Involvement of habenulo-interpeduncular circuitry in nicotine reward and aversion

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Project Summary/Abstract Smoking tobacco is one of the leading causes of preventable mortality in adults worldwide. However, there is currently a lack of pharmacological smoking cessation aids and their efficacy is limited. Therefore, there is an urgent need to better understand the neural mechanisms that underlie nicotine addiction for the development of novel smoking cessation treatments. Much of our understanding of the reinforcing effects of nicotine are derived from studies focused on canonical mesolimbic dopamine reward circuitry in the brain. Research suggests that the habenulo-interpeduncular pathway consisting of the medial habenula (MHb) and interpeduncular nucleus (IPN) contributes to the aversive motivational properties of high nicotine doses. It is speculated that activation of nicotinic cholinergic receptors (nAChRs) stimulates excitatory acetylcholine/glutamate (ACh/Glu) co-releasing projection neurons which activate ɣ-aminobutyric acid (GABA) neurons in the IPN. However, silencing IPN neurons in rodent models has also been shown to reduce nicotine consumption and reward. Thus, it is possible that modulation of MHb→IPN circuit activity may contribute to the balance of nicotine reward and aversion, a critical component of nicotine addiction liability. However, it is unknown how MHb→IPN neurons respond to nicotine within the context of reward related behavior. It is also unclear whether nicotine-induced activation of this circuit is necessary to elicit nicotine’s aversive properties. In the proposed project, I aim to test the hypothesis that modulation of IPN GABAergic neuron activity by nicotine is critical for balancing nicotine reward/aversion. I also aim to test the hypothesis that nicotine-induced control of ACh/Glu projection neuron activity from the MHb to IPN controls nicotine reward/aversion balance. Thus, I will assess the influence of rewarding or aversive nicotine doses on MHb or IPN neural activity during the performance of conditioned place preference/conditioned place aversion (CPP/CPA) procedures using in vivo fiber photometry combined with genetically encoded calcium indicators (GCaMPs). Finally, I will use in vivo optogenetics to selectively activate or silence MHb or IPN neurons to investigate whether specific components of this circuit are sufficient to drive nicotine reward/aversion balance. The goal of this project is to provide a better understanding of circuit-specific mechanisms that may contribute to nicotine reward/aversion balance, which will aid in the development of precise pharmacological treatments for smoking cessation.