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: 8998067
• 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/8998067
• 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; Health; 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; depression model; dopamine system; dopaminergic neuron; dorsal raphe nucleus; gamma-Aminobutyric Acid; inhibitor/antagonist; insight; interpeduncular nucleus; mood regulation; mouse model; optogenetics; pars compacta; preference; 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（由适用提供）：Habenula是位于背丘脑中的成对核。它由培养基和侧面亚核（MHB，LHB）组成，它们通过共同的区域连接到脑干，但仍将不同的脑干目标支配。在最初的三年 在这个项目中，我们使用转基因小鼠来定义MHB和LHB的基因表达模式和输出途径。最近的工作表明，一些LHB神经元通过局部GABA能中间神经元抑制腹侧对接区域（VTA）的多巴胺（DA）信号。人们认为，这种途径可以介导奖励预测错误和惩罚，可能在抑郁症中过度活跃的信号，并且一些初步的人类研究已将Habenula与Habenula联系在一起，尽管LHB的调节DA活动显然很重要，但我们发现LHB的90％> 90％的LHB输出项目> 90％，而不是Midbrain/Pontine Raphe Raphe核和Dorsal Pergemation（包括DORSAL）区域（包括Rich ricr），包括该地区（包括区域）神经元。关于从LHB和Raphe/DTG的途径的特定连接或行为函数知之甚少。鉴于5HT在调节睡眠，情绪和压力中的已知作用，LHB-Raphe途径可能具有极大的临床意义。除了了解DA活性的LHB调节外，还需要其他LHB功能的模型。在该项目的第4 - 8年中，我们将使用光辅助电路映射来定义从LHB到RAPHE和DTG中特定神经元的功能途径。我们还将测试这些LHB途径在运动，焦虑，增强和压力的行为模型中的功能。目标1：确定LHB是否与脑干GABA能神经元直接建立突触连接。我们假设LHB与Raphe和DTG中的GABA能神经元突触，就像在VTA中一样。我们将使用特定神经元中CHR2的CRE重组酶驱动的CRE重组酶驱动的表达来评估LHB与Raphe和DTG中遗传标记的GABA能神经元之间的连接，并使用细胞内大脑SLICE SLICE录音中的细胞内“ Visual Patch”记录。 AIM 2：确定LHB与5HT系统的直接和多突触连接。在此目的中，我们将使用光遗传电路映射来确定RAPHE核中LHB核中LHB输入的LHB和5HT神经元之间是否存在单突触连接。我们还将使用特定神经递质系统的电生理学和抑制剂来确定通过GABAergic INTERRONS中LHB和5HT神经元之间的多突触连接，与LHB-RMTG-VTA系统类似。目标3：检查LHB输入对Raphe系统的行为作用。在这里，我们将在LHB中表达光激活的离子通道CHR2，然后在自由移动小鼠中刺激Raphe核中的LHB纤维末端，以确定LHB-RAPHE途径在运动，动画，自我刺激强化的模型和对压力的行为反应中的作用。