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

脑成像研究发现多种精神疾病中纹状体多巴胺 D2R 结合发生改变 尽管如此，与动机改变有关，包括精神分裂症、多动症和毒瘾。 目前尚不清楚 D2R 水平的变化如何改变纹状体回路功能和动机。 在这个 RO1 项目的前 4.5 年里，我们发现 D2R 在腹侧纹状体中过度表达 （伏隔核；NAcc）增强小鼠的动机 我们进一步确定了一种新机制。 D2R 可以通过其调节动机：就像多巴胺神经元中的突触前 D2R 一样抑制多巴胺 释放后，我们发现 D2R 抑制从间接通路神经元到直接通路神经元的侧向传递。 通路是纹状体两条功能相反的输出通路之一，它促进丘脑皮质。 活动，从而传递“走”信号，而间接途径抑制丘脑皮质活动，从而 我们发现，减少侧枝抑制将增强直接通路。 活动从而促进动机行为。 纹状体内的络脉也应该影响腹侧主要间接输出终端的传输 因此，我们认为 NAcc 中的 D2R 通过两种机制增强动机： 抑制直接途径活性和抑制间接途径输出。 为了开发新的动机障碍治疗策略，了解如何治疗动机障碍至关重要 腹侧纹状体 D2R 通过两个下游 D2R 信号在分子水平上调节动机。 一种途径是 G 蛋白依赖性的，另一种途径是 G 蛋白依赖性的，并且涉及抑制蛋白。 将比较功能选择性 D2R 在增强动机和抑制能力方面的效率 由于 D2R 介导的多巴胺抑制需要 G 蛋白信号传导。 我们发现 G 蛋白而非抑制蛋白信号传导对于抑制间接途径是必需的 传播导致动力增强。 间接途径传播的减少是否会抑制直接途径和下游 VP 活性 未知，但对于理解 D2R 如何调节动机至关重要，因此我们将测量神经元。 我们将在 VP 以及动机行为期间的直接或间接路径中选择性地进行活动。 将 Cre/loxP 系统与 Cre 依赖性病毒结合使用，选择性过表达野生型或 NAcc 间接通路中突变的功能选择性 D2R 并采用膜片钳切片 生理学、体内钙成像和行为分析，以实现以下目标： 目标 1：确定 NAcc D2R 在 VP 抑制和激励中的功能 目标 2：确定 NAcc D2R 调节动机的信号通路

项目成果

Can we use mice to study schizophrenia?

我们可以用老鼠来研究精神分裂症吗？

• 发表时间: 2018-03-19
• 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.

纹状体中多巴胺 D3 受体的选择性过度表达会破坏动机，但不会破坏认知。

• 发表时间: 2014-11-15
• 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

Striatal dopamine 2 receptor upregulation during development predisposes to diet-induced obesity by reducing energy output in mice.

发育过程中纹状体多巴胺 2 受体的上调会减少小鼠的能量输出，从而导致饮食诱发的肥胖。

• 发表时间: 2018-10-09
• 影响因子: 11.1
• 作者: Labouesse, Marie A;Sartori, Andrea M;Weinmann, Oliver;Simpson, Eleanor H;Kellendonk, Christoph;Weber
• 通讯作者: Weber

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

多巴胺 D2 受体双向调节纹状体脑啡肽表达：对可卡因奖励的影响。

• 发表时间: 2022-09-27
• 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