New models of lateral habenula function in pathways regulating anxiety and mood

外侧缰核在调节焦虑和情绪通路中的功能新模型

• 批准号: 8894293
• 负责人: Eric E. Turner
• 金额: $ 48.5万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-10 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894293
• 关键词: Acute; Anxiety; Anxiety Disorders; Area; Behavior; Behavioral; Behavioral Model; Biological Assay; Brain; Brain Stem; Brain region; Bypass; Cell Nucleus; Cues; Dopamine; Dorsal; Electrophysiology (science); Epithalamic structure; Event; Fiber; Fire - disasters; Gene Expression Profile; Genetic; Habenula; Human; Hypothalamic structure; Interneurons; Ion Channel; Label; Lateral; Learned Helplessness; Light; Link; Locomotion; Maps; Medial; Mediating; Mental Depression; Methods; Midbrain structure; Modeling; Mood Disorders; Moods; Mus; Neurons; Neurophysiology - biologic function; Neurotransmitters; Output; Pathway interactions; Play; Pontine structure; Posterior Hypothalamus; Preparation; Primates; Prosencephalon; Psychological reinforcement; Punishment; Regulation; Rewards; Role; Self Stimulation; Serotonin; Signal Transduction; Slice; Source; Stress; Substantia nigra structure; Synapses; System; Tegmentum Mesencephali; Testing; Thalamic structure; Time; Transgenic Mice; Transgenic Organisms; Ventral Tegmental Area; Visual; Work; behavioral response; behavioral study; clinically significant; dopamine system; dopaminergic neuron; dorsal raphe nucleus; gamma-Aminobutyric Acid; inhibitor/antagonist; insight; interpeduncular nucleus; mood regulation; mouse model; optogenetics; pars compacta; preference; public health relevance; raphe nuclei; recombinase; response; sleep regulation; synaptic function; tool

 DESCRIPTION (provided by applicant): The habenula is a paired nucleus residing in the dorsal thalamus. It consists of medial and lateral subnuclei (MHb, LHb), which connect to the brainstem via a common tract, yet innervate different brainstem targets. In the initial three years of this project, we have used transgenic mice to define the gene expression patterns and output pathways of the MHb and LHb. Recent work has shown that some LHb neurons inhibit dopamine (DA) signaling in the ventral tegmental area (VTA) via local GABAergic interneurons. This pathway is thought to mediate reward prediction error and punishment, signals which could be overactive in depression, and a few preliminary human studies have linked the habenula to mechanisms of depression. Although LHb regulation of DA activity is clearly important, we find that >90% of LHb outputs project instead to the midbrain/pontine raphe nuclei and dorsal tegmental (DTg) area, including regions rich in serotonergic (5HT) neurons. Little is known about the specific connections or the behavioral function of the pathway from the LHb and the raphe/DTg. Given the known roles of 5HT in the regulation of sleep, mood, and stress, the LHb-raphe pathway may be of great clinical significance. Thus in addition to understanding LHb regulation of DA activity, additional models of LHb function are needed. In years 4-8 of this project, we will use optogenetically assisted circuit mapping to define functional pathways from the LHb to specific neurons in the raphe and DTg. We will also test the function of these LHb pathways in behavioral models of locomotion, anxiety, reinforcement and stress. Aim 1: Determine if the LHb makes direct synaptic connections with brainstem GABAergic neurons. We hypothesize that the LHb synapses with GABAergic neurons in the raphe and DTg, as it does in the VTA. We will use optogenetically-assisted circuit mapping, with Cre recombinase-driven expression of ChR2 in specific neurons, to assess the connection between the LHb and genetically-labeled GABAergic neurons in the raphe and DTg, using intracellular "visual patch" recording in brain slice preparations. Aim 2: Determine the direct and polysynaptic connections of the LHb with the 5HT system. In this aim we will use optogenetic circuit mapping to determine if there is a monosynaptic connection between the LHb and 5HT neurons in the raphe nuclei receiving LHb inputs. We will also use electrophysiology and inhibitors of specific neurotransmitter systems to determine if there is a polysynaptic link between the LHb and 5HT neurons in the raphe via GABAergic interneurons, analogous to the LHb-RMTg-VTA system. Aim 3: Examine the behavioral role of LHb inputs to the raphe system. Here we will express the light-activated ion channel ChR2 in the LHb, then stimulate LHb fiber terminals in the raphe nuclei in freely moving mice to determine the role of the LHb-raphe pathway in locomotion, models of anxiety, self- stimulation reinforcement, and behavioral responses to stress.

 描述（由申请人提供）：缰核是位于背侧丘脑中的成对核团。它由内侧和外侧亚核（MHb，LHb）组成，它们通过共同的束连接到脑干，但支配不同的脑干靶点。在最初的三年里， 在本研究中，我们使用转基因小鼠来确定MHb和LHb的基因表达模式和输出途径。最近的研究表明，一些LHb神经元通过局部GABA能中间神经元抑制腹侧被盖区（VTA）的多巴胺（DA）信号。这条通路被认为介导奖励预测错误和惩罚，这些信号可能在抑郁症中过度活跃，一些初步的人类研究将缰与抑郁症的机制联系起来。 虽然LHb对DA活性的调节显然很重要，但我们发现>90%的LHb输出投射到中脑/脑桥中缝核和背侧被盖（DTg）区，包括富含多巴胺能（5 HT）神经元的区域。关于LHb和中缝/DTg通路的特定连接或行为功能知之甚少。鉴于5-HT在睡眠、情绪和压力调节中的已知作用，LHb-中缝通路可能具有重要的临床意义。因此，除了了解LHb调节DA活性，LHb功能的其他模型是必要的。在本项目的第4-8年，我们将使用光遗传学辅助电路映射来定义从LHb到中缝和DTg中特定神经元的功能通路。我们还将测试这些LHb通路在运动，焦虑，强化和压力的行为模型中的功能。 目的1：确定LHb是否与脑干GABA能神经元形成直接突触联系。我们假设LHb与中缝和DTg中的GABA能神经元形成突触，就像在VTA中一样。我们将使用光遗传学辅助的电路映射，Cre重组酶驱动的ChR 2在特定神经元中的表达，以评估LHb和遗传标记的GABA能神经元之间的联系，在中缝和DTg，使用细胞内的“视觉补丁”记录在脑切片制备。 目的2：确定LHb与5-HT系统的直接和多突触联系。在这个目标中，我们将使用光遗传学电路映射来确定是否有一个单突触连接之间的LHb和5 HT神经元在中缝核接受LHb输入。我们还将使用电生理学和特定的神经递质系统的抑制剂，以确定是否有一个多突触之间的联系LHb和5 HT神经元之间的中缝通过GABA能中间神经元，类似于LHb-RMTg-VTA系统。 目的3：研究LHb输入中缝系统的行为作用。在这里，我们将在LHb中表达光激活离子通道ChR 2，然后刺激自由运动小鼠中缝核中的LHb纤维末端，以确定LHb-中缝通路在运动、焦虑模型、自我刺激强化和对应激的行为反应中的作用。