CAREER: Defining the mechanistic role of striosomal microcircuits in decision-making

在动物每天做出的许多决定中，许多都涉及到成本和回报。自从神经科学出现以来，研究人员一直试图回答这样一个问题：相互连接的大脑区域是如何结合起来对复杂问题做出决定的。该项目的研究人员先前的工作表明，纹状体的纹状体斑块对于成本和收益的整合至关重要。在这个项目中，研究人员使用先进的计算和实验技术测试了涉及复杂决策的大脑区域的多方面模型。该模型试图定义涉及成本和回报的复杂决策背后的计算原理。为了测试这一模型，研究人员在执行一项新颖的、自然的成本效益决策任务的大鼠中记录并操纵纹状体神经元回路。研究人员应用新颖的机器学习概念来帮助识别不同决策环境下回路活动和决策转变的机制基础。除了追求科学目标外，研究人员还开发和建立了以决策机制为重点的本科和研究生课程，以及研究决策和神经回路记录的分析和实验工具。这些课程旨在培养未来的研究人员作为桥梁实验神经科学和计算的批判性思考者。从这些教育活动中受益的学生中，很大一部分来自STEM学科中代表性不足的少数民族。每天，人类和其他动物都要做出数百个关于食物偏好、成本规避、繁殖和社会互动的决定。研究人员最近的研究提供了第一个线索，纹状体的纹状体隔室是影响决策过程中追求回报和避免成本之间平衡的关键通道。值得注意的是，纹状体选择性地投射到侧链（LH，主要的代价来源）和黑质致密的多巴胺能神经元（DA） （SNC，主要的奖励来源）。这种纹状体- da - lh回路在人类、猴子、猫、大鼠甚至七鳃鳗中都是保守的，因此，理解这种回路在决策中的作用具有广泛的意义。研究人员验证了一种假设，即纹状体是影响大脑成本/奖励评估系统中关键参与者之间相互作用的枢纽，从而影响对成本和奖励的主观评估。为了验证这一假设，研究人员记录并操纵了参与一项新的高通量决策任务的大鼠的特定纹状体回路。具体来说，研究人员使用高通量电生理学和Ca++成像来剖析纹状体LH-和da -投射群体的作用，并使用光遗传学方法来确定每种途径在决策中的因果作用。此外，利用先进的计算建模技术，研究人员确定了计算原理，这些计算原理定义了这些电路如何共同调节依赖于上下文的决策状态并影响选择行为。这项工作有望揭示纹状体在环境依赖的成本和收益感知中的作用，以及它们融入影响决策的主观价值。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Of the many decisions animals make daily, many entail choices that involve cost and reward. Since the dawn of neuroscience, researchers have sought to answer the question of how connected brain regions combine to produce decisions to complex problems. Previous work by the researchers of this project showed that the striosomal patches of the striatum are essential for integration of cost and benefit. In this project, the researchers test a multifaceted model of brain regions involved in complex decisions using advanced computational and experimental techniques. The model seeks to define the computational principles behind complex decisions involving cost and reward. To test this model, the researchers record and manipulate striosomal neuronal circuits in rats carrying out a novel, naturalistic cost-benefit decision-making task. The researchers apply novel machine learning concepts to aid identifying a mechanistic basis for the shift in circuit activity and decision-making between different decision-making contexts. In addition to pursuing the scientific objectives, the researchers develop and establish undergraduate and graduate courses that focus on the mechanisms of decision-making, and the analytical and experimental tools to study decision-making and neural circuit recordings. These courses aim to train future researchers to serve as critical thinkers that bridge experimental neuroscience and computation. A large fraction of the students benefiting from these educational activities comes from underrepresented minorities in STEM disciplines.Every day, humans and other animals make hundreds of decisions regarding food preference, cost avoidance, reproduction, and social interaction. The investigators’ recent research has provided the first clues that the striosomal compartments of the striatum are crucial gateways that affect the balance between the pursuit of reward and avoidance of costs during decision-making. Notably, striosomes selectively project to the lateral habenula (LH, predominant source of cost) and the dopaminergic neurons (DA) of the substantia nigra compacta (SNC, predominant source of reward). This Striosomal-DA-LH circuit is conserved across humans, monkeys, cats, rats, and even lampreys, and, therefore, understanding the role of this circuit in decision-making has broad implications. The investigators test the hypothesis that striosomes are a hub that affects interaction between the crucial players of the brain’s cost/reward evaluation system and, thus, influences subjective valuation of costs and rewards. To test this hypothesis, the investigators record and manipulate specific striosomal circuits in rats engaged in a novel, high-throughput decision-making task. Specifically, the investigators use high-throughput electrophysiology and Ca++ imaging to dissect the role of striosomal LH- and DA-projecting populations and an optogenetic approach to determine the causal role of each pathway in decision-making. Furthermore, using advanced computational modeling techniques, the investigators identify the computational principles that define how these circuits collectively mediate context-dependent decision-making states and influence choice behavior. The work is expected to reveal the role of striosomes in context-dependent perceptions of cost and benefit and their integration into one subjective value that affects decision-making.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.