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

基本信息

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
项目类别：
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

项目摘要

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）：缰核是位于丘脑背侧的成对核，由内侧和外侧亚核（MHb、LHb）组成，通过共同束连接到脑干，但支配不同的脑干目标。最初三年在这个项目中，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被盖区 (VTA) 中的多巴胺 (DA) 信号传导。该通路被认为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的机制联系起来，尽管 LHb 对 DA 进行调节。活性显然很重要，我们发现 > 90% 的 LHb 输出投射到中脑/脑桥中缝核和背被盖 (DTg) 区域，包括富含血清素能 (5HT) 神经元的区域，但我们对具体连接或神经元知之甚少。 LHb 和中缝/DTg 通路的行为功能鉴于 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作用。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图谱来定义从 LHb 到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 是否与脑干建立直接突触连接。我们勇敢地说，LHb 与中缝和 DTg 中的 GABA 神经元有突触，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 Cre 重组酶驱动的 ChR2 表达来评估这种连接。目标 2：使用细胞内“视觉斑块”记录中缝和 DTg 中的 LHb 和基因标记的 GABA 能神经元。确定 LHb 与 5HT 系统的直接和多突触连接在此目标中，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。和特定神经递质系统的抑制剂，以确定中缝中的 LHb 和 5HT 神经元之间是否通过 GABAergic 存在多突触联系中间神经元，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，我们将表达 LHb 中的光激活离子通道 ChR2，然后刺激中缝中的 LHb 纤维末端。自由活动小鼠的细胞核，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。