BACKGROUND:Glutamate relays a reward signal from the dorsal raphe (DR) to the ventral tegmental area (VTA). However, the role of the different subtypes of N-methyl-D-aspartate (NMDA) receptors is complex and not clearly understood. Therefore, we measured NMDA receptors subunits expression in limbic brain areas. In addition, we studied the effects of VTA down-regulation of GluN2C NMDA receptor on the reward signal that arises from DR electrical stimulation.METHODS:Using qPCR, we identified the relative composition of the different Grin2a-d subunits of the NMDA receptors in several brain areas. Then, we used fluorescent in situ hybridization (FISH) to evaluate the colocalization of Grin2c and tyrosine hydroxylase (TH) mRNA in VTA neurons. To assess the role of GluN2C in brain stimulation reward, we downregulated this receptor using small interfering RNA (siRNA) in rats self-stimulating for electrical pulses delivered to the DR. To delineate further the specific role of GluN2C in relaying the reward signal, we pharmacologically altered the function of VTA NMDA receptors by bilaterally microinjecting the NMDA receptor antagonist PPPA.RESULTS:We identified GluN2C as the most abundant subunit of the NMDA receptor expressed in the VTA. FISH revealed that about 50% of TH-positive neurons colocalize with Grin2c transcript. siRNA manipulation produced a selective down-regulation of the GluN2C protein subunit and a significant reduction in brain stimulation reward. Interestingly, PPPA enhanced brain stimulation reward, but only in rats that received the nonactive RNA sequence.CONCLUSION:The present results suggest that VTA glutamate neurotransmission relays a reward signal initiated by DR stimulation by acting on GluN2C NMDA receptors.

In Parkinson’s disease (PD), motor dysfunctions only become apparent after extensive loss of DA innervation. This resilience has been hypothesized to be due to the ability of many motor behaviors to be sustained through a diffuse basal tone of DA; but experimental evidence for this is limited. Here we show that conditional deletion of the calcium sensor synaptotagmin-1 (Syt1) in DA neurons (Syt1 cKO DA mice) abrogates most activity-dependent axonal DA release in the striatum and mesencephalon, leaving somatodendritic (STD) DA release intact. Strikingly, Syt1 cKO DA mice showed intact performance in multiple unconditioned DA-dependent motor tasks and even in a task evaluating conditioned motivation for food. Considering that basal extracellular DA levels in the striatum were unchanged, our findings suggest that activity-dependent DA release is dispensable for such tasks and that they can be sustained by a basal tone of extracellular DA. Taken together, our findings reveal the striking resilience of DA-dependent motor functions in the context of a near-abolition of phasic DA release, shedding new light on why extensive loss of DA innervation is required to reveal motor dysfunctions in PD.

NR4A receptors, including NUR77 (NR4A1), NURR1 (NR4A2) and NOR-1 (NR4A3), form a family of nuclear receptors that act as transcription factors to regulate many physiological and pathological processes such as cell cycle and apoptosis, lipid metabolism, inflammation, carcinogenesis, vascular and neuronal functions. In the absence of known endogenous ligand modulating their physiological functions, the NR4A family remains a class of orphan receptors. However, several post-translational modifications (PTMs), including SUMOylation, have been shown to regulate the expression and/or activity of these receptors. Addition of Small Ubiquitin-like MOdifier (SUMO) proteins is a dynamic and reversible enzymatic process that regulates multiple essential functions of proteins, including nuclear receptors. This review aims at summarizing what is known about the impact of SUMOylation on NR4A family member transcriptional activities and physiological functions.

Neurotensin is an endogenous neuropeptide that acts as a potent modulator of ventral tegmental area (VTA) neurotransmission. The present study was aimed at determining VTA cell population and neurotensin receptor subtype responsible for the initiation of amphetamine‐induced psychomotor activity and extracellular signal‐regulated kinases (ERK1/2) sensitization. During an induction phase, rats were injected intra‐VTA on two occasions, every second day, with [D‐Tyr11]‐neurotensin (D‐Tyr‐NT), SR142948 (a mix Ntsr1/Ntsr2 receptor subtype antagonist), SR48692 (a Ntsr1 antagonist), D‐Tyr‐NT + SR142498, D‐Tyr‐NT + SR48692, or the vehicle. Effects of intra‐VTA drugs were evaluated at locomotor activity and ERK1/2 phosphorylation. Five days after the last VTA microinjection, the effect of a systemic injection of amphetamine was tested (sensitization test). Results show that D‐Tyr‐NT stimulated locomotor activity during the induction phase, an effect that was blocked by SR142948, but not SR48692. Amphetamine also induced significantly higher ambulatory activity in rats preinjected with D‐Tyr‐NT than in rats preinjected with the vehicle. This sensitization effect was again attenuated by SR142948, but not SR48692, hence suggesting that this effect is mediated by Ntsr2 receptors. To confirm this, we tested a highly selective Ntsr2 peptide–peptoid hybrid ligand, NT150. At the concentration tested, NT150 stimulated locomotor activity and lead to sensitized locomotor activity and a selective neurochemical (pERK1/2) response in tyrosine hydroxylase‐positive neurons of the VTA. Both effects were prevented by SR142948. Taken together, these results show that neurotensin, acting on Ntsr2 receptor subtypes, stimulates locomotor activity and initiates neural changes (ERK1/2 phosphorylation) that lead to amphetamine‐induced sensitization.

L-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay treatment for Parkinson's disease, but its effectiveness during early disease is marred by the eventual development of L-DOPA induced dyskinesia. In hemi-parkinsonian rats, the serotonin type 3 (5-HT3) antagonists ondansetron and granisetron alleviated dyskinesia induced by L- DOPA without impeding its anti-parkinsonian action; in parkinsonian marmosets, ondansetron alleviated dyskinesia and enhanced L-DOPA anti-parkinsonian action. Here, we sought to gain insight into the mechanisms governing the anti-dyskinetic action of 5-HT3 antagonists and measured 5-HT3 receptor levels across different brain, using [3H]GR65630 autoradiographic binding. Brain sections were chosen from 6-hydroxydopamine (6OHDA)-lesioned rats exhibiting abnormal involuntary movements (AIMs), as well as L-DOPA-naive 6-OHDA and sham-lesioned animals. [H-3]GR65630 binding increased in the ipsilateral subthalamic nucleus of 6-OHDAlesioned rats with mild and severe AIMs, (3-fold changes, P < 0.001). [3H]GR65630 binding also increased in the ipsilateral entopeduncular nucleus and thalamus of 6-OHDA-lesioned rats with severe AIMs (75 % and 88 %, P < 0.05). AIMs scores negatively correlated with [3H]GR65630 binding in the ipsilateral dorsolateral striatum and contralateral subthalamic nucleus (P < 0.05). These results suggest that alterations in 5-HT3 mediated neurotransmission may contribute to the pathophysiology of L-DOPA induced dyskinesia.

Antipsychotic treatment can produce a dopamine-supersensitive state, potentiating the response to dopamine receptor stimulation. In both schizophrenia patients and rats, this is linked to tolerance to ongoing antipsychotic treatment. In rodents, dopamine supersensitivity is often confirmed by an exaggerated psychomotor response to d-amphetamine after discontinuation of antipsychotic exposure. Here we examined in rats the dopaminergic mechanisms mediating this enhanced behavioural response, as this could uncover pathophysiological processes underlying the expression of antipsychotic-evoked dopamine supersensitivity. Rats received 0.5 mg/kg/day haloperidol via osmotic minipump for 2 weeks, before treatment was discontinued. After cessation of antipsychotic treatment, rats showed a supersensitive psychomotor response to the D2 agonist quinpirole, but not to the D1 partial agonist SKF38393 or the dopamine reuptake blocker GBR12783. Furthermore, acute D1 receptor blockade (using SCH39166) decreased the exaggerated psychomotor response to d-amphetamine in haloperidol-pretreated rats, whereas acute D2 receptor blockade (using sulpiride) enhanced it. Thus, after discontinuation of antipsychotic treatment, D1- and D2-mediated transmission differentially modulate the expression of a supersensitive response to d-amphetamine. This supersensitive behavioural response was accompanied by enhanced GSK3β activity and suppressed ERK1/2 activity in the nucleus accumbens (but not caudate-putamen), suggesting increased mesolimbic D2 transmission. Finally, after discontinuing haloperidol treatment, neither increasing ventral midbrain dopamine impulse flow nor infusing d-amphetamine into the cerebral ventricles triggered the expression of already established dopamine supersensitivity, suggesting that peripheral effects are required. Thus, while dopamine receptor-mediated signalling regulates the expression of antipsychotic-evoked dopamine supersensitivity, a simple increase in central dopamine neurotransmission is insufficient to trigger this supersensitivity.

