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1.
Brain Behav Immun ; 53: 207-222, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26772151

RESUMO

Most psychiatric and neurological diseases are exacerbated by stress. Because this may partially result from stress-induced inflammation, we examined factors involved in this stress response. After a paradigm of inescapable foot shock stress that causes learned helplessness depression-like behavior, eighteen cytokines and chemokines increased in mouse hippocampus, peaking 6-12h after stress. A 24h prior pre-conditioning stress accelerated the rate of stress-induced hippocampal cytokine and chemokine increases, with most reaching peak levels after 1-3h, often without altering the maximal levels. Toll-like receptor 4 (TLR4) was involved in this response because most stress-induced hippocampal cytokines and chemokines were attenuated in TLR4 knockout mice. Stress activated glycogen synthase kinase-3 (GSK3) in wild-type mouse hippocampus, but not in TLR4 knockout mice. Administration of the antidepressant fluoxetine or the GSK3 inhibitor TDZD-8 reduced the stress-induced increases of most hippocampal cytokines and chemokines. Stress increased hippocampal levels of the danger-associated molecular pattern (DAMP) protein high mobility group box 1 (HMGB1), activated the inflammatory transcription factor NF-κB, and the NLRP3 inflammasome. Knockdown of HMGB1 blocked the acceleration of cytokine and chemokine increases in the hippocampus caused by two successive stresses. Fluoxetine treatment blocked stress-induced up-regulation of HMGB1 and subsequent NF-κB activation, whereas TDZD-8 administration attenuated NF-κB activation downstream of HMGB1. To test if stress-induced cytokines and chemokines contribute to depression-like behavior, the learned helplessness model was assessed. Antagonism of TNFα modestly reduced susceptibility to learned helplessness induction, whereas TLR4 knockout mice were resistant to learned helplessness. Thus, stress-induces a broad inflammatory response in mouse hippocampus that involves TLR4, GSK3, and downstream inflammatory signaling, and these stress responses contribute to susceptibility to depression-like behavior in mice.


Assuntos
Depressão/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Estresse Fisiológico/fisiologia , Receptor 4 Toll-Like/metabolismo , Animais , Citocinas/imunologia , Citocinas/metabolismo , Depressão/genética , Depressão/imunologia , Fluoxetina/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/imunologia , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Neuroimunomodulação , Transdução de Sinais , Estresse Fisiológico/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
2.
Neurosci Biobehav Rev ; 46 Pt 3: 472-96, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25316571

RESUMO

Panic disorder (PD) patients are specifically sensitive to 5­7% carbon dioxide. Another startling feature of clinical panic is the counterintuitive lack of increments in 'stress hormones'. PD is also more frequent in women and highly comorbid with childhood separation anxiety (CSA). On the other hand, increasing evidence suggests that panic is mediated at dorsal periaqueductal grey matter (DPAG). In line with prior studies showing that DPAG-evoked panic-like behaviours are attenuated by clinically-effective treatments with panicolytics, we show here that (i) the DPAG harbors a hypoxia-sensitive alarm system, which is activated by hypoxia and potentiated by hypercapnia, (ii) the DPAG suffocation alarm system is inhibited by clinically-effective treatments with panicolytics, (iii) DPAG stimulations do not increase stress hormones in the absence of physical exertion, (iv) DPAG-evoked panic-like behaviours are facilitated in neonatally-isolated adult rats, a model of CSA, and (v) DPAG-evoked responses are enhanced in the late diestrus of female rats. Data are consistent with the DPAG mediation of both respiratory and non-respiratory types of panic attacks.


Assuntos
Asfixia/complicações , Transtorno de Pânico/etiologia , Pesquisa Translacional Biomédica , Animais , Asfixia/patologia , Modelos Animais de Doenças , Transtorno de Pânico/metabolismo , Substância Cinzenta Periaquedutal/fisiologia , Ratos
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