Mapping Thalamo-striatal Neuronal Circuits Underlying Motivational Drive

绘制动机驱动下的丘脑纹状体神经元回路

• 批准号: 10621405
• 负责人: Sofia Beas
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621405
• 关键词: Address; Anatomy; Aversive Stimulus; Behavior; Behavioral; Brain Stem; Brain region; Cells; Characteristics; Chronic stress; Collaborations; Corpus striatum structure; Data; Data Analyses; Decision Making; Desire for food; Dopamine D2 Receptor; Drug abuse; Electrophysiology (science); Ensure; Food; Generations; Genetic Identity; Glutamates; Goals; Head; Hypothalamic structure; Impairment; Individual; Locomotion; Major Depressive Disorder; Maps; Measures; Mediating; Mediation; Mental Health; Mental disorders; Microscope; Mission; Motivation; Mus; National Institute of Mental Health; Neurons; Nucleus Accumbens; Pain; Pathway interactions; Play; Positioning Attribute; Process; Quality of life; Research; Reversal Learning; Rewards; Role; Shelter facility; Signal Transduction; Speed; Stimulus; Structure of paraventricular nucleus of thalamus; Synapses; Techniques; Testing; Thalamic structure; Training; Work; anatomic imaging; base; behavior test; data acquisition; experimental study; goal oriented behavior; insight; interdisciplinary approach; microscopic imaging; miniaturize; motivated behavior; motivational processes; neural circuit; neuronal circuitry; novel; novel strategies; optogenetics; patch clamp; programs; response; tool

Motivational drive is an adaptive process that helps individuals overcome obstacles to obtain essential needs and hence ensure survival. Motivation is composed of two major components. The first component is the directionality of motivation (the orientation of goal-oriented behavior), such as seek food/shelter or avoid pain. The second is the activational motivation (the energizing of goal-oriented behaviors) such as increase vigor, and persistence of these actions. Impairments in these components of motivation are common characteristic among individuals who suffer from psychiatric disorders. However, the underlying mechanisms controlling different components of motivational drive have yet to be conclusively identified. It is known that the nucleus accumbens (NAc) mediates different components of motivation through different subregions, the NAc shell (NAcshell) and the NAc core (NAccore). Indeed, the NAcshell facilitates the directionality of motivation through suppression of goal-irrelevant behaviors; whereas the NAccore is known to mediate the activational, or invigorating aspects, of motivational drive. However, NAc neurons rely on glutamatergic extra-striatal inputs to initiate and maintain goal-oriented behavior and motivation. The paraventricular nucleus of the thalamus (PVT) integrates visceroceptive signals (originating from the brainstem and hypothalamus) to promote adaptive responses via projections to the NAc. Previous research and my preliminary data show that the PVT has two major distinct subpopulations of neurons, Type1PVT and Type2PVT, which differ on their genetic identity, connectional features, and functionality. Particularly, Type1PVT neurons send strong inputs to the NAccore and are activated during the activational components of motivational drive. Whereas, Type2PVT neurons project almost exclusively to the NAcshell and are active during omissions of expected rewards. However, despite this evidence, the contribution of PVT inputs to the NAc in mediation of goal-oriented behavior and motivation remain largely unknown. My central hypothesis is that Type1PVT–NAccore and Type2PVT–NAcshell neurons are part of independent but complementary thalamo-striatal pathways and they each play a distinct role in motivation. Specifically, Type1PVT-NAccore neurons are critical for the activational component of motivational drive, while Type2PVT–NAcshell neurons facilitate the directionality of motivation by suppression of goal-irrelevant behaviors. Using a multidisciplinary approach that includes a combination of anatomical, imaging, optogenetic, and behavioral techniques, I will characterize PVT-NAc connectivity with anatomical and functional precision. Thereafter, I will then establish the role of Type1PVT–NAccore neurons and Type2PVT–NAcshell neurons in mediating the activational and directionality components of motivated behavior. These findings will advance our understanding of the contributions of thalamo-striatal circuits promoting motivational drive that can create fundamental insights to develop novel approaches for individuals suffering from motivational deficits.

动机是一个适应性过程，可以帮助个人克服障碍以获得基本需求，从而确保生存。动机由两个主要部分组成。第一个组成部分是动机的方向性（以目标为导向的行为的方向），例如寻求食物/住所或避免痛苦。第二个是激活动机（以目标为导向的行为的激励），例如增加活力和这些行为的持久性。这些动机成分的受损是患有精神疾病的人的共同特征。然而，控制动机驱动不同组成部分的潜在机制尚未最终确定。 众所周知，伏隔核 (NAc) 通过不同的子区域、NAc 壳 (NAcshell) 和 NAc 核心 (NAccore) 介导不同的动机成分。事实上，NAcshell 通过抑制与目标无关的行为来促进动机的方向性；而众所周知，NAccore 可以调节动机驱动的激活或振奋方面。然而，NAc 神经元依赖纹状体外谷氨酸输入来启动和维持目标导向的行为和动机。丘脑室旁核 (PVT) 整合内脏感受信号（源自脑干和下丘脑），通过投射到 NAc 来促进适应性反应。之前的研究和我的初步数据表明，PVT 有两个主要的不同神经元亚群：Type1PVT 和 Type2PVT，它们在遗传特性、连接特征和功能上有所不同。特别是，Type1PVT 神经元向 NAccore 发送强输入，并在动机驱动的激活部分被激活。而 Type2PVT 神经元几乎只投射到 NAcshell，并且在忽略预期奖励时活跃。然而，尽管有这些证据，PVT 输入对 NAc 在调节目标导向行为和动机方面的贡献仍然很大程度上未知。 我的中心假设是 Type1PVT-NAccore 和 Type2PVT-NAcshell 神经元是独立但互补的丘脑纹状体通路的一部分，并且它们各自在动机中发挥着独特的作用。具体来说，Type1PVT-NAccore 神经元对于动机驱动的激活部分至关重要，而 Type2PVT-NAcshell 神经元则通过抑制与目标无关的行为来促进动机的方向性。我将使用包括解剖学、成像、光遗传学和行为技术相结合的多学科方法，以解剖学和功能精度来表征 PVT-NAc 连接。此后，我将确定 Type1PVT-NAccore 神经元和 Type2PVT-NAcshell 神经元在介导动机行为的激活和方向性成分中的作用。这些发现将增进我们对丘脑纹状体回路促进动机驱动的贡献的理解，从而为患有动机缺陷的个体开发新方法提供基本见解。