The role of activity-dependent transcription in nicotine addiction-associated neuronal ensembles

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Tobacco use is the leading preventable cause of death and disease, with over 7 million deaths per year worldwide and an annual direct healthcare burden of $170 billion in the USA alone. Despite this, the neural mechanisms involved in nicotine addiction are poorly understood. Many brain regions are activated by nicotine, but little is known about the cell types and their circuit connections and what changes in these cells and circuits when they are exposed to nicotine in vivo. Memory is encoded by unique patterns of activity across neuronal ensembles whose synaptic connectivity and excitability are altered by experience to facilitate or repress their reactivation in the future. Such reactivation of a neuronal ensemble represents long-term memory, whether conscious or subliminal, and these memories shape our behavior. We wish to identify nicotine sensitive ensembles within the sub-cortical reward circuitry of the brain and discover how their synaptic connectivity and excitability are altered by nicotine exposure. We will attempt to block the formation of nicotine induced reward by interfering with cell signaling and gene transcription factors which are activated by nicotine in these cell types and which mediate cellular and behavioral adaptations elsewhere in the brain. We recently published the most extensive study to date to identify nicotine-activated neuronal ensembles using immunohistochemistry. Since then, our lab has developed molecular tools to fluorescently tag nicotine-activated neurons in vivo allowing us to visually identify them in live brain slices or fixed tissue blocks to investigate not only their cell type and brain region but also their electrophysiological properties, synaptic connectivity and dendritic structure. Our electrophysiological analysis has revealed several channel types in these cells which are known to control excitability as well nicotine-activated nuclear calcium signals and a nuclear calcium activated transcription factor, Npas4, which is known to be critical for modifications of synaptic connectivity and behavioral adaptations in other brain regions and contexts. Further work is required to reveal the neurotransmitters, circuits, channel properties and dendritic structure of these cell types, whether whey are modified by nicotine and whether these modifications require activation of nuclear calcium and Npas4 regulated gene expression. We have the tools to identify, analyze and selectively manipulate these cells and their nicotine responses and to assess the behavioral adaptations to nicotine exposure. In this way we hope to discover functional mechanisms and signaling pathways in specific cell types critical for the development of nicotine dependence. This approach may generate novel targets for strategies to interfere with nicotine addiction as well as identify the molecular and cellular mechanisms of long-term changes in sub-cortical neuronal ensembles.