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Article
Peer Reviewed

Nicotine-induced dopamine plasticity: a gateway to neurotransmitter replacement?

UC San Diego Previously Published Works (2020)

Thesis
Peer Reviewed

Nicotine-induced Neurotransmitter Plasticity in the Substantia Nigra: Implications for Parkinson’s Disease

UC San Diego Electronic Theses and Dissertations (2018)

Cigarette smoking is generally known for its detrimental effects on health; however, extensive epidemiological studies have indicated inverse correlation between smoking and Parkinson’s Disease (PD), a progressive neurodegenerative disorder characterized by loss of dopaminergic (DAergic) neurons in the substantia nigra (SN). Subsequent studies have shown that nicotine protects DAergic neurons against nigrostriatal damage in PD primate and rodent models. Nicotine became the focus of these studies due to its well-known ability to modulate function and activity of midbrain DAergic neurons. Because altered circuit activation can induce neurons to acquire a DAergic phenotype in the mature brain, we hypothesized that chronic nicotine treatment contributes to neuroprotection against nigrostriatal damage in an animal model of PD via a mechanism of neurotransmitter plasticity.

Nicotine was given to adult mice in drinking water for two weeks. Brains of various transgenic reporter mouse lines were subsequently processed for immunohistochemistry and retrobead tracing for detection of tyrosine hydroxylase and other cell markers in the SN, and neuronal connectivity. Selective overexpression of human A53T alpha synuclein in midbrain DAergic neurons was used as a PD mouse model.

Our findings showed that chronic nicotine treatment significantly increased DA expression within a pool of SNr (pars reticulata) GABAergic neurons that express transcription factors associated with DA differentiation, such as Nurr1 and Foxa2, prior to nicotine exposure. More importantly, our retrograde labelling experiments showed that this GABAergic neuronal pool in the SNr projects to the caudate nucleus, the same target of SNc (pars compacta) DAergic neurons. Ongoing behavioral experiments on a PD mouse model confirmed that nicotine treatment ameliorates some motor deficits in these mice. Our results indicate that neurotransmitter plasticity occurs in the SN in response to chronic nicotine treatment. Understanding its role in neuroprotection against nigrostriatal damages in PD could reveal insights that may lead to the development of new treatments for Parkinson’s Disease.

Cover page: Nicotine-induced Neurotransmitter Plasticity in the Substantia Nigra: Implications for Parkinson’s Disease

Article
Peer Reviewed

A cell type-specific expression map of NCoR1 and SMRT transcriptional co-repressors in the mouse brain.

UC San Diego Previously Published Works (2020)

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.

Article
Peer Reviewed

A cell type-specific expression map of NCoR1 and SMRT transcriptional co-repressors in the mouse brain.

UC San Diego Previously Published Works (2020)

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.