Nur77 (NGFI-B) is a nuclear receptor that belongs to the Nr4a family of orphan nuclear receptors (Nr4a1). This transcription factor has been implicated in the regulation of multiple functions, such as cell cycle regulation, apoptosis, inflammation, glucose and lipid metabolism, and brain function. However, the mechanisms involved in its different regulatory properties remain unclear. In search for regulatory mechanisms of Nur77 function, we identified that Protein Inhibitor of Activated STAT gamma (PIASγ), an E3 SUMO-protein ligase, potently repressed Nur77 transcriptional activity in HEK-293T cells. This PIASγ activity was sensitive to Sentrin SUMO-specific protease 1 (SENP1). Substitution of two putative phylogenetically well-conserved small ubiquitin-like modifier (SUMO) acceptor sites, lysine 102 (K102) and 577 (K577) by arginine residues (R) modulated Nur77 transcriptional activity. In particular, Nur77-K102R and Nur77-K102R/K577R mutants strongly decreased the transcriptional activity of Nur77, whereas single K577R substitution increased transcriptional activity of Nur77. Repression of Nur77 transcriptional activity by SUMO2 and PIASγ was reduced by the K577R mutation, whereas the K102R mutant remained insensitive to SUMO2. Interestingly, the roles of these SUMO acceptor sites in Nur77 are distinct from previously observed activities on its close homolog Nurr1. Thus, the present study identified SUMO2 and PIASγ as important transcriptional co-regulators of Nur77.

The National Research Council of Canada has developed a novel ultrasound based Rock Bolt Sensor (RBS™) to monitor load, deformation, and integrity of rock bolts.Several RBSs were deployed to monitor bolts in the roof of an intersection of two drifts and with another region of monitoring tens of metres away in the roof of the drift.The intersection spanned two rock types with different stiffness characteristics.The region was also covered by an extensive seismic system with a mixture of triaxial geophones and both triaxial and uniaxial accelerometers.Using three weeks of recorded data, the loading on 12 bolts was monitored during the production of several nearby stopes and analysed alongside the recorded seismicity.A significant increase in loading on the bolts in the roof was recorded when production occurred within 40 m of the instrumented intersection despite several other stopes producing more significant seismicity following blasting.The load was also taken up asymmetrically, with more substantial changes in load occurring in the bolts in the greywacke.During the study period, several large seismic events occurred within 500 m of the study area.Seismic moment tensor analysis was conducted on several of the seismic events to estimate the mechanism of failure and, using seismic stress inversion, the orientation of the observed fractures was estimated and the directions of principal stress.There was a strong increase in the load on the bolts located in the intersection, across the two different formations, several hours after a large seismic event occurred on that contact several hundred metres away.This work showed a connection between loading on the bolt and large changes in the local stress field due to nearby production and significant seismicity along structures in the region.In addition to monitoring the loading of the rock bolts, the Rock Bolt Sensor can be utilised to better understand the coseismic and post-seismic deformation within the mine and improve models of the local stress field.

The rostromedial tegmental nucleus also referred to as the tail of the ventral tegmental area (tVTA) contains a cluster of gamma-aminobutyric acid (GABA)ergic neurons that receive dense glutamatergic afferents from the lateral habenula (LHb), and project to dopamine (DA) neurons of the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). In light of previous evidence implicating glutamate transmission in the regulation of midbrain DA neuronal activity, we first assessed the impact of intra-tVTA microinjection of NBQX (0.8 nmol/side) and PPPA (0.825 nmol/side), respectively AMPA and NMDA receptor antagonists, on reward induced by intracranial self-stimulation (ICSS) and on locomotor activity. Since the tVTA contains a large concentration of mu opioid receptors, additional measures were obtained following microinjection of endomorphin-1 (EM-1, 1 nmol/side) to confirm tVTA placements. Then, using small interfering RNAs (siRNAs), we tested the effect of tVTA downregulation of the GluN1 subunit of the NMDA receptor on reward and locomotor activity. Results show that NBQX, PPPA and EM-1 all enhance reward and locomotor activity, effects that were of different magnitude in rostral and intermediate parts of the tVTA. On the other hand, a reduction in GluN1 subunits used a marked decrease in operant responding for ICSS, but failed to alter ICSS reward and the reward-enhancing effect of PPPA. Our results support a role for the tVTA as a main inhibitory component of DA-dependent behavioral measures, and suggest that tVTA NMDA receptors that modulate reward are most likely expressed on tVTA afferent terminals.

