Functionally selective D2Rs, striatal circuit function and motivation

功能选择性 D2R、纹状体回路功能和动机

• 批准号: 9914328
• 负责人: Christoph Kellendonk
• 金额: $ 61.25万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-20 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914328
• 关键词: Address; Affect; Animals; Arousal; Arrestins; Attention deficit hyperactivity disorder; Attenuated; Behavior; Behavioral; Biology; Brain; Brain imaging; Corpus striatum structure; Coupled; Data; Development; Disease; Disinhibition; Dopamine; Dopamine D2 Receptor; Drug Addiction; GTP-Binding Proteins; Generations; Globus Pallidus; Goals; Image; Measures; Mediating; Mental disorders; Molecular; Motivation; Mus; Mutate; Neurons; Nucleus Accumbens; Output; Pathway interactions; Pharmaceutical Preparations; Physiology; Preparation; Receptor Signaling; Rewards; Role; Schizophrenia; Signal Pathway; Signal Transduction; Signaling Protein; Slice; Synaptic Transmission; Testing; Up-Regulation; Ventral Striatum; Virus; Work; addiction; dopaminergic neuron; imaging study; in vivo; in vivo calcium imaging; motivated behavior; novel therapeutic intervention; overexpression; patch clamp; presynaptic; receptor; receptor binding; receptor function; receptor upregulation; recombinase-mediated cassette exchange; transmission process

Brain imaging studies have found alterations in striatal dopamine D2R binding in several mental disorders associated with altered motivation including schizophrenia, ADHD and drug addiction. In spite of these observations it is still unclear how changes in D2R levels alter striatal circuit function and motivation. In the first 4.5 years of this RO1 project we have found that D2R overexpression in the ventral striatum (Nucleus accumbens core; NAcc) of the mouse enhances motivation. We further identified a new mechanism by which D2Rs could regulate motivation: Like presynaptic D2Rs in dopamine neurons inhibit dopamine release, we found that D2Rs inhibit collateral transmission from indirect to direct pathway neurons. The direct pathway is one of the two functionally opposing output pathways of the striatum. It promotes thalamo-cortical activity, thereby relaying a “go” signal, whereas the indirect pathway inhibits thalamo-cortical activity, thus relaying a “no go” signal. We hypothesize that decreased collateral inhibition will enhance direct pathway activity thereby promoting motivated behavior. The same mechanism that regulates synaptic transmission at intrastriatal collaterals should also affect transmission at the main indirect output terminals in the ventral pallidum (VP). We therefore hypothesize that D2Rs in the NAcc enhance motivation via two mechanisms, dis- inhibition of direct pathway activity and inhibition of indirect pathway output. To develop new therapeutic strategies for disorders of motivation it will be crucial to understand how ventral-striatal D2Rs regulate motivation at the molecular level. D2Rs signal via two downstream pathways one that is G-protein dependent and one is G-protein independent and involves arrestin. Here, we will compare the efficiencies of functionally selective D2Rs in their ability to enhance motivation and to inhibit indirect pathway transmission. Since G-protein signaling is required for D2R-mediated inhibition of dopamine release we hypothesize that G-protein but not arrestin signaling is necessary for inhibiting indirect pathway transmission leading to enhanced motivation. Whether decreased indirect pathway transmission disinhibits direct pathway and downstream VP activity is unknown but essential for understanding how D2Rs regulate motivation. We will therefore measure neuronal activity selectively in the VP as well as in the direct or the indirect pathway during motivated behavior. We will use the Cre/loxP system in combination with Cre-dependent viruses to selectively overexpress wild-type or mutated functionally selective D2Rs in the indirect-pathway of the NAcc and employ patch clamp slice physiology, in vivo calcium imaging and a behavioral analysis to address the following aims: Aim 1: To determine the function of NAcc D2Rs in VP inhibition and motivation Aim 2: To identify the signaling pathway(s) by which NAcc D2Rs regulate motivation

脑成像研究发现，纹状体多巴胺D2R结合在几种精神障碍中的变化 与动机的改变有关，包括精神分裂症，多动症和药物成瘾。尽管有这些 观察仍然尚不清楚D2R水平的变化如何改变纹状体电路的功能和动机。 在此RO1项目的前4。5年中，我们发现腹侧纹状体中的D2R过表达 小鼠的（伏隔核核心； NACC）增强了动机。我们进一步确定了一种新机制 D2RS可以调节动机：像多巴胺神经元中的突触前D2R抑制多巴胺 释放，我们发现D2RS抑制了从间接到直接途径神经元的附带传播。 途径是纹状体的两个功能相对的输出途径之一。它促进了丘脑皮层 活性，从而传达“ GO”信号，而间接途径则抑制丘脑皮层活性，因此 传递“无GO”信号。我们假设减少的抵押抑制作用将增强直接途径 活动，从而促进动机行为。相同的机制调节突触传播 纹状体侧支也应影响腹侧主要间接输出端子的传播 Pallidum（VP）。因此，我们假设NACC增强动机中的D2R通过两种机制，分辨率 抑制直接途径活性并抑制间接途径输出。 为了制定动机疾病的新治疗策略，了解如何了解 腹侧纹状体D2RS调节分子水平的动机。 D2RS信号通过两个下游 途径是G蛋白依赖性的，一种是G蛋白独立的，涉及逮捕蛋白。在这里，我们 将比较功能选择性D2R的效率，以增强动力和抑制能力 间接途径传输。由于D2R介导的多巴胺抑制需要G蛋白信号传导 释放我们假设G蛋白但没有阻止蛋白信号对于抑制间接途径是必要的 传播导致动力增强。 间接途径传播减少是否抑制直接途径和下游VP活动是 未知但对于理解D2RS如何调节动机至关重要。因此，我们将测量神经元 在动机行为过程中，在VP以及直接或间接途径中有选择性的活动。我们将 将CRE/LOXP系统与CRE依赖性病毒结合使用，以选择性表达野生型或 在NACC和员工贴片夹片的间接校园中，功能性选择性D2RS在功能上选择性D2RS 生理学，体内钙成像和行为分析以解决以下目的： 目标1：确定NACC D2R在VP抑制和动机中的功能 目标2：确定NACC D2RS调节动机的信号传导途径

项目成果

Dopamine D2 receptors bidirectionally regulate striatal enkephalin expression: Implications for cocaine reward.

• DOI: 10.1016/j.celrep.2022.111440
• 发表时间: 2022-09-27
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Dai, Kathy Z.;Choi, In Bae;Levitt, Ryan;Blegen, Mariah B.;Kaplan, Alanna R.;Matsui, Aya;Shin, J. Hoon;Bocarsly, Miriam E.;Simpson, Eleanor H.;Kellendonk, Christoph;Alvarez, Veronica A.;Dobbs, Lauren K.
• 通讯作者: Dobbs, Lauren K.

Can we use mice to study schizophrenia?

• DOI: 10.1098/rstb.2017.0032
• 发表时间: 2018-03-19
• 期刊: PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
• 影响因子: 6.3
• 作者: Canetta, Sarah;Kellendonk, Christoph
• 通讯作者: Kellendonk, Christoph

Selective overexpression of dopamine D3 receptors in the striatum disrupts motivation but not cognition.

• DOI: 10.1016/j.biopsych.2013.11.023
• 发表时间: 2014-11-15
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Simpson, Eleanor H.;Winiger, Vanessa;Biezonski, Dominik K.;Haq, Iram;Kandel, Eric R.;Kellendonk, Christoph
• 通讯作者: Kellendonk, Christoph