Alpha7 nicotinic receptors as potential theranostic targets for experimental stroke

Inflammatory reflex and cholinergic anti-inflammatory pathway:Innate immune system triggers a local inflammatory response following an injury or a pathogen invasion.Likewise,this inflammatory response is limited by rapid,localized,and adaptive anti-inflammatory responses which are crucial for maintaining homeostasis.Hence,the loss of these responses converts a limited and protective inflammatory response into an excessive and harmful response.Anti-inflammatory responses are integrated into the central nervous system,since the central nervous system accumulates information about harmful events,activates defenses,and builds memory for survival.At the same time,it has been demonstrated that hypothalamic neuronal signaling can be altered by inflammation in peripheral tissues.Additionally,immune cells release neuropeptides and neurotransmitters such as acetylcholine(ACh),the main neurotransmitter of the parasympathetic autonomic nervous system,evidencing the communication between the immune and nervous systems(Tracey,2002).

Clearing the corpses： regulatory mechanisms, novel tools, and therapeutic potential of harnessing microglial phagocytosis in the diseased brain

Apoptosis is a widespread phenomenon that occurs in the brain in both physiological and pathological conditions. Dead ceils must be quickly removed to avoid the further toxic effects they exert in the pa- renchyma, a process executed by microglia, the brain professional phagocytes. Although phagocytosis is critical to maintain tissue homeostasis, it has long been either overlooked or indirectly assessed based on microglial morphology, expression of classical activation markers, or engulfment of artificial phagocytic targets in vitro. Nevertheless, these indirect methods present several limitations and, thus, direct obser- vation and quantification of microglial phagocytosis is still necessary to fully grasp its relevance in the diseased brain. To overcome these caveats and obtain a comprehensive, quantitative picture of microglial phagocytosis we have developed a novel set of parameters. These parameters have allowed us to identify the different strategies utilized by microglia to cope with apoptotic challenges induced by excitotoxicity or inflammation. In contrast, we discovered that in mouse and human epilepsy microglia failed to find and engulf apoptotic ceils, resulting in accumulation of debris and inflammation. Herein, we advocate that the efficiency of microglial phagocytosis should be routinely tested in neurodegenerative and neuro- logical disorders, in order to determine the extent to which it contributes to apoptosis and inflammation found in these conditions. Finally, our findings point towards enhancing microglial phagocytosis as a novel therapeutic strategy to control tissue damage and inflammation, and accelerate recovery in brain diseases.

Evaluation of glial cell proliferation with non-invasive molecular imaging methods after stroke

Glial proliferation:For the last decades,glial cells have been wrongly believed to have a mere passive supporting role for neurons.Nevertheless,this notion has clearly changed and it is now admitted that these cells are essential for the correct development and regulation of the nervous system.Glia cell population are commonly subdivided in astrocytes,oligodendrocytes and microglia.During the development,neural stem cells(NSCs)(called neuroepithelial progenitor cells or NPCs)transform into radial glia,the primary progenitor cells for neurons,astrocytes and oligodendrocytes(Zuchero and Barres,2015).Microglial cells,however,derive from a mesenchymal precursor infiltration,meaning that during brain development,precursors generated in the bone narrow invade the nervous parenchyma and differentiate into microglial cells(Zuchero and Barres,2015).This proliferative capacity is preserved in the adult mammalian brain,and neurogenic NSCs are stored in two restricted regions of the central nervous system(CNS),the forebrain subventricular zone(SVZ)and the hippocampal dentate gyrus(subgranular zone).These cells continue to produce neurons and glial cells during the adulthood,being activated after certain signals and leaving the quiescent state(Urbán et al.,2019).This process,in which glial progenitor cells differentiate into mature glia during development and in the adult brain to maintain and regulate brain function,is called gliogenesis(Ardaya et al.,2020).