Neuroadaptations in the Cellular and Postsynaptic Group 1 Metabotropic Glutamate Receptor mGluR5 and Homer Proteins Following Extinction of Cocaine Self-administration

This study examined the role of group1 metabotropic glutamate receptor mGluR5 and associated postsynaptic scaffolding protein Homer1b/c in behavioral plasticity after three withdrawal treatments from cocaine self-administration. Rats self-administered cocaine or saline for 14 days followed by a withdrawal period during which rats underwent extinction training, remained in their home cages, orwere placed in the self-administration chambers in the absence of extinction. Subsequently, the tissue level and distribution of proteins in the synaptosomal fraction associated with the postsynaptic densitywere examined. Cocaine self-administration followed by home cage exposure reduced the mGluR5 protein in nucleus accumbens (NA) shell and dorsolateral striatum. While extinction training reduced mGluR5 protein in NAshell, NAcore and dorsolateral striatum did not display any change. The scaffolding protein PSD95 increased in NAcore of the extinguished animals. Extinction of drug seeking was associated with a significant decrease in the synaptosomal mGluR5 protein in NAshell and an increase in dorsolateral striatum, while that of NAcore was not modified. Interestingly, both Homer1b/c and PSD95 scaffolding proteins were decreased in the synaptosomal fraction after extinction training in NAshell but not NAcore. Extinguished drug-seeking behavior was also associated with an increase in the synaptosomal actin proteins in dorsolateral striatum. Therefore, extinction of cocaine seeking is associated with neuroadaptations in mGluR5 expression and distribution that are region-specific and consist of extinction-induced reversal of cocaine-induced adaptations aswell as emergent extinction-induced alterations. Concurrent plasticity in the scaffolding proteins further suggests that mGluR5 receptor neuroadaptations may have implications for synaptic function

Augmented Cocaine Seeking in Response to Stress or CRF Delivered into the Ventral Tegmental Area Following Long-Access Self-Administration Is Mediated by CRF Receptor Type 1 But Not CRF Receptor Type 2

Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 h daily) conditions for 14 d when compared with rats provided shorter daily cocaine access [short access (ShA) rats; 2 h daily]. Further, we have demonstrated that reinstatement in response to intracerebroventricular CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress-induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-receptor type 1 (CRF-R1) antagonist antalarmin (500 ng/side) or CP-376395 (500 ng/side), but not the CRF-R2 antagonist astressin-2B (500 ng or 1 μg/side) or antisauvagine-30(ASV-30; 500 ng/side) into the VTA. Likewise, intra-VTA antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1-selective agonist cortagine (100 ng/side) but not the CRF-R2-selective agonist rat urocortin II (rUCN II; 250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1-dependent regulation of addiction-related neurocircuitry in the VTA

Open-Loop Flight Testing of COBALT GN&C Technologies for Precise Soft Landing

A terrestrial, open-loop (OL) flight test campaign of the NASA COBALT (CoOperative Blending of Autonomous Landing Technologies) platform was conducted onboard the Masten Xodiac suborbital rocket testbed, with support through the NASA Advanced Exploration Systems (AES), Game Changing Development (GCD), and Flight Opportunities (FO) Programs. The COBALT platform integrates NASA Guidance, Navigation and Control (GN&C) sensing technologies for autonomous, precise soft landing, including the Navigation Doppler Lidar (NDL) velocity and range sensor and the Lander Vision System (LVS) Terrain Relative Navigation (TRN) system. A specialized navigation filter running onboard COBALT fuzes the NDL and LVS data in real time to produce a precise navigation solution that is independent of the Global Positioning System (GPS) and suitable for future, autonomous planetary landing systems. The OL campaign tested COBALT as a passive payload, with COBALT data collection and filter execution, but with the Xodiac vehicle Guidance and Control (G&C) loops closed on a Masten GPS-based navigation solution. The OL test was performed as a risk reduction activity in preparation for an upcoming 2017 closed-loop (CL) flight campaign in which Xodiac G&C will act on the COBALT navigation solution and the GPS-based navigation will serve only as a backup monitor

