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

基本信息

批准号：
9059062
负责人：
Eric E. Turner
金额：
$ 41.02万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
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/9059062
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)Fright Gene Expression Profile Genetic Glutamates Habenula Halorhodopsins Health 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 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 feeding gamma-Aminobutyric Acid hindbrain inducible gene expression inhibitory neuron interpeduncular nucleus monoamine novel optogenetics pars compacta postsynaptic neurons preference presynaptic neurons recombinase research study response tool transcription factor

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 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）：Habenula是位于背丘脑中的成对核。它由内侧和外侧亚核（MHB，LHB）组成，它们连接到腹中脑中的不同靶标。对动物的整个Habenula的病变研究已将这一领域牵涉到各种功能，包括昼夜节律和睡眠，压力反应，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将Habenula奖励途径与可能的抑郁机制联系起来，但是该核的功能仍然在很大程度上不清楚。最近的工作表明，一些LHB神经元抑制腹侧对段区域（VTA）的多巴胺（DA）信号，从而介导了负奖励信号。相比之下，MHB几乎完全投影到毗邻VTA的枝间核（IP），后者又投射到Raphe和背侧侧向区域。 MHB具有背侧（DMHB）和腹侧（VMHB）亚核，分别与外侧和内侧IP建立了特定的连接。先前的研究没有区分这些亚核的作用，但是有理由认为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，DMHB的刺激会产生正奖励信号，我们假设这是通过MHB-IP途径介导的，可以通过MHB-IP途径介导。在这里，我们将使用针对DMHB和VMHB的CRE驱动器，结合转基因小鼠，可允许光遗传蛋白的诱导表达ChanneRhopopsin和Halorhopopsin，以激活和沉默MHB神经元，以检查MHB与iP中GABA神经元的功能链接。遗传靶向方法还将使用神经解剖学，电生理和行为读数来检查与Raphe中5HT神经元的IP连接。 AIM 1。我们将使用Cre介导的转基因，病毒和常规段追踪来确定从Habenula，通过IP，通过IP来确定途径的解剖连通性，用于介导奖励和恐惧反应的后脑中心。我们将在这些途径中的神经元中分配神经递质表型，以确定它们是传输兴奋性还是抑制信号。 AIM 2。我们将使用特定的突触前神经元的光遗传激活与后突触后神经元的细胞内记录，并鉴定有记录的神经元具有转基因标记物，并使用特定突触前神经元的光遗传激活来测试MHB-IP与IP-RAPHE之间的生理联系。 AIM 3。我们将使用光遗传学在奖励和抑郁症的行为模型中激活和沉默DMHB和VMHB，包括开放式运动，颅内自我刺激，实时地点偏好/厌恶，条件的地方偏好/厌恶/厌恶和学习的无助性。在这些实验的结论中，我们将更好地了解特定的Habenula成分及其下游途径，以及Habenula在情绪障碍中的潜在作用。