The ability to rapidly change gene expression patterns is essential for differentiation, development, and functioning of the brain. Throughout development, or in response to environmental stimuli, gene expression patterns are tightly regulated by the dynamic interplay between transcription activators and repressors. Nuclear receptor corepressor 1 (NCoR1) and silencing mediator for retinoid or thyroid-hormone receptors (SMRT) are the best characterized transcriptional co-repressors from a molecular point of view. They mediate epigenetic silencing of gene expression in a wide range of developmental and homeostatic processes in many tissues, including the brain. For instance, NCoR1 and SMRT regulate neuronal stem cell proliferation and differentiation during brain development and they have been implicated in learning and memory. However, we still have a limited understanding of their regional and cell type-specific expression in the brain. In this study, we used fluorescent immunohistochemistry to map their expression patterns throughout the adult mouse brain. Our findings reveal that NCoR1 and SMRT share an overall neuroanatomical distribution, and are detected in both excitatory and inhibitory neurons. However, we observed striking differences in their cell type-specific expression in glial cells. Specifically, all oligodendrocytes express NCoR1, but only a subset express SMRT. In addition, NCoR1, but not SMRT, was detected in a subset of astrocytes and in the microglia. These novel observations are corroborated by single cell transcriptomics and emphasize how NCoR1 and SMRT may contribute to distinct biological functions, suggesting an exclusive role of NCoR1 in innate immune responses in the brain.

Previous work revealed an inverse correlation between tobacco smoking and Parkinson’s disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. Here, we investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function. Wild-type and α-syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in situ hybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation. We found that nicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of α-syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum. Finally, concomitant depolarization and Nurr1 overexpression within GABA neurons were sufficient to mimic nicotine-mediated dopamine plasticity. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD.

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BACKGROUND: Previous work revealed an inverse correlation between smoking and Parkinson's disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. We investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function. METHODS: Wild-type and α-syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in-situ hybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation. RESULTS: Nicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of α-syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1 in non-DA neurons. Retrograde labeling revealed that a fraction of these GABAergic neurons project to the dorsal striatum. CONCLUSIONS: Nicotine exposure initiates neuroprotective mechanisms counteracting the neurodegenerative effects of α-syn accumulation in DA neurons and contributing to Nurr1-mediated therapeutic effects. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD.