Connectivity and Function of the Asymmetric Habenulo-Interpeduncular Pathway

不对称缰核-脚间通路的连接性和功能

基本信息

批准号：
10450629
负责人：
MARNIE E HALPERN
金额：
$ 51.24万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450629
关键词：
Adult Amphibia Anti-Anxiety Agents Anxiety Attention Attenuated Aversive Stimulus Axon Basal Ganglia Behavior Behavioral Behavioral Assay Bilateral Biological Assay Brain Brain region CRISPR/Cas technology Cells Chemicals Cues Data Dorsal Dyslexia Exposure to Fishes Freezing Fright Functional disorder Gene Expression Profiling Genes Goals Habenular Nucleus Hand Health Human Image Knowledge Laboratories Laser Scanning Microscopy Learning Left Mammals Maps Medial Mediating Midbrain structure Modeling Molecular Mood Disorders Motivation Neural Conduction Neural Pathways Neurologic Neurons Neuropeptides Neurotransmitters Nicotine Dependence Nicotine Withdrawal Odors Pain Pathologic Pathway interactions Pattern Pharmaceutical Preparations Pheromone Physiological Play Population Process Property Prosencephalon Proteins Recovery Reproduction Reptiles Research Rewards Role Sampling Schizophrenia Shock Side Signal Transduction Sleep Somatostatin Swimming Synapses System Techniques Testing Toxin Transgenic Organisms United States Vertebrates Withdrawal Symptom Work Zebrafish addiction behavioral response calcium indicator cholinergic diencephalon experimental study feeding information processing innovation interest interpeduncular nucleus novel olfactory bulb optogenetics relating to nervous system response tool two-photon

项目摘要

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.

缰核-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、进食、繁殖和奖励，以及人类的病理状况，例如情绪障碍和成瘾。尽管他们的重要性和不同的作用，但人们对双边配对中神经元亚型的全部知识知之甚少背侧间脑的内侧缰核（mHb）或其与主要目标的精确连接，中脑腹侧不成对的脚间核（IPN）。人们对这条途径重新产生了兴趣来自它与尼古丁依赖和戒断的关联，以及来自斑马鱼的发现与其他脊椎动物一样，背部Hb（相当于哺乳动物的mHb）表现出显着的左右差异它们的大小、组织、分子特性以及与 IPN 的联系。事实上，我们已经确定了新颖的， DHb 中不对称分布的神经元亚型投射到 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。在之前探索左右 dBHb 差异的功能意义的工作中，我们发现改变方向不对称性会引起幼虫和成虫的行为和生理变化表明恐惧/焦虑增强的斑马鱼。我们最近发现神经元活动主要在左侧 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 中提出的实验将结合光遗传学、转基因和行为方法来识别负责的神经元。拟议的研究不仅将增加我们对重要但尚未充分研究的神经通路的了解，他们还将阐明如何左右脑神经元对信息的处理有差异，从而产生适当的信息行为反应。