Functional studies of the medial habenula in models of reward and mood disorders

奖赏和情绪障碍模型中内侧缰核的功能研究

• 批准号: 9263966
• 负责人: Eric E. Turner
• 金额: $ 41.44万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9263966
• 关键词: Anatomy; Animals; Anxiety Disorders; Area; Attention; Behavior; Behavioral; Behavioral Model; Brain; Brain Stem; Brain region; Cell Nucleus; Characteristics; Circadian Rhythms; Clinical; Clinical Research; Data; Disease; Dopamine; Dorsal; Drug Addiction; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Fright; Gene Expression Profile; Genetic; Glutamates; Habenula; Halorhodopsins; Human; Interneurons; Lateral; Learned Helplessness; Learning; Lesion; Light; Link; Locomotion; Medial; Mediating; Mental Depression; Methods; Midbrain structure; Modeling; Molecular; Mood Disorders; Mus; Neurons; Neurotransmitters; Nicotine; Opioid; Output; Pathway interactions; Pharmacology; Phenotype; Physiological; Physiology; Play; Preparation; Property; Proteins; Reproductive Behavior; Research; Rewards; Role; Self Stimulation; Serotonergic System; Serotonin; Signal Transduction; Sleep; Sleep Wake Cycle; Slice; Stimulus; Substantia nigra structure; Swimming; System; Testing; Thalamic structure; Time; Transgenic Mice; Transgenic Organisms; Ventral Tegmental Area; Viral; Work; base; behavioral response; biological adaptation to stress; cholinergic; dopamine system; dopaminergic neuron; drug of abuse; experimental study; feeding; gamma-Aminobutyric Acid; hindbrain; inducible gene expression; inhibitory neuron; interpeduncular nucleus; monoamine; novel; optogenetics; pars compacta; postsynaptic neurons; preference; presynaptic neurons; public health relevance; response; tool; transcription factor

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 distinct targets in the ventral midbrain. Lesion studies of the entire habenula in animals have implicated this area in diverse functions, including circadian rhythms and sleep, stress responses, intracranial self-stimulation reward, and the behavioral effects of nicotine and other drugs of abuse. In humans, a few preliminary clinical studies have linked habenula reward pathways to possible mechanisms of depression, but the function of this nucleus remains largely unclear. Recent work has shown that some LHb neurons inhibit dopamine (DA) signaling in the ventral tegmental area (VTA), and thus mediate a negative reward signal. In contrast, the MHb projects almost exclusively to the interpeduncular nucleus (IP), adjacent to the VTA, which projects in turn to the raphe and dorsal tegmental areas. The MHb has dorsal (dMHb) and ventral (vMHb) subnuclei, which make specific connections to the lateral and medial IP, respectively. Prior studies have not distinguished the roles of these subnuclei, yet there is littl reason to believe they have the same function. Our new optogenetic data show that, in contrast to the LHb, stimulation of the dMHb generates a positive reward signal, and we hypothesize that this is mediated via a MHb-IP pathway to the brainstem. Here we will use Cre-drivers specific for the dMHb and vMHb, combined with transgenic mice that allow inducible expression of the optogenetic proteins Channelrhodopsin and Halorhodopsin, to activate and silence MHb neurons in order to examine the functional link from the MHb to GABA neurons in the IP. Genetically targeted approaches will also be used to examine the IP connection to 5HT neurons in the raphe, using neuroanatomical, electrophysiological, and behavioral readouts. Aim 1. We will use Cre-mediated transgenic, viral, and conventional tract-tracing to determine the anatomical connectivity of pathways from the habenula, via the IP, to hindbrain centers mediating reward and fear responses. We will assign neurotransmitter phenotypes to the neurons in these pathways to determine whether they transmit excitatory or inhibitory signals. Aim 2. We will test the physiological connections between the MHb-IP and the IP-raphe in brain slice preparations, using optogenetic activation of specific presynaptic neurons combined with intracellular recording of postsynaptic neurons, and identification of the recorded neurons with transgenic markers. Aim 3. We will use optogenetics to activate and silence the dMHb and vMHb in behavioral models of reward and depression, including open field locomotion, intracranial self-stimulation, real-time place preference/aversion, conditioned place preference/aversion, and learned helplessness. At the conclusion of these experiments we will better understand the specific habenula components and their downstream pathways, and the potential role of the habenula in mood disorders.

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，连接到腹侧中脑的不同目标。对动物整个缰核的损伤研究表明该区域具有多种功能，包括昼夜节律和睡眠、应激反应、颅内自我刺激奖励以及尼古丁和其他滥用药物的行为影响。在人类中，一些初步的临床研究已将缰核奖赏通路与抑郁症的可能机制联系起来，但该核的功能仍不清楚。最近的研究表明，一些 LHb 神经元抑制腹侧被盖区 (VTA) 的多巴胺 (DA) 信号传导，从而介导负奖赏信号。相比之下，MHb 几乎完全投射到与 VTA 相邻的脚间核 (IP)，而 VTA 又投射到中缝和背侧被盖区域。 MHb 具有背侧 (dMHb) 和腹侧 (vMHb) 亚核，分别与外侧和内侧 IP 进行特定连接。先前的研究尚未区分这些亚核的作用，但没有理由相信它们具有相同的功能。我们的新光遗传学数据表明，与 LHb 相比，刺激 dMHb 会产生积极的奖励信号，我们假设这是通过通往脑干的 MHb-IP 途径介导的。在这里，我们将使用 dMHb 和 vMHb 特异性的 Cre 驱动程序，与允许诱导表达光遗传学蛋白通道视紫红质和盐视紫红质的转基因小鼠相结合，激活和沉默 MHb 神经元，以检查 IP 中从 MHb 到 GABA 神经元的功能联系。基因靶向方法还将用于通过神经解剖学、电生理学和行为读数来检查 IP 与中缝 5HT 神经元的连接。 目标 1. 我们将使用 Cre 介导的转基因、病毒和传统纤维束追踪来确定从缰核、IP 到介导奖励和恐惧反应的后脑中心的通路的解剖学连接性。我们将为这些通路中的神经元分配神经递质表型，以确定它们是否传递兴奋性或抑制性信号。 目标 2. 我们将使用特定突触前神经元的光遗传学激活结合突触后神经元的细胞内记录，并用转基因标记识别记录的神经元，测试脑切片制剂中 MHb-IP 和 IP-中缝之间的生理联系。 目标 3. 我们将利用光遗传学激活和沉默奖励和抑郁行为模型中的 dMHb 和 vMHb，包括开放场运动、颅内自我刺激、实时位置偏好/厌恶、条件性位置偏好/厌恶和习得性无助。在这些实验结束时，我们将更好地了解特定的缰核成分及其下游途径，以及缰核在情绪障碍中的潜在作用。