Connectivity and Function of the Asymmetric Habenulo-Interpeduncular Pathway

缰-脚间通路是脊椎动物大脑中高度保守的传导系统， 涉及许多过程，从睡眠到恐惧/焦虑，疼痛，学习，动机，喂养，繁殖 和奖励，以及人类的病理条件，如情绪障碍和成瘾。尽管他们 重要性和不同的作用，很少有人知道的剧目，神经元亚型在双边配对 背侧间脑的内侧缰核（mHb）或其与主要靶点的精确连接， 中脑腹侧的不成对脚间核（IPN）。对这一途径的新兴趣 来自它与尼古丁依赖和戒断的联系，以及在斑马鱼中发现， 与其他脊椎动物相比，背部Hb（相当于哺乳动物的mHb）显示出显著的左右差异 在它们的大小、组织、分子性质和与IPN的连接方面。的确，我们已经确定了新的， dHb中不对称分布的神经元亚型，其投射到IPN的限制区域。 初步数据支持dHb传出神经与特定IPN形成精确连接图的假设 神经元，现在将通过具体目标1和2中提出的实验进行验证。 在以前的工作中，探索左和右dHb之间差异的功能意义，我们 发现改变方向的不对称性会引起幼虫和成虫的行为和生理变化 斑马鱼，这是增强恐惧/焦虑的指示。我们最近发现神经元活动 主要在左dHb减弱冻结，幼虫的恐惧反应，从而促进恢复， 游泳活动。使用最先进的技术，目标3中提出的实验将联合收割机结合光遗传学， 转基因和行为的方法来识别负责的神经元。这项研究不仅将 增加了我们对一个重要但研究不足的神经通路的了解，他们还将阐明如何 大脑左侧和右侧神经元对信息的不同处理导致了适当的 行为反应

The habenulo-interpeduncular pathway, a highly conserved conduction system in the vertebrate brain, has been implicated in many processes, from sleep to fear/anxiety, pain, learning, motivation, feeding, reproduction and reward, and in pathological conditions in humans such as mood disorders and addiction. Despite their importance and diverse roles, little is known about the repertoire of neuronal subtypes in the bilaterally paired medial habenular nuclei (mHb) of the dorsal diencephalon or their precise connections with their major target, the unpaired interpeduncular nucleus (IPN) in the ventral midbrain. A renewed interest in this pathway has come from its association with nicotine dependence and withdrawal and from the discovery that, in zebrafish and other vertebrates, the dorsal Hb (equivalent to the mHb of mammals) show prominent left-right differences in their size, organization, molecular properties and connections to the IPN. Indeed, we have identified novel, asymmetrically distributed neuronal subtypes in the dHb that project to restricted regions of the IPN. Preliminary data support the hypothesis that dHb efferents form a precise connectivity map with specific IPN neurons, which will now be validated by experiments proposed in Specific Aims 1 and 2. In previous work to explore the functional significance of differences between the left and right dHb, we found that altering directional asymmetry induces behavioral and physiological changes in larval and adult zebrafish that are indicative of enhanced fear/anxiety. We recently discovered that neuronal activity predominantly in the left dHb attenuates freezing, a larval fear response, thereby promoting recovery of swimming activity. Using state-of-the-art techniques, experiments proposed in Aim 3 will combine optogenetic, transgenic and behavioral approaches to identify the responsible neurons. The proposed research will not only increase our knowledge of an essential but understudied neural pathway, they will also elucidate how differential processing of information by neurons on the left and right sides of the brain leads to appropriate behavioral responses.