Opto-pharmacological dissection of nicotinic signaling in the medial habenulo-interpeduncular axis – CHOLHAB

Smoking remains the major cause of preventable death in humans. Worldwide, 100 million people are expected to die this century from the consequences of prolonged tobacco consumption and of the ensuing addiction to nicotine.

In the brain, nicotine acts through nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of receptors that are largely distributed throughout the central nervous system. Repeated exposure to nicotine produces molecular and cellular adaptations in multiple neuronal circuits, leading to addiction. In recent years, the medial habenulo-interpeduncular (MHb-IPN) axis has emerged as a central pathway translating negative emotional states such as fear and anxiety and mediating the aversive properties of nicotine. Remarkably, the MHb-IPN tract shows the highest density and diversity of nAChRs in the brain, and thus constitutes one of the most promising pharmacological targets for smoking cessation therapies. Nevertheless, the endogenous functions of these receptors and their roles in nicotine addiction are not known, hampering development of clinically effective treatments.

Our goal is to understand how nicotine affects the MHb-IPN circuit, and to test the hypothesis that chronic exposure to nicotine profoundly modifies the physiology of this pathway, thus triggering the emergence of negatively-valued behaviors. In this project, we will use cutting-edge optopharmacological approaches, that enable photo-targeted inactivation of specific nAChR isoforms in defined neurons in the awake, behaving animal. This method relies on the covalent attachment of a photoswitchable antagonist onto a cysteine-substituted subunit to produce light-controllable receptors (LinAChRs). LinAChRs are minimally modified, and thus retain their ability to be activated by acetylcholine (ACh) or nicotine in darkness. However, they can be optically and reversibly blocked at specific synapses and at specific times, with absolute pharmacological specificity. We will integrate optopharmacology with optogenetics, electrophysiology and behavioral readout methods in transgenic mice models, to explore the causal, temporally precise, and behaviorally relevant roles of MHb-IPN nAChRs, in both health and in disease.

Our project will follow a comprehensive work plan covering all aspects of nicotinic actions on the components of the MHb-IPN axis, from activity dependent synaptic mechanisms in ex-vivo preparations, to behavioral implications in freely moving animals. Our aim is to unravel the sources of habenular ACh, to characterize how endogenous ACh modulates the activity of MHb and IPN neuronal (sub)populations, and to identify the nAChR subtypes involved. We will decipher the mechanisms by which acute and chronic nicotine alters the physiology of the MHb-IPN axis at both cellular and network levels. The neuroadaptations of this pathway will thus be investigated as nicotine administration progresses from acute to chronic and to withdrawal, mirroring the progression experienced by smokers. Finally, we will causally implicate ACh and the nAChRs of this pathway in the development and the expression of nicotine abuse and aversive behaviors. In-vivo exploitation of LinAChRs will indeed allow us to control nicotine-related behaviors in mice, namely consumption and withdrawal-associated phenotypes, with the unprecedented spatial, temporal and pharmacological precision peculiar to these newly-developed tools.
Our collaboration thus promises to provide crucial information on how the components of the MHb-IPN circuit are (dys)regulated by nicotine; an essential step towards the development of innovative therapies for this socially burdensome form of addiction.