The hot deformation and subsequent annealing of two C-Mn steels have been investigated using a Gleeble 3500 simulator. The flow stress during deformation and subsequent relaxation stress were recorded. The grain size evolution was simultaneously evaluated by the in-situ laser-ultrasonic (LUS) measurements. The LUS data allowed clear identification of the dominant annealing phenomena. Excellent correlation was obtained between stress relaxation and laser-ultrasonic data, which provided additional confidence in the identification of the processes taking place. The solute drag effect of niobium led to the delayed onset and completion of recrystallization. Lower temperature generally slowed down the kinetics. Robust models combining deformation, recovery, recrystallization and grain growth have been developed and validated against the experimental data. The onset of recrystallization can be predicted precisely, as well as the time for recrystallization completion. As can be seen, the models are in good agreements with both the mechanical (stress evolution) and grain-size (laser-ultrasonic) data.

The effect of levodopa in alleviating the symptoms of Parkinson's disease is altered in a highly nonlinear manner as the disease progresses. This can be attributed to different compensation mechanisms taking place in the basal ganglia where the dopaminergic neurons are progressively lost. This alteration in the effect of levodopa complicates the optimization of a drug regimen. The present work aims at investigating the nonlinear dynamics of Parkinson's disease and its therapy through mechanistic mathematical modeling. Using a holistic approach, a pharmacokinetic model of levodopa was combined to a dopamine dynamics and a neurocomputational model of basal ganglia. The influence of neuronal death on these different mechanisms was also integrated. Using this model, we were able to investigate the nonlinear relationships between the levodopa plasma concentration, the dopamine brain concentration, and a response to a motor task. Variations in dopamine concentrations in the brain for different levodopa doses were also studied. Finally, we investigated the narrowing of a levodopa therapeutic index with the progression of the disease as a result of these nonlinearities. In conclusion, various consequences of nonlinear dynamics in Parkinson's disease treatment were studied by developing an integrative model. This model paves the way toward individualization of a dosing regimen. Using sensor based information, the parameters of the model could be fitted to individual data to propose optimal individual regimens.

Despite high hopes and expectations that modern antipsychotic drug therapy would finally come to grips with tardive dyskinesia (TD) and pave the way for its burial, this potentially irreversible complication remained a fearsome and challenging issue, particularly in older age groups. Long-term prevalence rates >20% are still reported even in patients never exposed to firstgeneration drugs. The gospel of TD has taught generations that striatal dopamine D2 receptors become supersensitive during antipsychotic drug treatment. In the interval, the body of research supporting this hypothesis in human TD has remained deceptively thin, only to promote the development of novel antipsychotic drugs lacking robust affinity and selectivity for D2 receptors supposed to avoid TD. Evidently, this has not panned out yet. Unfortunately, drug management of moderate-to-severe TD remains limited, attributable, in large part, to knowledge gaps in pathophysiology. Alleviation of TD scores afforded by vesicular monoamine transporter type 2 (VMAT2) blockade with tetrabenazine, deutetrabenazine, and valbenazine proved their clinical relevance and supported two basic points in TD: (1) relative integrity of VMAT2 function and (2) implication of dopamine signaling. The proportion of responders’ rate (≥50% reduction in baseline TD scores on the Abnormal Involuntary Movements Scale) <50% with these drugs is a good indicator of the challenge awaiting clinicians managing TD. In this brief article, we present recent molecular findings indirectly suggesting the presence of enhanced striatal dopamine signaling in TD beyond D2 receptors and wish to call out researchers and clinicians in considering new dopaminergic and nondopaminergic targets to improve management through modulation of glycogen synthase kinase (GSK)-3 activity.

In most of today’s underground mines, ground support monitoring is mainly conducted through using microseismic sensors, LiDAR, extensometers, cameras, or visual inspection. These monitoring tools are complementary in nature. Due to high costs associated with purchase, installation, maintenance and utilisation, they are usually deployed or used at sparsely selected critical locations, some of them on a noncontinuous basis. This means that some important pieces of information on ground support conditions may be missing either location-wise or time-wise. In the last four years, the Energy, Mining and Environment Research Centre of the National Research Council Canada (NRC), in collaboration with CanmetMINING of Natural Resources Canada (NRCan), has developed next generation ultrasound rockbolt sensors (RBSTM) for monitoring load change and deformation experienced by rockbolts. Intrinsically low costing and installation onto exposed end of rockbolts using production bolters, the technology is meant to be deployed on a large number of rockbolts whereby the instrumented rockbolts become a network of ground condition sensors to provide on-demand 3D mapping of ground stress change and deformation all over excavated zones. Field trial data collected in a production mine has demonstrated that monitoring a cluster of rockbolts can provide much more meaningful and reliable information about ground condition when compared with information provided by a single instrumented rockbolt. Therefore, monitoring clusters of rockbolts is recommended as being an effective practice for ground support monitoring.

