Mapping Thalamo-striatal Neuronal Circuits Underlying Motivational Drive

动机驱动是一种适应过程，它帮助个体克服障碍，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（目标导向行为的方向），例如寻找食物/住所或避免痛苦。第二种是激活动机（目标导向行为的激励），如增加活力，并坚持这些行为。这些动机成分的损伤是精神障碍患者的共同特征。然而，控制动机驱动不同组成部分的潜在机制尚未得到最终确定。众所周知，伏隔核（NAc）通过不同的子区域，即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调节动机驱动的激活或激活方面。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）整合来自脑干和下丘脑的内脏感觉信号，通过投射到NAc来促进适应性反应。先前的研究和我的初步数据表明，PVT有两个主要的不同的神经元亚群，Type1PVT和Type2PVT，它们在遗传身份、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成分中被激活。然而，Type2PVT神经元几乎完全投射到NAcshell，并且在预期奖励缺失时活跃。然而，尽管有这些证据，PVT输入对NAc在目标导向行为和动机的中介中的作用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，它们各自在动机中发挥着独特的作用。具体而言，Type1PVT-NAccore神经元对动机驱动的激活成分至关重要，而Type2PVT-NAcshell神经元通过抑制目标无关行为来促进动机的方向性。使用多学科方法，包括解剖学、影像学、光遗传学和行为技术的结合，我将用解剖学和功能精度表征PVT-NAc连接。然后，我将建立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。这些发现将促进我们对丘脑纹状体回路促进动机驱动的贡献的理解，可以为患有动机缺陷的个体开发新方法提供基本见解。

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.