Habenular immune signaling and addiction

投射到脚间核的内侧缰核(MHB)神经元调节 尼古丁的厌恶和对尼古丁摄入量的调节起着关键作用。然而，人们对此知之甚少。 尼古丁摄入对这一回路功能的影响。我们收集了令人信服的初步资料 在啮齿动物中的数据表明，尼古丁减少缰核体积，诱导MHB胆碱能神经元的丢失，以及 触发投射纤维从MHB到IPN的退化。我们检测到类似的缰核体积减少。 人类吸烟者与不吸烟者的比较。缰核-IPN环路明显选择性损害 增加大鼠的尼古丁摄入量，这表明尼古丁可能导致缰核-IPN回路的损害 以增加药物的激励意义。MHB中的神经元独特地表达白介素18(IL-18)。 18)，一种调节小胶质细胞和先天免疫系统其他成分功能的细胞因子。 已知小胶质细胞通过修剪神经元和控制兴奋和抑制传递的强度 突触形成大脑中的环路。我们发现尼古丁对缰核有更大的刺激作用-- IL18-/-小鼠的IPN环路高于野生型小鼠。初步研究表明，尼古丁的诱导性要强得多。 对IL18-/-小鼠MHB神经元的损伤大于野生型窝种。最后，IL18-/-小鼠表现出较低的 与野生型小鼠相比，缰核中的小胶质细胞数量和小胶质细胞衍生细胞因子水平降低。 基于这些发现，我们假设尼古丁引发缰核变性，IL-18， 由缰核神经元产生，对这种反应具有保护作用。我们进一步假设IL-18通过 募集局部小胶质细胞修剪缰核神经元，从而对抗尼古丁对 这些细胞。在这里，我们将使用最先进的分子、细胞和行为方法来测试这些 假设。在特定的目标I中，我们将使用iDISCO组织透明结合光片显微镜进行超 3D分辨率以充分表征IL-18和小胶质细胞在调节尼古丁的兴奋性毒性效应中的作用 MHB神经元。在特定的目标II中，我们将研究IL-18和小胶质细胞在调节 尼古丁对MHB神经元的兴奋作用。在特定的目标III中，我们将调查尼古丁的相关性- 诱导的MHB损伤，以及IL-18和小胶质细胞在这一过程中的参与，对动力 尼古丁的特性。这一极具创新性的研究计划可能会产生对 大脑免疫功能、缰核可塑性和尼古丁成瘾之间的联系。

Medial habenula (mHb) neurons that project to the interpeduncular nucleus (IPn) regulate the “set-point” for nicotine aversion and play a critical role in regulating nicotine intake. Nevertheless, little is known about the consequences of nicotine consumption on the function of this circuit. We have collected compelling preliminary data in rodents showing that nicotine reduces habenular volume, induces loss of mHb cholinergic neurons, and triggers degeneration of projection fibers from mHb to IPn. We detect similar reductions of habenular volume in human cigarette smokers compared with non-smokers. Selective lesion of the habenula-IPn circuit markedly increases nicotine intake in rats, suggesting that nicotine-induced damage to the habenula-IPn circuit is likely to increase the motivational significance of the drug. Uniquely, neurons in the mHb express interleukin-18 (IL- 18), a cytokine that regulates the function of microglia and other components of the innate immune system. Microglia are known to control the strength of excitatory and inhibitory transmission by pruning neurons and synapses to sculpt circuits in the brain. We find that nicotine has greater stimulatory effects on the habenula- IPn circuit of Il18-/- mice than wild-type mice. Preliminary findings suggest that nicotine induces far greater damage to mHb neurons in Il18-/- mice than wild-type littermates. Finally, Il18-/- mice demonstrate lower numbers of microglia and reduced levels of microglia-derived cytokines in the habenula than wild-type mice. Based on these findings, we hypothesize that nicotine triggers habenular degeneration and that IL-18, produced by habenular neurons, protects against this response. We further hypothesize that IL-18 acts by recruiting local microglia to prune habenular neurons, thereby opposing the excitatory actions of nicotine on these cells. Here, we will use state-of-the-art molecular, cellular and behavioral approaches to test these hypotheses. In Specific Aim I, we will use iDISCO tissue clearing coupled with light-sheet microscopy for super 3D resolution to fully characterize the role for IL-18 and microglia in regulating excitotoxic effects of nicotine on mHb neurons. In Specific Aim II, we will investigate the role for which IL-18 and microglia in regulating the stimulatory actions of nicotine on mHb neurons. In Specific Aim III, we will investigate the relevance of nicotine- induced damage to the mHb, and the involvement of IL-18 and microglia in this process, to the motivational properties of nicotine. This highly innovative program of research may yield fundamental new insights into the links between brain immune function, habenular plasticity and nicotine addiction.