Cold spray is a solid state coating technology with high deposition rates that is very suitable for large scale applications of additive manufacturing (AM). For quality control of complex parts, laser ultrasonics is particularly attractive due to its non-contact nature and is well adapted to online implementation. In this study, various inspection results performed off-line on metallic parts produced by the cold spray AM process are presented. Laser ultrasonics combined with the synthetic aperture focusing technique (SAFT) is used to detect flaws and through-thickness distributed porosity is investigated using the laser-ultrasonic backscattered signal. Also, laser shockwave is used to characterize bond strength at the interface between the deposition and the substrate. For post heat treatment of cold spray AM metallic parts, laser ultrasonics is used to monitor in real time recrystallization and sintering. Inspection results from either the top layer or the underside of the substrate are reported and discussed.

The detection and monitoring of oil spills in marine environment are crucial to respond rapidly and efficiently and it is especially important in ice-covered areas. Detection and quantitative characterization of the affected areas as well as monitoring of remediation measures are critical for optimized cleaning operation and minimal environment impact. In the recent years, techniques of oil spill detection from under the ice with Remote Operated Vehicle (ROV) or Autonomous Underwater Vehicle (AUV), have been explored and have shown promising results. These techniques are based on ultrasonic or sonar technologies to quantify the oil volume and on optical techniques to obtain a chemical signature of the oil presence. In this paper we present a new promising technique based on photoacoustics for detection and sizing of oil spill under the ice, encapsulated within ice, or on open water. The technique has the advantage to provide signal in the presence of oil and no signal in its absence. It is also much less sensitive to alignment compared to ultrasonic and sonar techniques. Experimental results on detection of oil under the ice are presented and discussed. A first prototype with a scanning unit that can be operated in ROV is also presented. The solution proposed should be especially useful as a tool for emergency response, but should also be suitable when operated in AUV for monitoring high risky areas due to navigation, transportation or oil exploration and production.

Tardive dyskinesia is a delayed and potentially irreversible motor complication arising from chronic exposure to antipsychotic drugs. Interaction of antipsychotic drugs with G protein‐coupled receptors triggers multiple intracellular events. Nevertheless, signaling pathways that might be associated with chronic unwanted effects of antipsychotic drugs remain elusive. In this study, we aimed to better understand kinase signaling associated with the expression of tardive dyskinesia in nonhuman primates.

The U.S. National Nuclear Security Administration Material Management and Minimization (M3) program is enabling the transformation of research and test reactors to Low Enriched Uranium (LEU) fuels using reactor safety analysis and new fuel designs. The M3 program has developed LEU based alternative fuels that will enable reactors to continue their missions while operating safely and cost effectively. A salient performance factor of the fuel plate is the bond strength of the fuel foil (including the Zr interlayer) to the Al substrate. The laser shock technique will be used to provide interface strength feedback for fabrication process development and to understand the effects of reactor irradiation. This paper focuses on modifying a laser shock system built for laboratory use. The resulting system designed for installation in a nuclear hot cell uses only optical fibers without polarization elements as the salient delivery and collection of signal light. The laser shock (LS) system based on fiber optics is more practical for the rigors and remote operation requirements in a nuclear hot cell. This paper will also discuss the bond strength results from round robin testing obtained in the laboratory comparing the LS laboratory and hot cell systems.

As part of the U.S. High Performance Research Reactor program, a laser shock test system is being developed by the Idaho National Laboratory (INL) to characterize interface strength in innovative plate fuel for research reactors around the world. The INL has been working with National Research Council Canada (NRC) on this project for the last five years. One of the concerns is the difficulty of calibrating and standardizing the laser shock technique. A recent analytical study and testing support the use of the Hugoniot Elastic Limit (HEL) in materials as a robust and simple benchmark to compare stresses generated by different laser shock systems. Using a non-contact laser velocimeter based on a solid Fabry-Perot etalon, the systems at NRC and INL show that the back-surface velocity reached at the HEL is consistent, and independent of the laser power used. In this work, the laser velocimeter of the NRC system is tested against a fast rotating wheel to verify accuracy and determine best operating conditions. A round robin test between the two laser shock systems on plates of different aluminum alloys is presented that shows the consistent characterization of the aluminum alloys based on the HEL velocities as well as determines the bias between the systems. The effects of setup parameters on other characteristics of the back-surface velocity trace and corresponding stress wave are also discussed.