Cholinergic modulation of glutamatergic signaling in nicotine addiction and relapse

项目摘要/摘要 尼古丁滥用和上瘾是公共卫生的重大负担。尼古丁，一种活性生物碱 在烟草中，负责对含烟草产品，如雪茄、香烟和汽化的上瘾 液体电子烟。鉴于尼古丁成瘾对健康的巨大负面影响，以及最近尼古丁成瘾的激增 随着含尼古丁电子烟的普及，对电子烟的创新研究非常必要 尼古丁成瘾和复发的神经生物学基础。尼古丁在大脑中产生细胞适应 与药物奖励相关的区域，如伏隔核(NA)。然而，神经行为 成瘾和复发易感性形成的潜在机制相对未知。核 伏隔核(NAcore)谷氨酸能机制参与尼古丁复发，包括快速、短暂的 突触强度的增强(测量为树突棘直径和AMPA电流的增加)和 伴随谷氨酸受体的变化。有趣的是，烟碱型乙酰胆碱受体(NAChRs)， 具体地说，含有α7和β2的基因在大脑中介导了这种与尼古丁复发相关的快速、短暂的可塑性 纳科尔。提出的研究的主要假设是，线索诱导的前额叶谷氨酸释放 皮质(PFC)-NA投射(具体地说，PFC和NAcore的初级(PL)亚区)被激活 前馈促进延长的NA胆碱能中间神经元释放乙酰胆碱(ACh) 谷氨酸的释放有助于尼古丁寻求行为的复发。在这种情况下，CHIS可能会调制异常 谷氨酸能信号通过加剧信号，从而解锁从对毒品的渴望到寻求的转变。 由于吸烟行为对线索的依赖，接触尼古丁相关线索是复发的危险因素。 在拟议的研究中，我们将探索CHI特有的调节尼古丁恢复的机制 以及突触可塑性的相关变化，并对神经元相互作用进行电路级分析 潜在的复发脆弱性。在特定的目标1中，我们将研究CHI信号对前额叶的影响 皮层谷氨酸能投射到伏隔核，以及这一亚回路对线索诱导的影响 尼古丁寻求和ACh释放。在特定目标2中，CHIS将被化学激活或抑制在 伏隔核与中棘神经元的快速、瞬时突触可塑性 尼古丁寻找行为将被测量。我们预测，操纵CHIS将导致变态的复发- MSN中相关的突触可塑性，这反过来将导致尼古丁寻求动机的改变。在这两个地方 旨在，新技术将从多个层次的分析中得到利用，包括光遗传学、化学遗传学、 微透析、行为和电生理学。总而言之，这些调查的结果将扩大到 未来的目标是定义尼古丁成瘾的神经回路和神经行为机制- 相关行为。

PROJECT SUMMARY/ABSTRACT Nicotine abuse and addiction represent a substantial burden to public health. Nicotine, an active alkaloid in tobacco, is responsible for addiction to tobacco-containing products such as cigars, cigarettes, and vaporized liquid e-cigarettes. Given the immense negative health impact of nicotine addiction as well as the recent surge in popularity of nicotine-containing e-cigarettes, there is a great need for innovative research on the neurobiological underpinnings of nicotine addiction and relapse. Nicotine produces cellular adaptations in brain regions associated with drug reward, such as the nucleus accumbens (NA). However, the neurobehavioral mechanisms underlying the development of addiction and relapse vulnerability are relatively unknown. Nucleus accumbens core (NAcore) glutamatergic mechanisms are involved in nicotine relapse, including rapid, transient potentiation of synaptic strength (measured as increased dendritic spine diameter and AMPA currents) and accompanying glutamate receptor changes. Interestingly, nicotinic acetylcholine receptors (nAChRs), specifically α7 and β2-containing, mediate this rapid, transient nicotine relapse-associated plasticity within the NAcore. The principal hypothesis of the proposed studies is that cue-induced glutamate release at prefrontal cortex (PFC)-NA projections (specifically, the prelimbic (PL) subregion of the PFC, and the NAcore) activates release of acetylcholine (ACh) from NA cholinergic interneurons (ChIs) that feeds forward to promote prolonged glutamate release contributing to relapse of nicotine-seeking behavior. In this way, ChIs may modulate aberrant glutamatergic signaling by exacerbating the signal and thus unlocking the transition from drug craving to seeking. Due to the cue dependency of smoking behavior, exposure to nicotine-associated cues is a risk factor for relapse. In the proposed studies, we will explore ChI-specific mechanisms modulating both cued nicotine reinstatement and associated changes in synaptic plasticity, and perform a circuit-level analysis of neuronal interactions underlying relapse vulnerability. In Specific Aim 1, we will examine the impact of ChI signaling on prefrontal cortex glutamatergic projections into the accumbens core, and the impact of this subcircuit on cue-induced nicotine seeking and ACh release. In Specific Aim 2, ChIs will be chemogenetically activated or inhibited within the accumbens core and rapid, transient synaptic plasticity in medium spiny neurons (MSNs) associated with nicotine seeking behavior will be measured. We predict that manipulation of ChIs will result in altered relapse- associated synaptic plasticity in MSNs, which in turn will lead to alterations in nicotine seeking motivation. In both aims, novel techniques will be utilized from multiple levels of analysis including optogenetics, chemogenetics, microdialysis, behavior, and electrophysiology. In conclusion, findings from these investigations will extend to future goals of defining the neural circuitry and neurobehavioral mechanisms underlying nicotine addiction- related behaviors.