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

在动物每天做出的许多决定中，许多决定涉及成本和回报。自神经科学诞生以来，研究人员一直在试图回答这样一个问题，即相互连接的大脑区域是如何联合收割机产生对复杂问题的决策的。该项目的研究人员以前的工作表明，纹状体的纹状体斑块对于成本和效益的整合至关重要。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参与复杂决策的大脑区域的多方面模型。该模型旨在定义涉及成本和回报的复杂决策背后的计算原理。为了测试这个模型，研究人员记录并操纵大鼠的纹状体神经元回路，执行一个新颖的，自然的成本效益决策任务。研究人员应用新的机器学习概念来帮助确定不同决策环境之间电路活动和决策转变的机械基础。除了追求科学目标外，研究人员还开发和建立了本科和研究生课程，重点是决策机制，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成为连接实验神经科学和计算的批判性思想家。从这些教育活动中受益的学生中有很大一部分来自STEM学科中代表性不足的少数群体。每天，人类和其他动物都要做出数百项关于食物偏好、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，即纹状体的纹状体区室是影响决策过程中追求奖励和避免成本之间平衡的关键门户。值得注意的是，纹状体选择性地投射到外侧缰（LH，主要的代价来源）和黑质的多巴胺能神经元（DA）（SNC，主要的奖赏来源）。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，了解这种回路在决策中的作用具有广泛的意义。研究人员测试了一个假设，即纹状体是一个枢纽，影响大脑成本/回报评估系统的关键参与者之间的相互作用，从而影响对成本和回报的主观评估。为了验证这一假设，研究人员记录并操纵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，并采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，使用先进的计算建模技术，研究人员确定了计算原理，定义了这些电路如何共同调解上下文相关的决策状态和影响选择行为。这项工作预计将揭示纹状体的作用，在上下文依赖的成本和效益的看法，并将其整合到一个主观价值，影响决策。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.