Nicotine Disrupts Top-Down Habenular Control Over Cholinergic Inputs to the Ventral Tegmental Area to Increase Motivational Valence of Food Rewards

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BACKGROUND: Tobacco use significantly impacts reward-driven behavior, leading to comorbidities across a lifetime. While the addictive properties of nicotine are well studied, its effects on cellular mechanisms beyond drug-seeking behaviors remain elusive. Here, we investigated the circuit alterations that parallel drug-related behaviors. METHODS: Male mice were chronically exposed to nicotine in their drinking water for 6 weeks. Then, we combined behavioral measures in operant and non-operant tasks to evaluate changes in motivation while utilizing chemogenetics to selectively modulate cholinergic inputs to the ventral tegmental area (VTA). We combined patch clamp with optogenetics and in vivo electrophysiological recordings to provide a comprehensive cellular analysis of nicotine's impact. Functional assessments were paralleled with high-resolution array tomography to monitor structural adaptations. RESULTS: Chronic nicotine dampened the cholinergic modulation of VTA dopamine neuron activity, leading to an exaggerated motivation for food reward seeking. Selective chemogenetic enhancement of cholinergic tone from the laterodorsal tegmentum (LDT) to the VTA restored normal motivational control, while silencing of this projection triggered the opposite effect. We reveal structural and functional deficits in the synaptic integration of excitatory inputs from the lateral habenula (LHb) onto LDT cholinergic neurons projecting to the VTA that correlate with observed behavioral alterations. We identify specific cellular and synaptic changes that underlie nicotine-induced dysregulation of motivation. CONCLUSIONS: Chronic nicotine consumption alters motivation for natural rewards by disrupting top-down control of the LHb onto the LDT-VTA cholinergic axis. Our work highlights previously unrecognized contributors to nicotine's impact on mental health.

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