CID755673 were infused into the bilateral hippocampal CA1 areas (2 μL per side, over 5 min). The effects of these infusions and the effects of PKD1 knockdown were examined in MWM or NOD test.
RESULTS
DHPG infusion increased the latency to reach the platform in the MWM test and reduced the preference for the novel object in the NOD task. We found that the DHPG effects were dose-dependent and could be maintained for up to 2 days. Notably, these effects could be prevented by pre-infusion of the group1 mGluR antagonist MPEP, the dynamin-dependent internalization inhibitor Dynasore, the PKD1 inhibitor CID755673, or by PKD1 knockdown in the hippocampal CA1 area.
CONCLUSION
Altogether, these findings provide direct evidence that PKD1-mediated signaling may play a critical role in the induction of learning and memory impairments by DHPG infusion into the hippocampal CA1 area.
Topics: Animals; CA1 Region, Hippocampal; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Knockout Techniques; Hippocampus; Learning; Learning Disabilities; Locomotion; Male; Maze Learning; Memory; Memory Disorders; Methoxyhydroxyphenylglycol; Protein Kinase C; Rats; Spatial Memory
PubMed: 29614089
DOI: 10.1371/journal.pone.0195095 -
The Journal of Neuroscience : the... May 2009The dendrites of a number of neuron types function as presynaptic structures, releasing transmitter after action potentials and dendritic spikes. In this regard,...
The dendrites of a number of neuron types function as presynaptic structures, releasing transmitter after action potentials and dendritic spikes. In this regard, dendrites can function like axons, producing discrete outputs after suprathreshold electrical events. However, as the major site of synaptic inputs, dendrites experience ongoing subthreshold fluctuations in membrane potential, raising the question of whether these subthreshold changes can cause changes in transmitter release. Here, we show that mitral cells of the accessory olfactory bulb release glutamate from their dendrites in response to both subthreshold and suprathreshold stimuli. Whereas subthreshold output was typically low under control conditions, it could be enhanced several fold by pharmacological or endogenous activation of group I metabotropic glutamate receptors. These results indicate that presynaptic dendrites can support two distinct forms of output, and can dynamically regulate how electrical activity is coupled to transmitter release.
Topics: Animals; Animals, Newborn; Bicuculline; Biophysics; Calcium; Dendrites; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Antagonists; GABA Antagonists; Glutamic Acid; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Membrane Potentials; Methoxyhydroxyphenylglycol; Mice; Olfactory Bulb; Patch-Clamp Techniques; Pyridazines; Receptors, Metabotropic Glutamate; Sensory Receptor Cells
PubMed: 19474329
DOI: 10.1523/JNEUROSCI.5606-08.2009 -
Neuron Dec 2007Endocannabinoids are well established as inhibitors of chemical synaptic transmission via presynaptic activation of the cannabinoid type 1 receptor (CB1R). Contrasting...
Endocannabinoids are well established as inhibitors of chemical synaptic transmission via presynaptic activation of the cannabinoid type 1 receptor (CB1R). Contrasting this notion, we show that dendritic release of endocannabinoids mediates potentiation of synaptic transmission at mixed (electrical and chemical) synaptic contacts on the goldfish Mauthner cell. Remarkably, the observed enhancement was not restricted to the glutamatergic component of the synaptic response but also included a parallel increase in electrical transmission. This effect involved the activation of CB1 receptors and was indirectly mediated via the release of dopamine from nearby varicosities, which in turn led to potentiation of the synaptic response via a cAMP-dependent protein kinase-mediated postsynaptic mechanism. Thus, endocannabinoid release can potentiate synaptic transmission, and its functional roles include the regulation of gap junction-mediated electrical synapses. Similar interactions between endocannabinoid and dopaminergic systems may be widespread and potentially relevant for the motor and rewarding effects of cannabis derivatives.
Topics: Analysis of Variance; Animals; Benzoxazines; Cannabinoid Receptor Modulators; Connexins; Cyclic AMP-Dependent Protein Kinases; Dopamine; Electric Stimulation; Endocannabinoids; Eye Proteins; Gap Junctions; Goldfish; Inhibitory Postsynaptic Potentials; Methoxyhydroxyphenylglycol; Morpholines; Naphthalenes; Neural Inhibition; Neurons; Patch-Clamp Techniques; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Metabotropic Glutamate; Rimonabant; Synapses; Synaptic Transmission; Tyrosine 3-Monooxygenase
PubMed: 18093525
DOI: 10.1016/j.neuron.2007.11.014 -
Journal of the American Society of... May 2014Calcitonin gene-related peptide (CGRP) is reported to play important roles in cardiovascular regulation in human and animal models. In spite of this, its role remains...
