Nitric oxide in the medial prefrontal cortex contributes to the acquisition of cocaine place preference and synaptic plasticity in the laterodorsal tegmental nucleus

金沢大学医薬保健研究域薬学系Nitric oxide (NO), a gaseous neurotransmitter, is involved in a variety of brain functions, including drug addiction. Although previous studies have suggested that NO plays an important role in the development of cocaine addiction, the brain region(s) in which NO acts and how it contributes to cocaine addiction remain unclear. In this study, we examined these issues using a cocaine-induced conditioned place preference (CPP) paradigm and ex vivo electrophysiological recordings in rats. Specifically, we focused on the medial prefrontal cortex (mPFC) and laterodorsal tegmental nucleus (LDT), brain regions associated with cocaine CPP development and cocaine-induced plasticity. Intra-mPFC injection of the non-selective NO synthase (NOS) inhibitor L-NAME or the neuronal NOS (nNOS) selective inhibitor L-NPA during the conditioning phase disrupted cocaine CPP. Additionally, intra-mPFC injection of L-NPA prior to each cocaine injection prevented the induction of presynaptic plasticity, induced by repeated cocaine administration, in LDT cholinergic neurons. These findings indicate that NO generated in the mPFC contributes to the acquisition of cocaine CPP and the induction of neuroplasticity in LDT cholinergic neurons. Together with previous studies showing that NO induces membrane plasticity in mPFC neurons, that mPFC neurons project to the LDT, and that LDT activity is critical for the acquisition of cocaine CPP, the present findings suggest that NO-mediated neuroplasticity induced in the mPFC-LDT circuitry is critical for the development of cocaine addiction. © 2017 Elsevier B.V.Embargo Period 12 month

Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens

Abstract Single-cell level analysis is powerful tool to assess the heterogeneity of cellular components in tumor microenvironments (TME). In this study, we investigated immune-profiles using the single-cell analyses of endoscopically- or surgically-resected tumors, and peripheral blood mononuclear cells from gastric cancer patients. Furthermore, we technically characterized two distinct platforms of the single-cell analysis; RNA-seq-based analysis (scRNA-seq), and mass cytometry-based analysis (CyTOF), both of which are broadly embraced technologies. Our study revealed that the scRNA-seq analysis could cover a broader range of immune cells of TME in the biopsy-resected small samples of tumors, detecting even small subgroups of B cells or Treg cells in the tumors, although CyTOF could distinguish the specific populations in more depth. These findings demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of TME in small biopsy tumors, which would provide a novel strategies to overcome a therapeutic difficulties against cancer heterogeneity in TME