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McKnight Brain Research Foundation","doi-asserted-by":"publisher","award":["BSCIRTF"],"award-info":[{"award-number":["BSCIRTF"]}],"id":[{"id":"10.13039\/100007049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001787","name":"Parker Foundation","doi-asserted-by":"publisher","award":["Postdoc Fellowship Grant"],"award-info":[{"award-number":["Postdoc Fellowship Grant"]}],"id":[{"id":"10.13039\/100001787","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neuroinflammation"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Inflammation undermines multiple forms of neuroplasticity. Although inflammation and its influence on plasticity in multiple neural systems has been extensively studied, its effects on plasticity of neural networks controlling vital life functions, such as breathing, are less understood. In this study, we investigated the signaling mechanisms whereby lipopolysaccharide (LPS)-induced systemic inflammation impairs plasticity within the phrenic motor system\u2014a major spinal respiratory motor pool that drives contractions of the diaphragm muscle. Here, we tested the hypotheses that lipopolysaccharide-induced systemic inflammation (1) blocks phrenic motor plasticity by a mechanism that requires cervical spinal okadaic acid-sensitive serine\/threonine protein phosphatase (PP) 1\/2A activity and (2) prevents phosphorylation\/activation of extracellular signal-regulated kinase 1\/2 mitogen activated protein kinase (ERK1\/2 MAPK)\u2014a key enzyme necessary for the expression of phrenic motor plasticity.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>To study phrenic motor plasticity, we utilized a well-characterized model for spinal respiratory plasticity called phrenic long-term facilitation (pLTF). pLTF is characterized by a long-lasting, progressive enhancement of inspiratory phrenic nerve motor drive following exposures to moderate acute intermittent hypoxia (mAIH). In anesthetized, vagotomized and mechanically ventilated adult Sprague Dawley rats, we examined the effect of inhibiting cervical spinal serine\/threonine PP 1\/2A activity on pLTF expression in sham-vehicle and LPS-treated rats. Using immunofluorescence optical density analysis, we compared mAIH-induced phosphorylation\/activation of ERK 1\/2 MAPK with and without LPS-induced inflammation in identified phrenic motor neurons.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We confirmed that mAIH-induced pLTF is abolished 24\u2009h following low-dose systemic LPS (100 \u03bcg\/kg, i.p.). Cervical spinal delivery of the PP 1\/2A inhibitor, okadaic acid, restored pLTF in LPS-treated rats. LPS also prevented mAIH-induced enhancement in phrenic motor neuron ERK1\/2 MAPK phosphorylation. Thus, a likely target for the relevant okadaic acid-sensitive protein phosphatases is ERK1\/2 MAPK or its upstream activators.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This study increases our understanding of fundamental mechanisms whereby inflammation disrupts neuroplasticity in a critical population of motor neurons necessary for breathing, and highlights key roles for serine\/threonine protein phosphatases and ERK1\/2 MAPK kinase in the plasticity of mammalian spinal respiratory motor circuits.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12974-021-02074-6","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T13:02:56Z","timestamp":1611061376000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Systemic inflammation suppresses spinal respiratory motor plasticity via mechanisms that require serine\/threonine protein phosphatase activity"],"prefix":"10.1186","volume":"18","author":[{"given":"Arash","family":"Tadjalli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasin B.","family":"Seven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael R.","family":"Perim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon S.","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,19]]},"reference":[{"key":"2074_CR1","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1111\/imm.12233","volume":"142","author":"S Amor","year":"2014","unstructured":"Amor S, Peferoen LA, Vogel DY, Breur M, van der Valk P, Baker D, van Noort JM. 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Rats had access to food and water ad libitum and were kept in a 12-h daily light-dark cycle.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"28"}}