RESUMO
The ventral pallidum (VP) contains GABA and glutamate neurons projecting to ventral tegmental area (VTA) whose stimulation drives approach and avoidance, respectively. Yet little is known about the mechanisms by which VP cell types shape VTA activity and drive behavior. Here, we found that both VP GABA and glutamate neurons were activated during approach to reward or by delivery of an aversive stimulus. Stimulation of VP GABA neurons inhibited VTA GABA, but activated dopamine and glutamate neurons. Remarkably, stimulation-evoked activation was behavior-contingent such that VTA recruitment was inhibited when evoked by the subject's own action. Conversely, VP glutamate neurons activated VTA GABA, as well as dopamine and glutamate neurons, despite driving aversion. However, VP glutamate neurons evoked dopamine in aversion-associated ventromedial nucleus accumbens (NAc), but reduced dopamine release in reward-associated dorsomedial NAc. These findings show how heterogeneous VP projections to VTA can be engaged to shape approach and avoidance behaviors.
Assuntos
Aprendizagem da Esquiva , Prosencéfalo Basal , Neurônios GABAérgicos , Ácido Glutâmico , Recompensa , Área Tegmentar Ventral , Área Tegmentar Ventral/fisiologia , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/citologia , Animais , Ácido Glutâmico/metabolismo , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiologia , Masculino , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Aprendizagem da Esquiva/fisiologia , Camundongos , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/citologia , Núcleo Accumbens/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Ácido gama-Aminobutírico/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/fisiologia , Camundongos Endogâmicos C57BL , Comportamento Animal/fisiologiaRESUMO
The ventral pallidum (VP) contains GABA and glutamate (Glut) neurons projecting to ventral tegmental area (VTA) whose stimulation drives approach and avoidance, respectively. Yet little is known about the cell-type-specific mechanisms by which VP projections to VTA drive behavior. Here, we found that both VP GABA and Glut neurons were activated during approach to reward or delivery of an aversive stimulus. Stimulation of VP GABA neurons inhibited VTA GABA, but activated dopamine (DA) and glutamate neurons. Remarkably, this cell-type-specific recruitment was behavior-contingent such that VTA recruitment was inhibited when evoked by the subject's own action. Conversely, VP Glut neurons activated VTA GABA, as well as DA and Glut neurons, despite driving aversion. However, VP Glut neurons evoked DA in reward-associated ventromedial nucleus accumbens (NAc), but reduced DA in aversion-associated dorsomedial NAc. These findings show how heterogeneous VP cell types can engage VTA cell types to shape approach and avoidance behaviors.
RESUMO
Novel bicyclic[1,2,3]triazoles (4, 7, 11, 15) have been synthesized using a one-pot metal free strategy with high structural diversity as photoprotective agents, and their effect on UVA-induced senescence in human dermal fibroblast cells (FB) and the associated mechanism are delineated. 11d plus UVA can induce a decrease in reactive oxygen species (ROS) production and senescence-associated ß-galactosidase (SA-ß-gal) activity but an increase in adenosine triphosphate (ATP) synthesis and mitochondrial membrane potential (ΔΨmt). The mRNA levels of six senescence-associated genes, matrix metalloproteinase-1 (MMP-1), was decreased, while elastin, procollagen I type I, fibronectin, COL1α1, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were increased. 11d plus UVA also decreased MMP-1 and increased TIMP-1 protein levels. Additionally, the thickness of the murine dorsal skin and epidermis, by UVA, was decreased by topical 11d treatment. Our results indicate that bicyclic[1,2,3]triazoles protect UVA-induced senescence-like characteristics in FB cells, which may provide potential prevention against photoaging.
Assuntos
Fibroblastos/efeitos dos fármacos , Envelhecimento da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , Triazóis/farmacologia , Animais , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Desenho de Fármacos , Elastina/genética , Elastina/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Fibronectinas/genética , Fibronectinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos da radiação , Humanos , Immunoblotting , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Modelos Químicos , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/metabolismo , Pele/efeitos da radiação , Envelhecimento da Pele/efeitos da radiação , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Triazóis/síntese química , Triazóis/química , Raios UltravioletaRESUMO
Recently, considerable interest has focused on the ability of activated peroxisome proliferator-activated receptor gamma (PPARgamma) to promote cytodifferentiation in adipocytes and some carcinoma cells; however, the role of PPARgamma in normal epithelial cytodifferentiation is unknown. Using uroplakin (UP) gene expression as a specific correlate of terminal urothelial cytodifferentiation, we investigated the differentiation-inducing effects of PPARgamma activation in normal human urothelial (NHU) cells grown as finite cell lines in monoculture. Two high-affinity activators of PPARgamma, troglitazone (TZ) and rosiglitazone (RZ) induced the expression of mRNA for UPII and UPIb and, to a lesser extent, UPIa. The specificity of the effect was shown by pretreating cells with a PPARgamma antagonist, GW9662, which attenuated the TZ-induced response in a dose-specific manner. The PPARgamma-mediated effect on UP gene expression was maximal when there was concurrent inhibition of autocrine-activated epidermal growth factor receptor (EGFR) signalling through either the phosphatidylinositol 3-kinase or extracellular signal-regulated kinase (ERK) pathways. The use of a specific EGFR tyrosine kinase inhibitor, PD153035, correlated with PPARgamma dephosphorylation and translocation to the nucleus, indicating a mechanism for regulating the balance between proliferation and differentiation. This is the first identification of specific factors involved in regulating differentiation-associated gene changes in urothelium and the first unambiguous evidence of a role for PPARgamma signalling in the terminal differentiation programme of a normal epithelium.