RESUMEN
Neuroinflammation has been implicated in cognitive deficits of neurological and neurodegenerative diseases. There is abundant evidence that the application of ghrelin, an orexigenic hormone regulating appetite and energy balance, abrogates neuroinflammation and rescues associated memory impairment. However, the underlying mechanism is uncertain. In this study, we find that both intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) impairs spatial memory in mice. LPS treatment causes neuroinflammation and microglial activation in the hippocampus. Ghsr1a deletion suppresses LPS-induced microglial activation and neuroinflammation, and rescued LPS-induced memory impairment. Our findings thus suggest that GHS-R1a signaling may promote microglial immunoactivation and contribute to LPS-induced neuroinflammation. GHS-R1a may be a new therapeutic target for cognitive dysfunction associated with inflammatory conditions.
Asunto(s)
Lipopolisacáridos , Trastornos de la Memoria , Ratones Endogámicos C57BL , Microglía , Receptores de Ghrelina , Memoria Espacial , Animales , Memoria Espacial/efectos de los fármacos , Receptores de Ghrelina/deficiencia , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismo , Trastornos de la Memoria/genética , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Ratones , Masculino , Microglía/metabolismo , Microglía/efectos de los fármacos , Microglía/patología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ratones Noqueados , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patologíaRESUMEN
Ghrelin is an orexigenic gastric hormone that promotes feeding behaviors and regulating energy homeostasis in both humans and rodents. Our previous studies have shown that ghrelin, when locally infused into the basolateral amygdala (BLA), blocks both acquisition and extinction of conditioned taste aversion (CTA) memory in rats. In this study, we further investigated the effect of virus-mediated overexpression of ghrelin receptor growth hormone secretagogue receptor 1a (GHS-R1a) in BLA pyramidal neurons on CTA memory processes. We found that upregulation of GHS-R1a expression in BLA pyramidal neurons repressed CTA extinction while it had no effect on CTA acquisition. In addition, we reported that local infusion of the endogenous GHS-R1a antagonist, liver-expressed antimicrobial peptide 2 (LEAP2), in the BLA abolished the inhibitory effect of increased GHS-R1a on CTA memory extinction. Those findings provide new supportive evidence that ghrelin/GHS-R1a signaling in the BLA circuit shapes emotional memory processes.
Asunto(s)
Reacción de Prevención , Complejo Nuclear Basolateral , Receptores de Ghrelina , Animales , Complejo Nuclear Basolateral/metabolismo , Conducta Alimentaria , Ghrelina/farmacología , Ratas , Receptores de Ghrelina/metabolismo , Gusto/fisiologíaRESUMEN
BACKGROUND: Tissue inhibitors of metalloproteinase (TIMP) family proteins are peptidases involved in extracellular matrix (ECM) degradation. Various diseases are related to TIMPs, and the primary reason is that TIMPs can indirectly regulate remodelling of the ECM and cell signalling by regulating matrix metalloproteinase (MMP) activity. However, the link between TIMPs and glioblastoma (GBM) is unclear. OBJECTIVE: This study aimed to explore the role of TIMP expression and immune infiltration in GBM. METHODS: Oncomine, GEPIA, OSgbm, LinkedOmics, STRING, GeneMANIA, Enrichr, and TIMER were used to conduct differential expression, prognosis, and immune infiltration analyses of TIMPs in GBM. RESULTS: All members of the TIMP family had significantly higher expression levels in GBM. High TIMP3 expression correlated with better overall survival (OS) and disease-specific survival (DSS) in GBM patients. TIMP4 was associated with a long OS in GBM patients. We found a positive relationship between TIMP3 and TIMP4, identifying gene sets with similar or opposite expression directions to those in GBM patients. TIMPs and associated genes are mainly associated with extracellular matrix organization and involve proteoglycan pathways in cancer. The expression levels of TIMPs in GBM correlate with the infiltration of various immune cells, including CD4+ T cells, macrophages, neutrophils, B cells, CD8+ T cells, and dendritic cells. CONCLUSIONS: Our study inspires new ideas for the role of TIMPs in GBM and provides new directions for multiple treatment modalities, including immunotherapy, in GBM.
Asunto(s)
Glioblastoma , Inhibidores Tisulares de Metaloproteinasas , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Humanos , Metaloproteinasas de la Matriz , Pronóstico , Inhibidores Tisulares de Metaloproteinasas/genética , Inhibidores Tisulares de Metaloproteinasas/metabolismoRESUMEN
Ghrelin is a circulating peptide hormone promoting feeding and regulating energy metabolism in human and rodents. Ghrelin functions by binding to its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), which are widely distributed throughout the brain including the amygdala, a brain region important for regulating valenced behavior, such as aversion. Interestingly, GHSR1a was once characterized by highly constitutive, ligand-independent activity. However, the physiological importance of such ligand-independent signaling on aversive memory processing has not been tested yet. Here, we applied [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-Substance P (D-SP), a full inverse agonist for GHSR1a, into the lateral amygdala (LA) and investigated the effect of blocking GHSR1a constitutive activity on conditioned taste aversion (CTA) in rats. We found that intra-LA infusion of a single low dose of D-SP (8ng/0.5µl/side) facilitates CTA acquisition. Moreover, pre-administration of a high dose of D-SP into the LA abolishes the suppressive effect of exogenous ghrelin on CTA acquisition. In contrast, pre-administration of the same dose of D-SP does not affect the suppression of substance P, a potent neurokinin-1 (NK1) receptor ligand, on CTA. Therefore, our data indicated that the spontaneous or basal activity of GHSR1a signaling in the LA might interfere with CTA memory formation. D-SP decreases the constitutive activity of GHSR1a and thus facilitates CTA. Altogether, our present findings along with previous results support the idea that ghrelin/GHSR1a signaling in the LA circuit blocks conditioned taste aversion.
Asunto(s)
Reacción de Prevención , Complejo Nuclear Basolateral/fisiología , Condicionamiento Clásico , Receptores de Ghrelina/fisiología , Animales , Ghrelina/administración & dosificación , Ghrelina/fisiología , Masculino , Recuerdo Mental/efectos de los fármacos , Ratas Wistar , Receptores de Ghrelina/antagonistas & inhibidoresRESUMEN
Ghrelin is an orexigenic brain-gut hormone promoting feeding and regulating energy metabolism in human and rodents. Our previous study showed that ghrelin locally infused into the lateral amygdala (LA) activates its receptor GHS-R1a and blocks acquisition of conditioned taste aversion (CTA) in rats. In this study, we further investigated the effect of ghrelin/GHS-R1a signaling on extinction of CTA. We found that local infusion of ghrelin (5µM, 0.5µl/side) into the LA not only interfered with CTA memory formation, but also the extinction of CTA memory. Pre-administration of GHS-R1a antagonist blocked ghrelin's effect on both CTA acquisition and extinction. However, pre-treatment with PI3K inhibitor only abolished the inhibitory effect of ghrelin on acquisition, but not on extinction. Altogether, our data indicated that ghrelin/GHS-R1a signaling in the LA circuit modulates both acquisition and extinction of CTA, the two forms of taste aversion processes with distinct mechanisms may also share certain molecular and circuit components in common.