Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity

Stroke results in local neural disconnection and brain-wide neuronal network dysfunction leading to neurological deficits. Beyond the hyper-acute phase of ischaemic stroke, there is no clinically-approved pharmacological treatment that alleviates sensorimotor impairments. Functional recovery after stroke involves the formation of new or alternative neuronal circuits including existing neural connections. The type-5 metabotropic glutamate receptor (mGluR5) has been shown to modulate brain plasticity and function and is a therapeutic target in neurological diseases outside of stroke. We investigated whether mGluR5 influences functional recovery and network reorganization rodent models of focal ischaemia. Using multiple behavioural tests, we observed that treatment with negative allosteric modulators (NAMs) of mGluR5 (MTEP, fenobam and AFQ056) for 12 days, starting 2 or 10 days after stroke, restored lost sensorimotor functions, without diminishing infarct size. Recovery was evident within hours after initiation of treatment and progressed over the subsequent 12 days. Recovery was prevented by activation of mGluR5 with the positive allosteric modulator VU0360172 and accelerated in mGluR5 knock-out mice compared with wild-type mice. After stroke, multisensory stimulation by enriched environments enhanced recovery, a result prevented by VU0360172, implying a role of mGluR5 in enriched environment-mediated recovery. Additionally, MTEP treatment in conjunction with enriched environment housing provided an additive recovery enhancement compared to either MTEP or enriched environment alone. Using optical intrinsic signal imaging, we observed brain-wide disruptions in resting-state functional connectivity after stroke that were prevented by mGluR5 inhibition in distinct areas of contralesional sensorimotor and bilateral visual cortices. The levels of mGluR5 protein in mice and in tissue samples of stroke patients were unchanged after stroke. We conclude that neuronal circuitry subserving sensorimotor function after stroke is depressed by a mGluR5-dependent maladaptive plasticity mechanism that can be restored by mGluR5 inhibition. Post-acute stroke treatment with mGluR5 NAMs combined with rehabilitative training may represent a novel post-acute stroke therapy

Epigrammi

Ġabra ta’ poeżiji u proża li tinkludi: Id-daqq tal-qanpiena ta’ għonq il-mogħża ħasbu l-vjatku ta’ Dun A. Tabone – Għaddejja l-purċissjoni ta’ Dun Frans Camilleri – Nazju jidħol baħri ta’ Alfie Guillaumier – Lil marti ta’ Pawlu Aquilina – In-nawfraġju ta’ Br. Henry – Orqod tfajjel, orqod ta’ Peter A. Caruana – Epigrammi ta’ E. Quattromani.peer-reviewe

Stroke recovery activity-dependent mechanisms

Stroke is the leading cause of disability in developed countries and among the major causes of death worldwide. During a stroke, neurons deprived of their normal metabolic substrates cease to function in seconds and show signs of structural damage after only a few minutes which result in the impairment of sensory and motor function. Loss of function after stroke is due to neuronal death and irreversible ischemic damage in the infarct core but also to cell dysfunction in the areas surrounding the infarct. These areas represent the peri-infarct, a region of reduced blood supply and reversible damage, and the intact remote areas directly connected to the damaged tissue or hub regions of the brain network.Clinical evidence shows that physical and cognitive therapy, as well as social interactions, facilitate the recovery process and promote improvement of lost neurological function after stroke. In the experimental setting, these observations can be mimicked by an enriched environment (EE), which provides an activity-dependent stimulation of the brain. The EE is a housing condition for rodents combining multisensory stimulation and social interactions that improve lost neurological function without affecting the extent of brain damage after experimental stroke.This thesis deals with the concept of EE and mechanisms underlying activity-dependent plasticity in the brain after stroke and their influence on functional recovery. We propose that EE balances mechanisms critical for stroke recovery, such as the detrimental and beneficial components of the post-stroke inflammatory response, and the activation of ECM-degrading processes which ultimately lead to improved brain functional connectivity and behavioral outcome. Finally, this thesis suggests that a general stimulating and positive environment can be the optimal base for specific interventions in neurological rehabilitation

Environmental Audit of Beertzinut Beer Brewery in the Southern Arava

Three functional environmental audits were performed on the Beertzinut brewery to collect data on the brewery’s water use, waste generation, and electricity consumption. This report compiles the results of those environmental audits. The main takeaways from these audits were that a significant amount of water is used at the brewery for wort cooling, electricity usage is more efficient on days that handle larger processes, and the waste management practices are already environmentally sustainable. With these main takeaways, suggestions were made to decrease these environmental impacts and allow for Beertzinut to improve environmental sustainability

On the use of AR models for SHM: A global sensitivity and uncertainty analysis framework

This paper proposes a complete sensitivity analysis of the use of Autoregressive models (AR) and Mahalanobis Squared Distance in the field of Structural Health Monitoring (SHM). Autoregressive models come from econometrics and their use for modelling the response of a physical system has been well established in the last twenty years. However, their aware application in engineering should be supported by knowledge about how they describe phenomena which are well defined by physics. Since autoregressive models are estimated by a least square minimization, statistical tools like Global Sensitivity Analysis and uncertainty propagation are powerful methods to investigate the performance of AR models applied to SHM. These methodologies allow one to understand the role of the uncertainty and uncorrelated noise by a rigorous approach based on statistical motivations. Moreover, it is possible to quantify the link between the mechanical properties of a system and the AR parameters, as well as the Mahalanobis Squared Distance. By fixing a factor prioritization among the variables of a AR model, it is possible to understand which are the parameters playing a main role in damage detection and which type of structural changes is possible to efficiently detect

The Role of Communication between Formation and Information

The Role of Communication between Formation and Informatio

Editorial: "Performing control" of the COVID-19 crisis

Peer reviewe