Evaluating the function and activity dynamics of thalamic inputs for reward seeking and consumption

 描述(申请人提供)：寻找奖赏的丘脑输入的功能和自然活动动态。强迫性寻求奖励和索取是上瘾的特征，尽管协调这些基本动机状态的准确神经回路仍不清楚。这在一定程度上是因为缺乏实验的可行性，因为很难控制和监测体内细胞类型的特定神经元的活动。例如，丘脑室旁核(PVT)是丘脑的中线核，与动力回路相连，是进食的关键调节器，对于恢复几种药物寻找模式是必要的。尽管如此，PVT神经元如何在更广泛的回路中调节这些动机状态尚不清楚。因此，这个项目的目标是使用现代工具来研究参与PVT控制奖赏寻求的精确神经回路。在这里，我建议确定两个主要的PVT输入的功能和自然活动动力学，特别是来自下丘脑外侧(LH)和初级皮质(PLC)，以控制奖赏寻求。在线索诱导的奖赏寻找任务的不同阶段，将用抑制光遗传学来评估PVT输入对奖赏寻找的作用(目标1)。此外，在清醒、自由移动的小鼠中，这些投射特定神经元的自然活动动态将在寻找奖赏和通过脑深部钙成像进行可视化(目标2)。根据我的初步数据，以及我的发起人和其他人发表的工作，我假设PVT投射的LH神经元将是活跃的，并且是寻求奖励和消费所必需的。相反，根据我的初步数据和我之前发表的工作，我假设PVT投射PLC神经元将是活跃的和特定于线索驱动的奖赏寻求所必需的，但不是一般的奖赏寻求和消费。这些数据表明，PVT整合了关于动机驱动(LH)和环境刺激(PLC)的不同信号，以调节奖励寻求行为。无论结果如何，这些实验都将确定黄体生成素-PVT和PLC-PVT神经元的功能和自然活动动力学，以控制奖赏寻求和获取。

 DESCRIPTION (provided by applicant): Function and natural activity dynamics of thalamic inputs for reward seeking. Compulsive reward seeking and taking are hallmarks of addiction, although the precise neural circuits that orchestrate these basic motivational states remain unclear. This is in part due to a lack of experimental feasibility, as it has been difficult to conrol and monitor the activity of cell-type specific neurons in vivo. For example, the paraventricular thalamus (PVT) is a midline thalamic nucleus that interfaces with motivational circuits, is a critical regulator of feeding, and is necessary for reinstatement in several models of drug seeking. Despite this, how PVT neurons function within a broader circuit to regulate these motivational states is unknown. Thus, the objective of this project is to use contemporary tools to study the precise neurocircuitry that engages PVT for the control of reward seeking. Here I propose to identify the function and natural activity dynamics of two primary PVT inputs, particularly from the lateral hypothalamus (LH) and prelimbic cortex (PLc), for the control of reward seeking. The function of PVT inputs for reward seeking will be evaluated with inhibitory optogenetics during distinct phases of a cue-induced reward-seeking task (Aim 1). Furthermore, the natural activity dynamics of these projection-specific neurons will be visualized during reward seeking and taking through deep-brain calcium imaging in awake, freely moving mice (Aim 2). Based on my preliminary data and published work by my sponsor and others, I hypothesize that PVT-projecting LH neurons will be active and necessary for reward seeking and consumption. In contrast, based on my preliminary data and my previously published work, I hypothesize that PVT-projecting PLc neurons will be active and necessary specifically for cue-driven reward seeking, but not reward seeking and consumption in general. These data would suggest that the PVT acts to integrate distinct signals regarding motivational drive (LH) and environmental stimuli (PLc) to regulate reward-seeking behavior. Regardless of the results, these experiments will identify the function and natural activity dynamics of LH-PVT and PLc-PVT neurons for the control of reward seeking and taking.