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

 描述（由申请人提供）：用于奖励寻求的丘脑输入的功能和自然活动动力学。强迫性的奖赏寻求和索取是成瘾的标志，尽管协调这些基本动机状态的精确神经回路仍不清楚。这部分是由于缺乏实验可行性，因为难以控制和监测体内细胞类型特异性神经元的活性。例如，室旁丘脑（PVT）是一个中线丘脑核，与动机回路相连接，是进食的关键调节器，并且在几种药物寻求模型中是恢复所必需的。尽管如此，PVT神经元如何在更广泛的回路中发挥作用来调节这些动机状态仍然是未知的。因此，本项目的目标是使用当代工具来研究参与PVT控制奖励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，特别是从外侧下丘脑（LH）和前边缘皮层（PLC）的功能和自然的活动动力学，为寻求奖励的控制。将在线索诱导的奖励寻求任务的不同阶段期间用抑制性光遗传学评估PVT输入对于奖励寻求的功能（目标1）。此外，这些投射特异性神经元的自然活动动力学将在清醒、自由移动的小鼠中通过脑深部钙成像在奖赏寻求和获取期间可视化（目的2）。根据我的初步数据和我的赞助商和其他人发表的工作，我假设PVT投射LH神经元将是活跃的，并且是奖励寻求和消费所必需的。相比之下，根据我的初步数据和我以前发表的工作，我假设PVT投射PLc神经元将是活跃的，并且特别是对于线索驱动的奖励寻求来说是必要的，但一般来说不是奖励寻求和消费。这些数据表明，PVT的行为，整合不同的信号有关的动机驱动（LH）和环境刺激（PLc），以调节奖励寻求行为。无论结果如何，这些实验将确定LH-PVT和PLc-PVT神经元的功能和自然活动动力学，以控制奖励寻求和获取。

 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.