The relationship between locus coeruleus activity and pupil diameter

描述(申请人提供)：蓝斑(LC)是一个小的脑干核团，是去甲肾上腺素(NE)的主要来源，到达皮质、丘脑、中脑、小脑和脊髓。LC-NE系统被认为在许多正常的大脑功能中发挥重要作用，包括觉醒和感觉-运动处理。此外，LC-NE系统与许多临床疾病有关，包括注意力缺陷/多动障碍(ADHD)、焦虑、抑郁和精神分裂症。因此，更好地了解LC-NE系统的特性可能会为了解正常和异常的大脑功能提供重要的见解。这种研究的一个主要障碍是LC的大小和位置，这使得记录或成像的目标很难实现。这个问题的一个可能的解决方案是测量瞳孔直径，这是相对简单的测量，在某些弱光条件下被认为反映了LC的激活。然而，尽管有一些强烈的相反说法，但从来没有足够严谨的方法来建立LC激活和瞳孔直径之间的关系，从而允许用LC功能来解释瞳孔测量。拟议研究的目标是详细描述这种关系。我们将使用三种互补的方法：1)同时记录清醒的猴子在不同条件下的单个LC神经元和瞳孔直径；2)同时在LC中应用电微刺激并测量清醒的行为猴子的瞳孔直径；以及3)在与猴子相似的条件下测量受试者的瞳孔直径。总而言之，这些研究将对LC激活和瞳孔直径之间的关系提供迄今为止最严格的评估。鉴于人们对LC-NE系统在行为、认知和疾病中的作用越来越感兴趣，以及测量瞳孔直径的相对容易，这些结果很可能对未来许多研究的设计和解释产生强烈影响。 公共卫生相关性：这项拟议的工作旨在严格并首次测试瞳孔直径和蓝斑(LC)脑干神经元激活之间的拟议联系，蓝斑是去甲肾上腺素(NE)到大脑其他部位的主要来源。这项工作将为未来使用非侵入性瞳孔测量更好地了解正常的LC功能以及帮助诊断和治疗与LC功能异常相关的许多疾病奠定坚实的基础，包括ADHD、焦虑、抑郁和精神分裂症。

DESCRIPTION (provided by applicant): The locus coerulus (LC) is a small brainstem nucleus that is the primary source of norepinephrine (NE) to the cortex, thalamus, midbrain, cerebellum, and spinal cord. The LC-NE system is thought to play important roles in many normal brain functions, including arousal and sensory-motor processing. In addition, the LC-NE system has been implicated in a number of clinical disorders, including attention-deficit/hyperactivity disorder (ADHD), anxiety, depression, and schizophrenia. Thus, a better understanding of the properties of the LC-NE system is likely to provide important insights into both normal and abnormal brain function. A major obstacle to such research is the size and location of the LC, which make it difficult to target for recording or imaging. One possible solution to this problem is to measure pupil diameter, which is relatively straightforward to measure and under certain low-light conditions is thought to reflect LC activation. However, despite some strong claims to the contrary, the relationship between LC activation and pupil diameter has never been established with sufficient rigor to allow pupillometry measurements to be interpreted in terms of LC function. The goal of the proposed studies is to characterize this relationship in detail. We will use three complementary approaches: 1) simultaneous recording of individual LC neurons and pupil diameter in awake, behaving monkeys under a variety of conditions; 2) simultaneous application of electrical microstimulation in the LC and measurements of pupil diameter in awake, behaving monkeys; and 3) measurements of pupil diameter in human subjects under comparable conditions to those tested with monkeys. Together, these studies will provide by far the most rigorous assessment to date of the relationship between LC activation and pupil diameter. Given the growing interest in the role of the LC-NE system in behavior, cognition, and disease, and the relative ease with which pupil diameter can be measured, these results are highly likely to make a strong impact on the design and interpretation of many future studies. PUBLIC HEALTH RELEVANCE: The proposed work is designed to test, rigorously and for the first time, a proposed link between pupil diameter and the activation of brainstem neurons in the locus coeruleus (LC) that are the primary source of norepinephrine (NE) to the rest of the brain. This work will establish a solid foundation for future uses of non-invasive pupil measurements to better understand normal LC function and to help diagnose and treat the many disorders associated with abnormal LC function, including ADHD, anxiety, depression, and schizophrenia.