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Role of Brain Stimulation and the Blood–Brain Interface

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Role of Brain Stimulation and the Blood–Brain Interface biomolecules Review Monitoring and Modulating Inflammation-Associated Alterations in Synaptic Plasticity: Role of Brain Stimulation and the Blood–Brain Interface Maximilian Lenz 1,*, Amelie Eichler 1 and Andreas Vlachos 1,2,3,* 1 Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany 2 Center Brain Links Brain Tools, University of Freiburg, 79110 Freiburg, Germany 3 Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany * Correspondence: [email protected] (M.L.); [email protected] (A.V.) Abstract: Inflammation of the central nervous system can be triggered by endogenous and exogenous stimuli such as local or systemic infection, trauma, and stroke. In addition to neurodegeneration and cell death, alterations in physiological brain functions are often associated with neuroinflammation. Robust experimental evidence has demonstrated that inflammatory cytokines affect the ability of neurons to express plasticity. It has been well-established that inflammation-associated alterations in synaptic plasticity contribute to the development of neuropsychiatric symptoms. Nevertheless, diagnostic approaches and interventional strategies to restore inflammatory deficits in synaptic plasticity are limited. Here, we review recent findings on inflammation-associated alterations in synaptic plasticity and the potential role of the blood–brain interface, i.e., the blood–brain barrier, Citation: Lenz, M.; Eichler, A.; in modulating synaptic plasticity. Based on recent findings indicating that brain stimulation promotes Vlachos, A. Monitoring and plasticity and modulates vascular function, we argue that clinically employed non-invasive brain Modulating Inflammation-Associated stimulation techniques, such as transcranial magnetic stimulation, could be used for monitoring and Alterations in Synaptic Plasticity: modulating inflammation-induced alterations in synaptic plasticity. Role of Brain Stimulation and the Blood–Brain Interface. Biomolecules Keywords: synaptic plasticity; lipopolysaccharide; interleukin 10; transcranial magnetic stimulation 2021, 11, 359. https://doi.org/ 10.3390/biom11030359 Academic Editor: Nicola Maggio 1. Introduction Inflammatory processes aim at resolving tissue damage by facilitating repair and Received: 19 January 2021 recovery mechanisms [1]. However, unrestrained inflammation can cause damage, which Accepted: 20 February 2021 Published: 26 February 2021 may induce inflammation-associated pathologies [2]. Adaptive and acquired immune responses consist of complex pro- and anti-inflammatory signaling pathways that regulate Publisher’s Note: MDPI stays neutral inflammatory processes through distinct positive and negative feedback mechanisms [3]. with regard to jurisdictional claims in Dysregulation of these processes may disturb physiological repair and recovery mecha- published maps and institutional affil- nisms, thus contributing to disease progression and infaust outcomes, which has been iations. demonstrated in meningitis, encephalitis, and multiple sclerosis [4–6]. Two millennia ago, seminal work by Aulus Cornelius Celsus described signs of in- flammation including heat, redness, swelling and pain, suggesting a prominent role of the vascular system in inflammation. Indeed, altered vascular function has been determined to be a common feature of inflammatory processes [7]. Meanwhile, cellular and molecular Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. mechanisms that modulate vascular function during inflammation have been identified. This article is an open access article In addition to circulating and local endothelial factors that control vascular tone and per- distributed under the terms and meability, the regulation of cell migration across endothelial barriers has been recognized conditions of the Creative Commons to be a key step in inflammatory processes [8–10]. Attribution (CC BY) license (https:// In the 18th century Rudolph Virchow emphasized the disturbance of function (“functio creativecommons.org/licenses/by/ laesa”) as an important feature of inflammation [11,12]. However, the factors that promote 4.0/). inflammation-related tissue dysfunction remained unknown. Notably, Virchow was among Biomolecules 2021, 11, 359. https://doi.org/10.3390/biom11030359 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x 2 of 9 Biomolecules 2021, 11, 359 In the 18th century Rudolph Virchow emphasized the disturbance of function (“func-2 of 8 tio laesa”) as an important feature of inflammation [11,12]. However, the factors that pro- mote inflammation-related tissue dysfunction remained unknown. Notably, Virchow was among the first