Connectivity and Function of the Asymmetric Habenulo-Interpeduncular Pathway

缰核-脚间通路是脊椎动物大脑中一种高度保守的传导系统，具有 与许多过程有关，从睡眠到恐惧/焦虑、疼痛、学习、动力、进食、繁殖 和奖赏，以及在人类的病理条件下，如情绪障碍和成瘾。尽管他们 重要性和不同的角色，对双边配对的神经元亚型的谱系知之甚少 背侧间脑的内侧缰核(MHB)或它们与主要靶点的精确联系， 位于中脑腹侧的不成对的脚间核。人们对这一途径重新产生了兴趣 来自于它与尼古丁依赖和戒断的联系，以及在斑马鱼中发现 与其他脊椎动物一样，背侧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。事实上，我们已经确定了小说， DHb中投射到IPN受限区域的不对称分布的神经元亚型。 初步数据支持dHb传出与特定IPN形成精确连接图的假设 现在将通过具体目标1和2中提出的实验来验证这一点。 在之前探索左右dHb差异的功能意义的工作中，我们 发现改变方向不对称会导致幼虫和成虫的行为和生理变化 斑马鱼表明恐惧/焦虑加剧。我们最近发现，神经元的活动 主要是在左侧dHb减弱冻结，这是一种幼虫的恐惧反应，从而促进 游泳运动。使用最先进的技术，目标3中提出的实验将结合光遗传， 转基因和行为学方法，以确定负责的神经元。拟议的研究不仅将 增加我们对基本但未被研究的神经通路的知识，他们也将阐明如何 大脑左右两侧神经元对信息的不同处理导致适当的 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.