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1.
Neurosci Lett ; 792: 136940, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36336086

RESUMO

Sleep disturbances are common among disorders associated with hypothalamic pituitary-adrenal (HPA) axis dysfunction, such as depression and anxiety. This comorbidity may partly be the result of the intersection between the role of the HPA axis in mediating the stress response and its involvement in sleep-wake cyclicity. Our previous work has shown that following 20 h of sleep restriction, mice show a blunting of the HPA axis in response to an acute stressor. Furthermore, these responses differ in a sex-dependent manner. This study sought to examine the effect of sleep restriction on corticotropin-releasing factor (CRF)-containing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Male and female Crf-IRES-Cre: Ai14 (Tdtomato) reporter mice were sleep restricted for 20 h daily for either a single or three consecutive days using the modified multiple platform method. These mice allowed the visualization of CRF+ neurons throughout the brain. Animals were subjected to acute restraint stress, and their brains were collected to assess PVN neuronal activation via c-Fos immunohistochemistry. Analyses of cell counts revealed an ablation of the restraint-induced increase in both CRF/c-Fos colocalization and overall c-Fos expression in female mice following both a single day and three days of sleep restriction. Males showed an overall decrease in restraint-induced c-Fos levels following a single day of sleep restriction. However, male mice examined after three days of sleep restriction showed a recovery in PVN-CRF and overall PVN neuronal activation. These data suggest the sex dependent dysregulation in CRF function following sleep restriction.


Assuntos
Hormônio Liberador da Corticotropina , Núcleo Hipotalâmico Paraventricular , Masculino , Feminino , Animais , Camundongos , Hormônio Liberador da Corticotropina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Neurônios/metabolismo , Sono
2.
J Clin Invest ; 132(23)2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36194487

RESUMO

Platelets and megakaryocytes are critical players in immune responses. Recent reports suggest infection and inflammation alter the megakaryocyte and platelet transcriptome to induce altered platelet reactivity. We determined whether nonviral sepsis induces differential platelet gene expression and reactivity. Nonviral sepsis upregulated IFN-induced transmembrane protein 3 (IFITM3), an IFN-responsive gene that restricts viral replication. As IFITM3 has been linked to clathrin-mediated endocytosis, we determined whether IFITM3 promoted endocytosis of α-granule proteins. IFN stimulation enhanced fibrinogen endocytosis in megakaryocytes and platelets from Ifitm+/+ mice, but not Ifitm-/- mice. IFITM3 overexpression or deletion in megakaryocytes demonstrated IFITM3 was necessary and sufficient to regulate fibrinogen endocytosis. Mechanistically, IFITM3 interacted with clathrin and αIIb and altered their plasma membrane localization into lipid rafts. In vivo IFN administration increased fibrinogen endocytosis, platelet reactivity, and thrombosis in an IFITM-dependent manner. In contrast, Ifitm-/- mice were completely rescued from IFN-induced platelet hyperreactivity and thrombosis. During murine sepsis, platelets from Ifitm+/+ mice demonstrated increased fibrinogen content and platelet reactivity, which was dependent on IFN-α and IFITMs. Platelets from patients with nonviral sepsis had increases in platelet IFITM3 expression, fibrinogen content, and hyperreactivity. These data identify IFITM3 as a regulator of platelet endocytosis, hyperreactivity, and thrombosis during inflammatory stress.


Assuntos
Endocitose , Fibrinogênio , Proteínas de Membrana , Sepse , Animais , Camundongos , Clatrina , Fibrinogênio/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Sepse/genética
3.
Endocrinology ; 159(6): 2363-2375, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29701827

RESUMO

Traumatic brain injury (TBI) affects 10 million people worldwide, annually. TBI is linked to increased risk of psychiatric disorders. TBI, induced by explosive devices, has a unique phenotype. Over one-third of people exposed to blast-induced TBI (bTBI) have prolonged neuroendocrine deficits, shown by anterior pituitary dysfunction. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is linked to increased risk for psychiatric disorders. Not only is there limited information on how the HPA axis responds to mild bTBI (mbTBI), sex differences are understudied. We examined central and peripheral HPA axis reactivity, 7 to 10 days after mbTBI in male and female mice. Males exposed to mbTBI had increased restraint-induced serum corticosterone (CORT), but attenuated restraint-induced corticotropin-releasing factor (CRF)/c-Fos-immunoreactivity (ir) in the paraventricular nucleus of the hypothalamus (PVN). Females displayed an opposite response, with attenuated restraint-induced CORT and enhanced restraint-induced PVN CRF/c-Fos-ir. We examined potential mechanisms underlying this dysregulation and found that mbTBI did not affect pituitary (pro-opiomelanocortin and CRF receptor subtype 1) or adrenal (11ß-hydroxylase, 11ß-dehydrogenase 1, and melanocortin 2 receptor) gene expression. mbTBI did not alter mineralocorticoid or glucocorticoid gene expression in the PVN or relevant limbic structures. In females, but not males, mbTBI decreased c-Fos-ir in non-neuroendocrine (presumably preautonomic) CRF neurons in the PVN. Whereas we demonstrated a sex-dependent link to stress dysregulation of preautonomic neurons in females, we hypothesize that mbTBI may disrupt limbic pathways involved in HPA axis coordination in males. Overall, mbTBI altered the HPA axis in a sex-dependent manner, highlighting the importance of developing therapies to target individual strategies that males and females use to cope with mbTBI.


Assuntos
Traumatismos por Explosões/fisiopatologia , Lesões Encefálicas Traumáticas/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Animais , Traumatismos por Explosões/metabolismo , Traumatismos por Explosões/patologia , Peso Corporal/fisiologia , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Feminino , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal/metabolismo , Reflexo/fisiologia , Caracteres Sexuais , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Índices de Gravidade do Trauma
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