Slow time scale fluctuations in neurons and behavior

神经回路和行为表现之间的联系一直是神经科学中一个永恒的谜团。一个 对神经元和行为的基本观察表明，它们都表现出变异性。这 可变性可以表现在各种时间尺度上，从几分钟到几小时再到几天，以及许多空间 规模，从局部的神经元群体到整个大脑。我们的产品中缺少的一个重要功能 对认知和行为的理解，可能解释了一些明显的差异，但缺乏洞察力 在执行任何任务时进入大脑的内部认知状态。脑内神经元之间的协调 大脑对于达到任何内部认知状态都是至关重要的，比如注意力或唤醒。这种协调具有 人们在场电位水平上进行了广泛的研究，但在单个神经元的群体中相对较少。 此外，因为一对大脑区域中神经元之间的协调可能与 遥远的大脑回路，梳理出引起协调神经活动的基本神经回路， 而与行为的联系，一直是具有挑战性的。与此同时，有针对性的药理学方法 神经调节系统已被证明是影响行为和治疗疾病的一种强大的手段，尽管很粗糙。 我们将通过场电位和神经血管信号来研究不同尺度上的神经协调。 从头皮到皮层中大量的尖峰神经元，再到大脑深层结构中的单个神经元 调节大脑皮层活动。同时，我们还将测量认知和知觉任务中的行为 正如我们在之前的工作中所展示的那样，瞳孔在几分钟的时间尺度上表现出缓慢的波动 几个小时。我们的策略是确定皮质神经元的神经元协调是如何指示内部认知的 状态和神经调节输入，并且可以被修改以改变认知和行为。我们将在一个 将群体中神经元之间的变异性与大脑内部状态联系起来的计算框架 进而影响到行为。在我们的第一个具体目标中，我们将测试场势和 头皮上的神经血管信号直接与前额叶皮质和行为的神经元协调有关。 在第二个目标中，我们将检验这一假设，即前额叶皮质以及 从蓝斑流出的去甲肾上腺素会影响觉醒的系统指标。最后，在 第三个目的，我们将检验这样的假设，即通过微刺激轨迹来直接干预这个回路 蓝斑可以改变大脑皮层神经元的协调，进而影响行为。这样做的总体结果是 研究将在大脑皮层的协调活动、神经调节驱动和 认知和行为。这将有助于开发各种神经疾病的治疗方法，这些疾病包括 觉醒状态的改变或去甲肾上腺素驱动力的变化，并建立一个框架来理解 神经元协调的大规模测量(如头皮场电位的振荡)和 神经回路机制。

The link between neural circuits and behavioral performance has been an enduring mystery in neuroscience. A fundamental observation of both neurons and behavior has been that they both exhibit variability. This variability can manifest on a variety of time scales, from minutes to hours to days, and across many spatial scales, from local populations of neurons to the whole brain. One important missing feature in our understanding of cognition and behavior, that may explain some of the apparent variability, is a lack of insight into the brain’s internal cognitive state while performing any task. The coordination among neurons across the brain is critical to achieving any internal cognitive state, such as attention or arousal. This coordination has been extensively studied at the level of field potentials, but relatively rarely in populations of single neurons. Furthermore, because the coordination among neurons in a pair of brain areas may relate to the action of distant brain circuits, teasing apart the fundamental neural circuits that give rise to coordinated neural activity, and the link in turn to behavior, has been challenging. At the same time, pharmacological approaches targeted at neuromodulatory systems have proved a powerful, if coarse, means to influence behavior and treat disease. We will study neural coordination across scales, from field potentials and neurovascular signals measured at the scalp, to populations of spiking neurons in cortex, to individual neurons in a deep brain structure that modulates cortical activity. Simultaneously, we will measure behavior on cognitive and perceptual tasks as well as the pupil, which we have shown in previous work exhibit slow fluctuations on the time scale of minutes to hours. Our strategy is to identify how neuronal coordination of cortical neurons is indicative of internal cognitive state and neuromodulatory input, and can be modified to alter cognition and behavior. We will do this in a computational framework that links the variability among neurons in a population to internal states of the brain and in turn to behavior. In our first specific aim, we will test the hypothesis that field potentials and neurovascular signals at the scalp are directly linked to neuronal coordination in prefrontal cortex and behavior. In the second aim, we will test the hypothesis that neuronal coordination in prefrontal cortex as well as systemic indicators of arousal are influenced by norepinephrine efflux from the locus coeruleus. Finally, in the third aim, we will test the hypothesis that direct intervention in this circuit by microstimulating the locus coeruleus can alter neuronal coordination in cortex and in turn influence behavior. The overall result of this study will be to establish a direct link between coordinated activity in the cortex, neuromodulatory drive, and cognition and behavior. This will aid in developing treatments for myriad neurological disorders that involve altered states of arousal or changes in norepinephrine drive, and establish a framework for understanding the link between large-scale measures of neuronal coordination (like oscillations in field potentials at the scalp) and neuronal circuit mechanisms.