Identification of the higher-order cognitive mechanisms by which prefrontal and anterior cingulate circuits regulate negative emotion

作为个人，我们每天都会面临引发恐惧和焦虑的情况，无论是相对轻微的，例如在一群人面前演讲，还是更严重的，例如失去工作的前景。轻微的恐惧和焦虑与我们的行为变化以及随之而来的生理变化有关，包括心率加快、肌肉紧张和压力激素水平升高。这样的情绪反应使我们能够适应特定的情况，为我们做好准备，或者帮助我们避免负面事件。然而，如果过度且不受监管，这些反应会导致临床焦虑，这是焦虑症的核心症状（终生患病率为16%），但也可能是许多其他疾病的突出症状，包括抑郁症、强迫症、精神分裂症和反社会症。不幸的是，潜在治疗的范围相对有限，治疗成功的水平也变化很大。这可能是因为人们表现出临床焦虑的原因多种多样。例如，有很多因素影响我们处理消极事件的能力，包括它们的可预测性，我们是否能控制它们，我们让消极事件主导我们的思想并分散我们对环境中其他更积极事件的注意力的程度。大脑回路的损伤对预测事件或学习如何控制这些事件或控制我们的注意力很重要，它会导致焦虑加剧。例如，如果一个人的预测能力被破坏，因此负面事件似乎更不确定，这将产生焦虑。另外，注意力控制障碍会导致个体无法抑制对负面刺激的注意力，从而花费更多时间关注负面结果，从而导致焦虑加剧。然而，尽管焦虑在这两种情况下都很常见，但潜在的机制是不同的。这项研究计划的目标是确定大脑中帮助我们调节情绪的不同区域的不同功能。该建议特别关注大脑区域内的四个主要区域，即前额叶皮层和前扣带皮层。为了确定每个大脑区域的独特贡献，我们将在进行行为测试的实验动物中研究它们的功能。我们的方法的一个至关重要的特点是，我们对实验动物的行为分析将直接与人类受试者和患者的研究进行比较。这将有助于我们的研究结果转化为临床应用。我们将使用一种方法，使我们能够在短时间内暂时使给定的大脑区域失活。30分钟)，并调查其对情绪反应的影响。我们还将研究这些选择性大脑失活对大脑其他部位活动的影响，使我们不仅可以研究单一的大脑结构，还可以研究大脑回路。总的来说，这将使我们深入了解焦虑的不同原因，从而帮助我们改进诊断。它还将帮助我们根据这些不同的原因为个人量身定制现有的治疗方法，并开发新的治疗策略。

As individuals we are faced with situations that provoke fear and anxiety on a daily basis, whether they be relatively mild, e.g. giving a talk to a group of people, or more serious, e.g. the prospect of losing one's job. Mild fear and anxiety are associated with changes in our behaviour and accompanying changes in our physiology, including increased heart rate, muscle tension and stress hormone levels. Such emotional responses allow us to adapt to a given situation and either prepare us for, or help us to avoid, a negative event. However, in excess, and unregulated, these responses lead to clinical anxiety, which is a core symptom of anxiety disorders (which have a lifetime prevalence of 16%), but can also be a prominent symptom of many other disorders, including Depression, Obsessive Compulsive disorder, Schizophrenia and Sociopathy. Unfortunately, the range of potential treatments is relatively restricted and the level of treatment success, highly variable. This is probably because there are varied reasons as to why someone may show clinical anxiety. For example, there are many factors that contribute to how well we cope with negative events, including how predictable they are, whether we have control over them, how much we let negative events dominate our thoughts and distract us from paying attention to other, more positive events in our environment. Impairments in brain circuits that are important for predicting events or learning how to control such events or controlling what we attend to, can lead to enhanced anxiety. For example, if an individual's ability to predict is disrupted and thus negative events seem more uncertain, this will generate anxiety. Alternatively, an impairment in attentional control will result in an individual failing to inhibit their attention towards negative stimuli, thus spend more time focussing on negative outcomes, resulting in heightened anxiety. However, whilst the anxiety is common in both cases, the underlying mechanisms are different. The goal of this research proposal is to identify the different functions of distinct regions of the brain that help us to regulate our emotions. In particular, this proposal focuses on four main regions within areas of the brain called the prefrontal cortex and the anterior cingulate cortex. In order to identify the distinct contributions of each brain region we will investigate their functions in experimental animals performing behavioural tests. A critically important feature of our approach is that our behavioural analysis in experimental animals will be directly comparable with studies in human subjects and patients. This will facilitate the translatability of our findings into the clinic. We will use a methodology that will allow us to temporarily inactivate a given brain region for a short time period (approx. 30 minutes) and investigate the effects on emotional responses. We will also investigate the effects of these selective brain inactivations on activity elsewhere in the brain, allowing us to investigate not just single brain structures but brain circuits. Overall, this will provide insight into the distinct differentiable causes of anxiety and thus help us to refine our diagnoses. It will also help us to tailor existing treatments for individuals based on those different causes as well as develop novel treatment strategies.