Broad activation of the Parkin pathway induces synaptic mitochondrial deficits in early tauopathy

Mitochondrial defects are a hallmark of early pathophysiology in Alzheimer’s disease, with pathologically phosphorylated tau reported to induce mitochondrial toxicity. Mitophagy constitutes a key pathway in mitochondrial quality control by which damaged mitochondria are targeted for autophagy. However, few details are known regarding the intersection of mitophagy and pathologies in tauopathy. Here, by applying biochemical and cell biological approaches including time-lapse confocal imaging in live tauopathy neurons, combined with gene rescue experiments via stereotactic injections of adeno-associated virus particles into tauopathy mouse brains, electrophysiological recordings and behavioural tests, we demonstrate for the first time that mitochondrial distribution deficits at presynaptic terminals are an early pathological feature in tauopathy brains. Furthermore, Parkin-mediated mitophagy is extensively activated in tauopathy neurons, which accelerates mitochondrial Rho GTPase 1 (Miro1) turnover and consequently halts Miro1-mediated mitochondrial anterograde movement towards synaptic terminals. As a result, mitochondrial supply at tauopathy synapses is disrupted, impairing synaptic function. Strikingly, increasing Miro1 levels restores the synaptic mitochondrial population by enhancing mitochondrial anterograde movement and thus reverses tauopathy-associated synaptic failure. In tauopathy mouse brains, overexpression of Miro1 markedly elevates synaptic distribution of mitochondria and protects against synaptic damage and neurodegeneration, thereby counteracting impairments in learning and memory as well as synaptic plasticity. Taken together, our study reveals that activation of the Parkin pathway triggers an unexpected effect—depletion of mitochondria from synaptic terminals, a characteristic feature of early tauopathy. We further provide new mechanistic insights into how parkin activation-enhanced Miro1 degradation and impaired mitochondrial anterograde transport drive tauopathy-linked synaptic pathogenesis and establish a foundation for future investigations into new therapeutic strategies to prevent synaptic deterioration in Alzheimer’s disease and other tauopathies

Dynamic Modeling of Crew Performance for Long-Duration Space Missions

Crew time is one of the most valuable and limited resources during long-duration space missions. Crew time requirements fluctuate depending on variations in crew performance. The limited number of crewmembers, resources, and the myriad of tasks to be performed leave a tight schedule for crewmembers during long-duration space missions. This schedule needs to account for potential interventions (stress events) that may alter predicted performance and thus scheduling. A dynamic crew model using a stochastic Auto Regressive Integrated Moving Average (ARIMA) model of interrupted time series was developed to account for the effects of potential stress events on crew performance. This model aids in estimating crew time requirements for varying mission scenarios and for evaluating stress event effects on crew performance

The Role of Orphanin FQ/Nociceptin in Neuroplasticity: Relationship to Stress, Anxiety and Neuroinflammation

The neuropeptide, orphanin FQ/nociceptin (OFQ/N or simply, nociceptin), is expressed in both neuronal and nonneuronaltissue, including the immune system. In the brain, OFQ/N has been investigated in relation to stress, anxiety,learning and memory, and addiction. More recently, it has also been found that OFQ/N influences glial cell functions,including oligodendrocytes, astrocytes and microglial cells. However, this latter research is relatively small, butpotentially important, when observations regarding the relationship of OFQ/N to stress and emotional functions is takeninto consideration and integrated with the growing evidence for its involvement in cells that mediate inflammatory events.This review will first provide an overview and understanding of how OFQ/N has been implicated in the HPA axisresponse to stress, followed by an understanding of its influence on natural and learned anxiety-like behavior. Whatemerges from an examination of the literature is a neuropeptide that appears to counteract anxiogenic influences, butparadoxically, without attenuating HPA axis responses generated in response to stress. Studies utilized both centraladministration of OFQ/N, which was shown to activate the HPA axis, as well as antagonism of NOP-R, the OFQ/Nreceptor. In contrast, antagonist or transgenic OFQ/N or NOP-R knockout studies, showed augmentation of HPA axisresponses to stress, suggesting that OFQ/N may be needed to control the magnitude of the HPA axis response to stress.Investigations of behavior in standard exploratory tests of anxiogenic behavior (eg., elevated plus maze) or learned fearresponses have suggested that OFQ/N is needed to attenuate fear or anxiety-like behavior. However, some discrepantobservations, in particular, those that involve appetitive behaviors, suggest a failure of NOP-R deletion to increaseanxiety