COBALT CoOperative Blending of Autonomous Landing Technology

COBALT is a terrestrial test platform for development and maturation of GN&C (Guidance, Navigation and Control) technologies for PL&HA (Precision Landing and Hazard Avoidance). The project is developing a third generation, Langley Navigation Doppler Lidar (NDL) for ultra-precise velocity and range measurements, which will be integrated and tested with the JPL Lander Vision System (LVS) for Terrain Relative Navigation (TRN) position estimates. These technologies together provide navigation that enables controlled precision landing. The COBALT hardware will be integrated in 2017 into the GN&C subsystem of the Xodiac rocket-propulsive Vertical Test Bed (VTB) developed by Masten Space Systems (MSS), and two terrestrial flight campaigns will be conducted: one open-loop (i.e., passive) and one closed-loop (i.e., active)

Epoxyeicosatrienoic acids and cardioprotection: The road to translation

AbstractCardiovascular disease, including acute myocardial infarction (AMI), is the leading cause of morbidity and mortality globally, despite well-established treatments. The discovery and development of novel therapeutics that prevent the progression of devastating consequences following AMI are thus important in reducing the global burden of this devastating disease. Scientific evidence for the protective effects of epoxyeicosatrienoic acids (EETs) in the cardiovascular system is rapidly emerging and suggests that promoting the effects of these cytochrome P450-derived epoxyeicosanoids is a potentially viable clinical therapeutic strategy. Through a translational lens, this review will provide insight into the potential clinical utility of this therapeutic strategy for AMI by 1) outlining the known cardioprotective effects of EETs and underlying mechanisms demonstrated in preclinical models of AMI with a particular focus on myocardial ischemia–reperfusion injury, 2) describing studies in human cohorts that demonstrate a relationship between EETs and associated pathways with coronary artery disease risk, and 3) discussing preclinical and clinical areas that require further investigation in order to increase the probability of successfully translating this rapidly emerging body of evidence into a clinically applicable therapeutic strategy for AMI

Deficiency of Soluble Epoxide Hydrolase Protects Cardiac Function Impaired by LPS-Induced Acute Inflammation

Lipopolysaccharide (LPS) is a bacterial wall endotoxin producing many pathophysiological conditions including myocardial inflammation leading to cardiotoxicity. Linoleic acid (18:2n6, LA) is an essential n-6 PUFA which is converted to arachidonic acid (20:4n6, AA) by desaturation and elongation via enzyme systems within the body. Biological transformation of PUFA through CYP-mediated hydroxylation, epoxidation, and allylic oxidation produces lipid mediators, which may be subsequently hydrolyzed to corresponding diol metabolites by soluble epoxide hydrolase (sEH). In the current study, we investigate whether inhibition of sEH, which alters the PUFA metabolite profile, can influence LPS induced cardiotoxicity and mitochondrial function. Our data demonstrate that deletion of soluble epoxide hydrolase provides protective effects against LPS-induced cardiotoxicity by maintaining mitochondrial function. There was a marked alteration in the cardiac metabolite profile with notable increases in sEH-derived vicinal diols, 9,10- and 12,13-dihydroxyoctadecenoic acid (DiHOME) in WT hearts following LPS administration, which was absent in sEH null mice. We found that DiHOMEs triggered pronounced mitochondrial structural abnormalities, which also contributed to the development of extensive mitochondrial dysfunction in cardiac cells. Accumulation of DiHOMEs may represent an intermediate mechanism through which LPS-induced acute inflammation triggers deleterious alterations in the myocardium in vivo and cardiac cells in vitro. This study reveals novel research exploring the contribution of DiHOMEs in the progression of adverse inflammatory responses toward cardiac function in vitro and in vivo

COBALT: A GN&C Payload for Testing ALHAT Capabilities in Closed-Loop Terrestrial Rocket Flights

The COBALT (CoOperative Blending of Autonomous Landing Technology) payload is being developed within NASA as a risk reduction activity to mature, integrate and test ALHAT (Autonomous precision Landing and Hazard Avoidance Technology) systems targeted for infusion into near-term robotic and future human space flight missions. The initial COBALT payload instantiation is integrating the third-generation ALHAT Navigation Doppler Lidar (NDL) sensor, for ultra high-precision velocity plus range measurements, with the passive-optical Lander Vision System (LVS) that provides Terrain Relative Navigation (TRN) global-position estimates. The COBALT payload will be integrated onboard a rocket-propulsive terrestrial testbed and will provide precise navigation estimates and guidance planning during two flight test campaigns in 2017 (one open-loop and closed- loop). The NDL is targeting performance capabilities desired for future Mars and Moon Entry, Descent and Landing (EDL). The LVS is already baselined for TRN on the Mars 2020 robotic lander mission. The COBALT platform will provide NASA with a new risk-reduction capability to test integrated EDL Guidance, Navigation and Control (GN&C) components in closed-loop flight demonstrations prior to the actual mission EDL

