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: 9197913
• 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/9197913
• 关键词: Acute; Anatomy; Anxiety; Anxiety Disorders; Area; Behavior; Behavioral; Behavioral Model; Biological Assay; Brain; Brain Stem; Brain region; Bypass; Cell Nucleus; Cues; Dopamine; Dorsal; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; 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; depression model; dopamine system; dopaminergic neuron; gamma-Aminobutyric Acid; inhibitor/antagonist; insight; interpeduncular nucleus; mood regulation; mouse model; neural model; optogenetics; pars compacta; preference; public health relevance; raphe nuclei; 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的成对核。它由内侧和外侧亚核（MHb、LHb）组成，通过公共束连接到脑干，但神经支配不同的脑干目标。在最初的三年里 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) 信号传导。该通路被认为可以调节奖励预测错误和惩罚，这些信号在抑郁症中可能过度活跃，并且一些初步的人体研究已将缰核与抑郁症机制联系起来。 尽管 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) 区域，包括富含血清素能 (5HT) 神经元的区域。关于 LHb 和中缝/DTg 通路的具体连接或行为功能知之甚少。鉴于 5HT 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 对 DA 活性的调节之外，还需要其他 LHb 功能模型。在该项目的第 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、强化和压力行为模型中的功能。 目标 1：确定 LHb 是否与脑干 GABA 能神经元建立直接突触连接。我们假设 LHb 与中缝和 DTg 中的 GABA 能神经元发生突触，就像在 VTA 中一样。我们将使用光遗传学辅助电路映射，以及特定神经元中由 Cre 重组酶驱动的 ChR2 表达，以评估 LHb 与中缝和 DTg 中基因标记的 GABA 能神经元之间的连接，并在脑切片制剂中使用细胞内“视觉斑块”记录。 目标 2：确定 LHb 与 5HT 系统的直接和多突触连接。为此，我们将使用光遗传学电路映射来确定接收 LHb 输入的中缝核中的 LHb 和 5HT 神经元之间是否存在单突触连接。我们还将使用电生理学和特定神经递质系统的抑制剂来确定中缝中的 LHb 和 5HT 神经元之间是否通过 GABA 能中间神经元存在多突触联系，类似于 LHb-RMTg-VTA 系统。 目标 3：检查 LHb 输入对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 ChR2，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、自我刺激强化和对压力的行为反应中的作用。