Habenular immune signaling and addiction

投射到脚间核（interpeduncular nucleus，IPn）的内侧缰核（Medial habenula，mHb）神经元调节“设定点”， 尼古丁厌恶，并在调节尼古丁摄入量中发挥关键作用。然而，人们对它知之甚少。 尼古丁消耗对这一回路功能的影响。我们已经收集了令人信服的初步证据 啮齿类动物的数据显示，尼古丁减少缰核体积，诱导mHb胆碱能神经元丢失， 触发从mHb到IPn的投射纤维的变性。我们检测到类似的缰核体积减少， 吸烟者与不吸烟者相比。选择性损毁缰核-IPn回路， 增加大鼠的尼古丁摄入量，表明尼古丁诱导的缰核-IPn回路损伤可能是 来增加药物的激励作用独特的是，mHb中的神经元表达白细胞介素-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。 已知小神经胶质细胞通过修剪神经元和调节神经元的生长来控制兴奋性和抑制性传递的强度。 突触来塑造大脑中的回路。我们发现尼古丁对缰核有更强的刺激作用- I118-/-小鼠的IPn回路比野生型小鼠的更小。初步研究结果表明，尼古丁诱导的 IL 18-/-小鼠中mHb神经元的损伤比野生型同窝出生的小鼠明显。最后，Il 18-/-小鼠表现出较低的 与野生型小鼠相比，小胶质细胞的数量和缰核中小胶质细胞衍生的细胞因子的水平降低。 基于这些发现，我们假设尼古丁引发了缰核变性，而IL-18， 由缰核神经元产生，可以防止这种反应。我们进一步假设IL-18通过以下方式起作用： 招募局部小胶质细胞修剪缰神经元，从而对抗尼古丁对神经元的兴奋作用。 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Specific Aim I中，我们将使用iDISCO组织清除结合光片显微镜进行超级 3D分辨率，以充分表征IL-18和小胶质细胞在调节尼古丁兴奋性毒性作用中的作用， mHb神经元。在《特异性目标II》中，我们将研究IL-18和小胶质细胞在调节细胞凋亡中的作用。 尼古丁对mHb神经元的刺激作用。在具体目标III中，我们将研究尼古丁的相关性- 诱导mHb的损伤，以及IL-18和小胶质细胞在这一过程中的参与， 尼古丁的特性这一高度创新的研究计划可能会产生根本的新见解， 大脑免疫功能、缰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.