Cellular Basis of Nicotine Induced Aversion

描述（由申请人提供）：尼古丁成瘾仍然是美国和世界各地的主要健康问题。尼古丁的奖励作用是有据可查的，但更高剂量的尼古丁有强烈的厌恶作用。对尼古丁的最初反应可以预测 未来依赖性（即，相对于第一次尼古丁体验是厌恶的受试者，第一次尼古丁体验是有益的受试者更可能成为尼古丁依赖者）。因此，尼古丁奖赏和厌恶之间的平衡可能有助于尼古丁成瘾的发展和维持。尽管对尼古丁对奖赏相关回路的影响有相当多的了解，但尼古丁依赖人群的治疗仍然有限。了解尼古丁厌恶的机制可以为尼古丁依赖的因素提供新的见解。这些见解有可能揭示新的治疗靶点和策略。 最近，从内侧缰核（MHb）到脚间核（IPN）的投射被证明介导尼古丁厌恶。抑制MHb-IPN活性降低尼古丁的厌恶作用，而增强MHb-IPN活性增强对尼古丁的厌恶。虽然这些结果涉及MHb-IPN电路，下游突触后的IPN和神经递质的目标仍然在很大程度上未被表征。一些证据表明，这种回路最终抑制腹侧被盖区多巴胺（DA）神经元。DA神经元的爆发活动与动机行为有关，抑制DA神经元的输出会导致令人厌恶的体验。虽然IPN投射到几个脑区，但它强烈地支配外侧背侧被盖核（LDTg），这是一个控制腹侧被盖区DA神经元爆发性放电的脑干胆碱能中心。激活的LDTg神经元，项目的腹侧被盖区的结果在增强活动的腹侧被盖区以及条件性位置偏爱，而腹侧被盖区DA神经元的抑制已被链接到条件性位置厌恶。因此，抑制LDTg（通过IPN兴奋），从而抑制VTA DA神经元，可能会减少尼古丁的奖励作用。 本提案中概述的实验将研究尼古丁厌恶效应的细胞机制，以及这种厌恶如何影响奖励回路。我们将使用光遗传学策略来探索介导MHb-IPN通路和VTA DA神经元之间的通信的细胞机制。这些途径和尼古丁诱导的行为之间的因果关系将通过在测试尼古丁相关行为时光遗传学激发或抑制这些途径来探索。探索MHb-IPN电路介导尼古丁厌恶的机制可以产生新的治疗靶点和治疗策略，帮助吸烟者成功戒烟。

DESCRIPTION (provided by applicant): Nicotine addiction remains a major health problem in the US and throughout the world. The rewarding effects of nicotine are well-documented, but higher doses of nicotine have intensely aversive effects. Initial responses to nicotine can predict future dependence (i.e., subjects whose first nicotine experiences were rewarding are more likely to become nicotine dependent relative to subjects whose first nicotine experiences were aversive). Thus, the balance between nicotine reward and aversion likely contributes to the development and maintenance of nicotine addiction. Despite considerable understanding of the effects of nicotine on reward-related circuitry, treatments for nicotine dependent populations remain limited. Understanding the mechanisms that underlie aversion to nicotine can provide novel insights into the factors that contribute to nicotine dependence. These insights have the potential to reveal novel therapeutic targets and strategies. Recently, the projection from the medial habenula (MHb) to the interpeduncular nucleus (IPN) was shown to mediate nicotine aversion. Suppressing MHb-IPN activity reduces the aversive effects of nicotine, while enhancing MHb-IPN activity enhances aversion to nicotine. Although these results implicate the MHb-IPN circuitry, the downstream post-synaptic targets of the IPN and the neurotransmitters involved remain largely uncharacterized. Some evidence suggests that this circuitry ultimately suppresses VTA dopamine (DA) neurons. Burst activity in DA neurons has been linked to motivated behaviors, and suppression of DA neuron output results in an aversive experience. While the IPN projects to several brain areas, it strongly innervates the lateral dorsal tegmental nucleus (LDTg), a brainstem cholinergic center that controls burst firing of VTA DA neurons. Activation of LDTg neurons that project to the VTA results in enhanced activity in the VTA as well as conditioned place preference, whereas inhibition of VTA DA neurons has been linked to conditioned place aversion. Therefore, inhibiting the LDTg (via IPN excitation), and consequently VTA DA neurons, may diminish the rewarding effects of nicotine. Experiments outlined in this proposal will examine the cellular mechanisms underlying the aversive effects of nicotine and how this aversion impacts reward circuitry. We will use optogenetic strategies to explore the cellular mechanisms mediating the communication between the MHb-IPN pathway and VTA DA neurons. Causal links between these pathways and nicotine-induced behaviors will be explored by optogenetic excitation or inhibition of these pathways while testing nicotine-related behaviors. Exploring the mechanisms by which the MHb-IPN circuitry mediates nicotine-aversion could yield novel therapeutic targets and treatment strategies for helping smokers quit successfully.