The role of tissue-type plasminogen activator system in amphetamine-induced conditional place preference extinction and reinstatement

Extracellular serine proteases of the plasminogen activator family (tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) may modulate synaptic adhesion and associate with learning behavior. Psychostimulants strongly induce their expression in the mesolimbic dopaminergic pathway, but cocaine preferentially induces uPA, whereas morphine and amphetamine preferentially induce tPA. tPA-expressing animals displayed enhanced conditional place preference (CPP) for amphetamine compared with uPA-overexpressing animals. Thus, modulation of the plasminogen system in the brain might be a potential target against drugs of abuse. In the present study, we aim to identify whether tPA is involved in the acquisition/learning phase or in the expression/retrieval phase of conditioned drug preference. For this purpose, animals were injected with lentiviruses expressing or silencing tPA in the NAc and place preference was assessed. We found that tPA expression is associated with acquisition of place preference and animals overexpressing tPA spend >87% of the time in the drug-associated compartment, compared with 60% for control animals. When ectopic expression of tPA has been inhibited by doxycycline during acquisition, animals do no more associate the environment with the drug. Suppression of endogenous tPA expression in animals treated with LV-siRNA fully suppresses place preference, and these animals appear to avoid the drug-associated box. tPA overexpression delays extinction, but priming with low doses of amphetamine reinstates place preference even after full extinction. Together, these data clearly indicate that tPA plays an important role in acquisition of amphetamine-induced CPP, but its role in CPP expression does not seem important

MOESM1 of Strain differences in cuprizone induced demyelination

Additional file 1: Figure S1. Standard for blind scoring of LFB–PAS stained midline corpus callosum sections. A corresponds to a score of 3 (intact). B corresponds to a score of 2, C corresponds to 1 and D corresponds to 0 (complete demyelination with minimum blue stain of myelin).Scale bar, 100 µm. Figure S2. Examples of positively stained cells. A-C, Example images of Iba1+ cells. A, Iba1 fluorescence. B, To-pro-3. C, overlaid image. Arrows point to Iba1+ cells, which show colocalization of Iba1 fluorescence and nuclear to-pro. D-F, same as A-C, but for GFAP staining. Scale bar, 30 μm

Effects of urokinase-type plasminogen activator in the acquisition, expression and reinstatement of cocaine-induced conditioned-place preference

Cocaine and many other psychostimulants strongly induce urokinase-type plasminogen activator (uPA) expression in the mesolimbic dopaminergic pathway, which plays a major role in drug-mediated behavioral plasticity [Bahi A, Boyer F, Gumy C, Kafri T, Dreyer JL. In vivo gene delivery of urokinase-type plasminogen activator with regulatable lentivirus induces behavioral changes in chronic cocaine administration. Eur J Neurosci 2004;20:3473–88; Bahi A, Boyer F, Kafri T, Dreyer JL. Silencing urokinase in the ventral tegmental area in vivo induces changes in cocaine-induced hyperlocomotion. J Neurochem 2006;98:1619–31; Bahi A, Dreyer JL. Overexpression of plasminogen activators in the nucleus accumbens enhances cocaine-, amphetamine- and morphine-induced reward and behavioral sensitization. Genes Brain Behav 2007]. In this study, the role of mesolimbic dopamine (DA) pathways in the development of cocaine reward was examined by conditioned-place preference in rats with bilateral intra-accumbens injections of uPA-expressing lentiviral vectors. We show that overexpression of uPA in the Nac significantly augments cocaine-induced place preference. Furthermore, while this did not affect the ability of preference to be extinguished, reinstatement with a low dose of cocaine produced significantly greater preference to the cocaine-associated context. Once CPP had been established, and the preference extinguished, reinstatement induced by a priming dose of cocaine was facilitated by uPA. Inhibition of this serine protease expression using doxycycline abolished the augmented acquisition produced by overexpression of uPA but not the expression of the cocaine-induced CPP. When uPA is inhibited during the acquisition phase, animals no longer demonstrate place preference for the environment previously paired with cocaine. B428, a specific uPA inhibitor does not affect drug reinstatement after extinction if uPA has been activated during acquisition, a clear indication that uPA is involved in the acquisition phase of conditioned-place preference. Our results suggest that that increased uPA expression with repeated drug exposure produces conditions for enhanced acquisition of cocaine-induced CPP, indicating that cocaine-induced CPP and reinstatement may be dependent on active extracellular uPA