Secreted Amyloid β-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity

Evidence for a central role of amyloid β-protein (Aβ) in the genesis of Alzheimer’s disease (AD) has led to advanced human trials of Aβ-lowering agents. The “amyloid hypothesis” of AD postulates deleterious effects of small, soluble forms of Aβ on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble Aβ could be therapeutically advantageous, it is important to understand the full range of soluble Aβ derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ∼8 kDa Aβ species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded Aβ40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of Aβ-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of Aβ. These N-terminally extended Aβ-containing monomeric fragments are distinct from soluble Aβ oligomers formed from Aβ1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing β-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic Aβ-containing species can arise from APP processing events N-terminal to the classical β-secretase cleavage site

Inhibition of Soluble Epoxide Hydrolase Limits Mitochondrial Damage and Preserves Function Following Ischemic Injury

Aims: Myocardial ischemia can result in marked mitochondrial damage leading to cardiac dysfunction, as such identifying novel mechanisms to limit mitochondrial injury is important. This study investigated the hypothesis that inhibiting soluble epoxide hydrolase (sEH), responsible for converting epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids protects mitochondrial from injury caused by myocardial infarction. Methods: sEH null and WT littermate mice were subjected to surgical occlusion of the left anterior descending (LAD) artery or sham operation. A parallel group of WT mice received an sEH inhibitor, trans-4-[4-(3-adamantan-1-y1-ureido)-cyclohexyloxy]-benzoic acid (tAUCB; 10 mg/L) or vehicle in the drinking water 4 days prior and 7 days post-MI. Cardiac function was assessed by echocardiography prior- and 7-days post-surgery. Heart tissues were dissected into infarct, peri-, and non-infarct regions to assess ultrastructure by electron microscopy. Complexes I, II, IV, citrate synthase, PI3K activities, and mitochondrial respiration were assessed in non-infarct regions. Isolated working hearts were used to measure the rates of glucose and palmitate oxidation. Results: Echocardiography revealed that tAUCB treatment or sEH deficiency significantly improved systolic and diastolic function post-MI compared to controls. Reduced infarct expansion and less adverse cardiac remodeling were observed in tAUCB-treated and sEH null groups. EM data demonstrated mitochondrial ultrastructure damage occurred in infarct and peri-infarct regions but not in non-infarct regions. Inhibition of sEH resulted in significant improvements in mitochondrial respiration, ATP content, mitochondrial enzymatic activities and restored insulin sensitivity and PI3K activity. Conclusion: Inhibition or genetic deletion of sEH protects against long-term ischemia by preserving cardiac function and maintaining mitochondrial efficiency

COBALT: Development of a Platform to Flight Test Lander GN&C Technologies on Suborbital Rockets

The NASA COBALT Project (CoOperative Blending of Autonomous Landing Technologies) is developing and integrating new precision-landing Guidance, Navigation and Control (GN&C) technologies, along with developing a terrestrial fight-test platform for Technology Readiness Level (TRL) maturation. The current technologies include a third- generation Navigation Doppler Lidar (NDL) sensor for ultra-precise velocity and line- of-site (LOS) range measurements, and the Lander Vision System (LVS) that provides passive-optical Terrain Relative Navigation (TRN) estimates of map-relative position. The COBALT platform is self contained and includes the NDL and LVS sensors, blending filter, a custom compute element, power unit, and communication system. The platform incorporates a structural frame that has been designed to integrate with the payload frame onboard the new Masten Xodiac vertical take-o, vertical landing (VTVL) terrestrial rocket vehicle. Ground integration and testing is underway, and terrestrial fight testing onboard Xodiac is planned for 2017 with two flight campaigns: one open-loop and one closed-loop