Calcitonin gene-related peptide (CGRP) is reported to play important roles in cardiovascular regulation in human and animal models. In spite of this, its role remains controversial. We aim to clarify this by studying the autonomic cardiovascular function and vascular structure in CGRP knockout (CGRP(-/-)) mice. Blood pressure (BP) and heart rate (HR) were assessed by telemeters. Urine (24-hour) and blood were collected for catecholamines measurements. Baroreflex sensitivity was assessed using phenylephrine and sodium nitroprusside administered in an acute study. Daytime mean arterial pressure (MAP; 12-hour period) was significantly higher in the CGRP(-/-) mice than in the wild type (WT) mice (114.5 vs. 104.5 mm Hg; P = .04). Norepinephrine was elevated in plasma and 24-hour urine in the knockouts (Urine, 956 vs. 618 pg/mL; P = .004; Plasma, 2505 vs. 1168 pg/mL; P = .04). Paradoxically, cardiovagal baroreflex sensitivity was higher in CGRP(-/-) mice (3.2 vs. 1.4 ms/mm Hg; P = .03). To increase insight, we studied aortic stiffness in CGRP(-/-) mice and found it increased compared with age-matched WT mice, as evidenced by the depression of the compliance curve (P < .05). CGRP(-/-) mice have higher BP due to elevated sympathetic signals and abnormalities in blood vessel structure. Moreover, our data also showed that CGRP plays an important role in the regulation of the cardio-vagal tone.
Topics: Animals; Baroreflex; Blood Pressure; Calcitonin Gene-Related Peptide; Epinephrine; Gene Deletion; Heart Rate; Male; Methoxyhydroxyphenylglycol; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Norepinephrine; Vascular Stiffness
PubMed: 24746612
DOI: 10.1016/j.jash.2014.03.001 -
Psychiatry Research Sep 2015Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA),...
Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major degradation products of the monoamines dopamine, serotonin and noradrenaline, respectively, and their concentrations in the cerebrospinal fluid (CSF), mainly HVA, have been associated with schizophrenia. In the present study, we hypothesized that CSF HVA, 5-HIAA and MHPG concentrations represent intermediate phenotypes in the association between glutamate-related genes and psychosis. To test this hypothesis, we searched for association between 238 single nucleotide polymorphisms (SNPs) in ten genes shown to be directly or indirectly implicated in glutamate transmission and CSF HVA, 5-HIAA and MHPG concentrations in 74 patients with psychotic disease. Thirty-eight nominally significant associations were found. Further analyses in 111 healthy controls showed that 87% of the nominal associations were restricted to the patients with psychosis. Some of the psychosis-only-associated SNPs found in the d-amino acid oxidase activator (DAOA) and the kynurenine 3-monooxygenase (KMO) genes have previously been reported to be associated with schizophrenia. The present results suggest that CSF monoamine metabolite concentrations may represent intermediate phenotypes in the association between glutamate-related genes and psychosis.
Topics: Adult; Biogenic Monoamines; Biomarkers; Dopamine; Female; Glutamic Acid; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Kynurenine 3-Monooxygenase; Male; Methoxyhydroxyphenylglycol; Norepinephrine; Phenotype; Polymorphism, Single Nucleotide; Psychotic Disorders; Serotonin
PubMed: 26142836
DOI: 10.1016/j.psychres.2015.06.023 -
Journal of Neurophysiology May 2009Fragile X syndrome (FXS) is the most common form of inherited mental retardation. The syndrome results from the absence of the fragile X mental retardation protein...
Fragile X syndrome (FXS) is the most common form of inherited mental retardation. The syndrome results from the absence of the fragile X mental retardation protein (FMRP), which is encoded by the fragile X mental retardation 1 (FMR1) gene. FMR1 and its two paralogs, fragile X-related genes 1 and 2 (FXR1 and -2), form the Fmr1 gene family. Here, we examined long-lasting synaptic plasticity in Fmr1 knockout, Fxr2 knockout, and Fmr1/Fxr2 double knockout mice. We found that metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in the hippocampus was affected in Fmr1 knockout, Fxr2 knockout, and Fmr1/Fxr2 double knockout mice at young ages (4-6 wk old). In addition, Fmr1/Fxr2 double knockout mice showed significant deficiencies relative to either Fmr1 or Fxr2 knockout mice in baseline synaptic transmission and short-term presynaptic plasticity, suggesting FMRP and FXR2P may contribute in a cooperative manner to pathways regulating presynaptic plasticity. However, compared with wild-type littermates, late-phase long-term potentiation (L-LTP) was unaltered in all knockout mice at 4-6 mo of age. Interestingly, although Fmr1/Fxr2 double knockout mice exhibited a more robust enhancement in mGluR-LTD compared with that in Fmr1 knockout mice, Fxr2 knockout mice exhibited reduced mGluR-LTD. Furthermore, unlike Fmr1 knockout mice, mGluR-LTD in Fxr2 knockout mice required new protein synthesis, whereas mGluR-LTD in Fmr1/Fxr2 double knockout mice was partially dependent on protein synthesis. These results indicated that both FMRP and FXR2P function in synaptic plasticity and that they likely operate in related but independent pathways.