scientists to characterize a glial (non-neuronal) cell type in the brain simi- larthe to macrop first scientistshages of to the characterize immune system a glial [13 (non-neuronal)–15]. An early cell study type determined in the brain that similar these to cellsmacrophages contribute to of inflammation the immune systemin the central [13–15 ].nervous An early system, study e.g., determined through phagocytosis that these cells [16].contribute This initial to inflammationwork paved the in theway central for a deeper nervous understanding system, e.g., throughof the function phagocytosis of micro- [16]. gliThisa and initial the immune work paved system the in way the forbrain a deeper [17]. understanding of the function of microglia and the immune system in the brain [17]. The brain is an immune-privileged organ [18]. It is protected by the blood–brain in- The brain is an immune-privileged organ [18]. It is protected by the blood–brain terface (also referred to as the blood–brain barrier), which consists of tight junctions be- interface (also referred to as the blood–brain barrier), which consists of tight junctions tween endothelial cells, the basal lamina of the endothelial cells, and astrocyte endfeet between endothelial cells, the basal lamina of the endothelial cells, and astrocyte endfeet processes [19]. A substantial body of research is currently focused on investigating the processes [19]. A substantial body of research is currently focused on investigating the neuroimmune communication in healthy and diseased states including the role of blood– neuroimmune communication in healthy and diseased states including the role of blood– brain interfaces and more accessible meninges [20–23]. Here, we describe recent work that brain interfaces and more accessible meninges [20–23]. Here, we describe recent work that has identified a critical role for inflammatory cytokines in synaptic plasticity. We discuss has identified a critical role for inflammatory cytokines in synaptic plasticity. We discuss the interplay between endogenous sources of cytokines, such as microglial tumor necrosis the interplay between endogenous sources of cytokines, such as microglial tumor necrosis factor alpha (TNFα), and peripheral immune mediators (Figure 1). Finally, we highlight factor alpha (TNFα), and peripheral immune mediators (Figure1). Finally, we highlight thethe potential potential diagnostic diagnostic and and therapeutic therapeutic use use of of brain brain stimulation, i.e.,i.e., repetitiverepetitive transcranial transcra- nialmagnetic magnetic stimulation stimulation (rTMS), (rTMS), which which may may be usedbe used as a as tool a tool for monitoringfor monitoring and and modulating mod- ulatinginflammation-associated inflammation-associated disturbances disturbances of synaptic of synaptic function. function. FigureFigure 1. Blood 1. Blood–brain–brain communication communication is a crucial is a crucial regulatory regulatory element element in neural in neural circuit circuitfunction. function. NeuronsNeurons and and glial glial cells cells bilaterally bilaterally influence influence their theirfunction function through through various various mediators, mediators, such as such neu- as rotransmitters,neurotransmitters, metabolites metabolites and brain and derived brain derived cytokines. cytokines. Moreover, Moreover, soluble soluble and cellular and cellular blood blood componentscomponents can can enter enter the the central central nervous nervous system, system, when when the the permeability permeability of of the the blood blood–brain–brain interfaceinter- facechanges. changes. This This intruiging intruiging blood–brain blood–brain interaction interaction can can influence influencedistinct distinct featuresfeatures ofof neuralneural circuits,cir- cuits, e.g., network activity and the expression of synaptic plasticity. e.g., network activity and the expression of synaptic plasticity. 2. 2.Effects Effects of ofPro Pro-Inflammatory-Inflammatory Cytokines Cytokines on on Synaptic Synaptic Plasticity Plasticity in in Health Health and and Disease Disease It Ithas has been been well well-established-established that that inflammation inflammation affects affects cognitive cognitive function function and behavior,behav- ior,including including the the ability ability of of neuronsneurons toto express synaptic synaptic plasticity plasticity [24 [24––26].26]. While While the the mech- mech- anismsanisms through through which which pro pro-inflammatory-inflammatory cytokines cytokines affect affect complex complex brain brain functions functions have have recentlyrecently begun begun to tobe be elucidated elucidated [27,28], [27,28 little], little is known is known about about their their physiological physiological
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