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1.
Nat Commun ; 15(1): 4233, 2024 May 18.
Article in English | MEDLINE | ID: mdl-38762463

ABSTRACT

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.


Subject(s)
Avoidance Learning , Basal Forebrain , GABAergic Neurons , Glutamic Acid , Reward , Ventral Tegmental Area , Ventral Tegmental Area/physiology , Ventral Tegmental Area/metabolism , Ventral Tegmental Area/cytology , Animals , Glutamic Acid/metabolism , Basal Forebrain/metabolism , Basal Forebrain/physiology , Male , GABAergic Neurons/metabolism , GABAergic Neurons/physiology , Avoidance Learning/physiology , Mice , Dopamine/metabolism , Nucleus Accumbens/metabolism , Nucleus Accumbens/cytology , Nucleus Accumbens/physiology , Neurons/metabolism , Neurons/physiology , gamma-Aminobutyric Acid/metabolism , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/physiology , Mice, Inbred C57BL , Behavior, Animal/physiology
2.
bioRxiv ; 2023 Jul 12.
Article in English | MEDLINE | ID: mdl-37502884

ABSTRACT

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.

3.
J Med Chem ; 56(13): 5422-35, 2013 Jul 11.
Article in English | MEDLINE | ID: mdl-23763354

ABSTRACT

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.


Subject(s)
Fibroblasts/drug effects , Skin Aging/drug effects , Skin/drug effects , Triazoles/pharmacology , Animals , Cells, Cultured , Collagen Type I/genetics , Collagen Type I/metabolism , Collagen Type I, alpha 1 Chain , Drug Design , Elastin/genetics , Elastin/metabolism , Female , Fibroblasts/metabolism , Fibroblasts/radiation effects , Fibronectins/genetics , Fibronectins/metabolism , Gene Expression/drug effects , Gene Expression/radiation effects , Humans , Immunoblotting , Matrix Metalloproteinase 1/genetics , Matrix Metalloproteinase 1/metabolism , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred ICR , Models, Chemical , Molecular Structure , Reactive Oxygen Species/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Skin/metabolism , Skin/radiation effects , Skin Aging/radiation effects , Tissue Inhibitor of Metalloproteinase-1/genetics , Tissue Inhibitor of Metalloproteinase-1/metabolism , Triazoles/chemical synthesis , Triazoles/chemistry , Ultraviolet Rays
4.
J Cell Sci ; 117(Pt 10): 2029-36, 2004 Apr 15.
Article in English | MEDLINE | ID: mdl-15054105

ABSTRACT

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.


Subject(s)
ErbB Receptors/metabolism , PPAR gamma/physiology , Urothelium/metabolism , Active Transport, Cell Nucleus , Adipocytes/metabolism , Anilides/pharmacology , Animals , Blotting, Western , Cattle , Cell Differentiation , Cell Line , Cell Proliferation , Chromans/metabolism , Enzyme Inhibitors/pharmacology , Epidermal Growth Factor/metabolism , Epithelium/metabolism , Gene Expression Regulation , Humans , Immunoprecipitation , Ligands , Membrane Glycoproteins/metabolism , Membrane Proteins/metabolism , Microscopy, Fluorescence , PPAR gamma/metabolism , Phosphorylation , Promoter Regions, Genetic , Quinazolines/pharmacology , RNA, Messenger/metabolism , Ribonucleases/metabolism , Signal Transduction , Thiazolidinediones/metabolism , Time Factors , Troglitazone , Uroplakin II , Uroplakin III , Uroplakin Ia , Uroplakin Ib , Urothelium/cytology
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