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.

动机驱动是一种适应性过程，它帮助个体克服障碍以获得基本需求，从而确保生存。激励由两个主要部分组成。第一个因素是动机的方向性(以目标为导向的行为的取向)，比如寻找食物/住所或避免痛苦。第二种是激励性动机(以目标为导向的行为的激励)，如增加活力和这些行动的持久性。动机的这些组成部分的缺陷是患有精神障碍的人的共同特征。然而，控制动机驱动力不同成分的潜在机制尚未最终确定。众所周知，伏隔核(NAC)通过不同的亚区，即NAC外壳(NAcShell)和NAC核心(NAccore)，调节不同的动机成分。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NAccore则调节动机动力的激活性或激励性方面。然而，NAC神经元依赖谷氨酸能纹状体外输入来启动和维持目标导向的行为和动机。丘脑室旁核(PVT)整合内脏感觉信号(起源于脑干和下丘脑)，通过向NAC投射促进适应性反应。以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，类型1PVT和类型2PVT，它们在遗传特性、连接特征和功能上存在差异。特别是，1PVT类型神经元向NAccore发送强大的输入，并在动机驱动的激活部分被激活。然而，2PVT型神经元几乎完全投射到NAc壳，并在预期奖赏缺失时活跃。然而，尽管有这些证据，PVT输入对NAC在目标导向行为和动机调节中的作用仍然很大程度上是未知的。我的中心假设是，类型1PVT-NAccore和类型2PVT-NAcShell神经元是独立但互补的丘脑-纹状体通路的一部分，它们各自在动机中扮演着不同的角色。具体地说，类型1PVT-NAccore神经元对动机驱动的激活成分至关重要，而类型2PVT-NAcShell神经元通过抑制与目标无关的行为来促进动机的方向性。使用包括解剖学、成像学、光遗传学和行为学技术相结合的多学科方法，我将以解剖和功能的精确度来表征PVT-NAC的连通性。然后，我将确定类型1PVT-NAccore神经元和类型2PVT-NAclet神经元在调节动机行为的激活性和方向性成分中的作用。这些发现将促进我们对丘脑-纹状体回路促进动机驱动的贡献的理解，这可以为患有动机缺陷的个人开发新的方法提供基本的见解。