CRCNS: Gradients of receptors underlying distributed cognitive functions

NIMH的一个关键目标是定义复杂行为的机制。这需要一种方法 但我们一直缺乏一个单一的理论框架， 神经递质受体功能，大脑活动和认知的大规模模式。工作记忆是 认知的关键组成部分，但我们对为什么工作记忆出现在某些部分的理解， 皮质，而不是其他，是有限的。猕猴是研究高级认知功能的重要模型 与精神疾病有关，因为他们的智能行为和相对相似的大脑。我们 建议创建猕猴大脑的高分辨率3D图谱，并使用它来创建数据驱动的 神经回路模型，这将使我们对区域变化之间的关系的关键见解， 受体密度和分布式工作记忆的出现。地图集将使量化 14种受体（受体指纹）和细胞密度的区域和层分布 遍布整个猕猴皮层这将允许询问受体指纹和细胞密度 精确到亚毫米级它将伴随着一个新的包裹计划的基础上的梯度 细胞和受体的结构。本地图集将在NIMH猕猴 易于与猕猴/MRI数据集成的模板。我们将确定主要的梯度， 感受器在皮层的分布，并将其与感觉系统的层次进行比较， 认知网络使用开放访问层流追踪和/MRI数据。这种方法将揭示 不同功能层次下的受体签名。我们将使用分叉的概念， 数学来询问大脑皮层感受器密度的变化如何导致大脑皮层的 在大脑皮层的特定区域出现类似工作记忆的持续活动。最重要的是，我们将允许 通过实验测量的受体密度来衡量每个皮层区域中每个受体的作用 和层。我们假设，在大脑皮层区域观察到的工作记忆活动模式， 层关键地取决于受体的区域分布。此外，我们将扩展我们的模型， 包括区域间连通性数据，并研究神经调质释放如何改变皮质 认知网络之间的活动。我们提出的研究结果可能会大大推进 这一研究领域，具有广泛的影响。非常有希望的初步结果证实了 方法的有效性，确保计划的各个方面都有很高的成功可能性。 相关性（参见说明）： 精神疾病的认知症状很难治疗，但可能是患者最大的障碍 独立生活认知功能依赖于许多大脑区域通过化学物质进行交流， 受精神疾病和药物影响的受体。我们将绘制这些受体的模式 所以我们可以建立计算机模型来理解为什么大脑的认知功能不同 地区这可能会导致精神疾病认知症状的新治疗方法的发展。

A key goal of the NIMH is to define the mechanisms of complex behaviors. This necessitates an approach that spans biological scales, but we have been lacking a single theoretical framework that links neurotransmitter receptor function, large-scale patterns of brain activity and cognition. Working memory is a key building block of cognition, but our understanding of why working memory emerges in sorne parts of cortex, but not others, is limited. The macaque is an important model for studying higher cognitive function with relevance to psychiatric disease, due to their intelligent behavior and relatively similar brains. We propose the creation of a high-resolution 3D atlas of the macaque brain, and use it to create data-driven neural circuit models that will give us key insights into the relationship between regional variations in receptor densities and the emergence of distributed working memory. The atlas will enable quantification of the regional and laminar distribution of 14 types of receptors (receptor fingerprints) and cell densities across the entire macaque cortex. This will allow for interrogation of receptor fingerprints and cell densities with submillimeler precision. It will be accompanied by a novel parcellation scheme based on the gradients of cyto- and receptor-architecture across cortex. This atlas will be registered lo the NIMH Macaque Template for easy integration with macaque /MRI data. We will identify the principal gradients that underlie the distribution of receptors across cortex and compare these to hierarchies of sensory systems and cognitive networks using open-access laminar tract-tracing and /MRI data. This approach will uncover the receptor signature underlying distinct functional hierarchies. We will use the idea of bifurcations from mathematics to interrogate how changes lo the density of receptors across cortex may lead to the emergence of working-memory like persistent activity in particular regions of cortex. Crucially, we will allow the experimentally measured receptor densities lo scale the effects of each receptor in each cortical area and layer. We hypothesize that the pattern of working memory activity observed across cortical areas and lamina depends critically on the regional distribution of the receptors. Further, we will expand our model to include inter-areal connectivity data and investigate how release of neuromodulators can shift cortical activity between cognitive networks. The results of our proposed research are likely to significantly advance this area of research, with broad implications. The highly promising preliminary results have confirmed the validity of the approach, ensuring that all aspects of the program have a high likelihood of success. RELEVANCE (See instructions): Cognitive symptoms of mental illnesses are difficult to treat, but can be the biggest impediment to patients living independently. Cognitive functions rely on many brain areas communicating through chemicals and receptors, which are affected by mental illness and medication. We will map the pattern of these receptors in the brain, so we can build computer models to understand why cognitive functions differ across brain regions. This could lead to the development of new treatments for cognitive symptoms in mental illness.