Topics: Analysis of Variance; Animals; Anisomycin; Biophysics; Electric Stimulation; Excitatory Postsynaptic Potentials; Female; Fragile X Mental Retardation Protein; Hippocampus; In Vitro Techniques; Long-Term Potentiation; Male; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Pathways; Patch-Clamp Techniques; Protein Synthesis Inhibitors; RNA-Binding Proteins; Receptors, Metabotropic Glutamate; Synapses
PubMed: 19244359
DOI: 10.1152/jn.90558.2008 -
Journal of Neurophysiology Jul 1999G-protein coupled metabotropic glutamate receptors (mGluRs) are important modulators of synaptic transmission in the mammalian CNS and have been implicated in various...
G-protein coupled metabotropic glutamate receptors (mGluRs) are important modulators of synaptic transmission in the mammalian CNS and have been implicated in various forms of neuroplasticity and nervous system disorders. Increasing evidence also suggests an involvement of mGluRs in nociception and pain behavior although the contribution of individual mGluR subtypes is not yet clear. Subtypes mGluR1 and mGluR5 are classified as group I mGluRs and share the ability to stimulate phosphoinositide hydrolysis and activate protein kinase C. The present study examined the role of group I mGluRs in nociceptive processing and capsaicin-induced central sensitization of primate spinothalamic tract (STT) cells in vivo. In 10 anesthetized male monkeys (Macaca fascicularis) extracellular recordings were made from 20 STT cells in the lumbar dorsal horn. Responses to brief (15 s) cutaneous stimuli of innocuous (BRUSH) and barely and substantially noxious (PRESS and PINCH, respectively) intensity were recorded before, during, and after the infusion of group I mGluR agonists and antagonists into the dorsal horn by microdialysis. Cumulative concentration-response relationships were obtained by applying different concentrations for at least 20 min each (at 5 microl/min). The actual concentrations reached in the tissue are 2-3 orders of magnitude lower than those in the microdialysis fibers (values in this paper refer to the latter). The group I antagonists were also applied at 10-25 min after capsaicin injection. S-DHPG, a group I agonist at both mGluR1 and mGluR5, potentiated the responses to innocuous and noxious stimuli (BRUSH > PRESS > PINCH) at low concentrations (10-100 microM; n = 5) but had inhibitory effects at higher concentrations (1-10 mM; n = 5). The mGluR5 agonist CHPG (1 microM-100 mM; n = 5) did not potentiate but inhibited all responses (10-100 mM; n = 5). AIDA (1 microM-100 mM), a mGluR1-selective antagonist, dose-dependently depressed the responses to PINCH and PRESS but not to BRUSH (n = 6). The group I (mGluR1 > mGluR5) antagonist CPCCOEt (1 microM-100 mM) had similar effects (n = 6). Intradermal injections of capsaicin sensitized the STT cells to cutaneous mechanical stimuli. The enhancement of the responses by capsaicin resembled the potentiation by the group I mGluR agonist S-DHPG (BRUSH > PRESS > PINCH). CPCCOEt (1 mM) reversed the capsaicin-induced sensitization when given as posttreatment (n = 5). After washout of CPCCOEt, the sensitization resumed. Similarly, AIDA (1 mM; n = 7) reversed the capsaicin-induced sensitization and also blocked the potentiation by S-DHPG (n = 5). These data suggest that the mGluR1 subtype is activated endogenously during brief high-intensity cutaneous stimuli (PRESS, PINCH) and is critically involved in capsaicin-induced central sensitization.
Topics: Animals; Capsaicin; Chromones; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Infusions, Parenteral; Macaca fascicularis; Male; Methoxyhydroxyphenylglycol; Nerve Fibers; Neural Pathways; Nociceptors; Pain; Physical Stimulation; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Skin; Spinal Cord; Thalamus
PubMed: 10400956
DOI: 10.1152/jn.1999.82.1.272 -
Cell Reports Dec 2018A major mechanism contributing to synaptic plasticity involves alterations in the number of AMPA receptors (AMPARs) expressed at synapses. Hippocampal CA1 synapses,...
A major mechanism contributing to synaptic plasticity involves alterations in the number of AMPA receptors (AMPARs) expressed at synapses. Hippocampal CA1 synapses, where this process has been most extensively studied, are highly heterogeneous with respect to their probability of neurotransmitter release, P(r). It is unknown whether there is any relationship between the extent of plasticity-related AMPAR trafficking and the initial P(r) of a synapse. To address this question, we induced metabotropic glutamate receptor (mGluR) dependent long-term depression (mGluR-LTD) and assessed AMPAR trafficking and P(r) at individual synapses, using SEP-GluA2 and FM4-64, respectively. We found that either pharmacological or synaptic activation of mGluR1 reduced synaptic SEP-GluA2 in a manner that depends upon P(r); this process involved an activity-dependent reduction in surface mGluR1 that selectively protects high-P(r) synapses from synaptic weakening. Consequently, the extent of postsynaptic plasticity can be pre-tuned by presynaptic activity.
Topics: Animals; Cell Membrane; Dendritic Spines; Endocytosis; Glutamates; Long-Term Synaptic Depression; Male; Methoxyhydroxyphenylglycol; Neurotransmitter Agents; Probability; Protein Transport; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Metabotropic Glutamate; Synapses; Theta Rhythm
PubMed: 30590038
DOI: 10.1016/j.celrep.2018.12.010