Effort, timing and choice: a refined rodent effort choice task with excellent sensitivity to dopamine modulators

IF 7.6 1区 医学 Q1 NEUROSCIENCES
Suellen Almeida-Correa, Fynn-Sebastian Wesemann, Sarah Diez, Mary Jane Maynard, Lucas Yebra Garcia, Patrizia Voehringer, Boris Ferger, Michael Becker, Carsten T. Wotjak, Johann du Hoffmann
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引用次数: 0

Abstract

Motivational deficits and anhedonia are core features of psychiatric disorders such as depression, schizophrenia and addiction, yet current treatments rarely improve these symptoms. Progress towards targeted therapeutics requires preclinical tasks that reliably capture pharmacological modulation of relevant neural circuits. Here, we developed a modified effort-related choice task (mERC) that integrates high effort demands, extended intertrial intervals and choice, to enable robust bidirectional sensitivity to systemic pharmacology. Unlike standard paradigms, mERC detects both impairing and enhancing effects of dopamine modulators within a single task and reveals drug-sensitive anticipatory responses during intertrial intervals—a behavioral feature linked to interval timing and motivational vigor. Using neurochemical and photometric analyses, we show that mERC performance is associated with behavioral signatures consistent with dopaminergic signaling across different timescales and is potentially constrained by a bounded dynamic range beyond which behavioral modulation is lost. Species differences in drug efficacy map onto baseline dopamine tone and depletion dynamics, underscoring the interactions between task structure and neurochemical state. Together, these findings establish mERC as a stable and sensitive preclinical assay for enhancing our understanding of effort-based decision-making and for screening novel therapeutics targeting motivational dysfunction.
努力,时间和选择:一种精细的啮齿动物努力选择任务,对多巴胺调节剂具有极好的敏感性。
动机缺陷和快感缺乏是抑郁症、精神分裂症和成瘾等精神疾病的核心特征,但目前的治疗方法很少能改善这些症状。靶向治疗的进展需要可靠地捕获相关神经回路的药理调节的临床前任务。在这里,我们开发了一个改进的努力相关选择任务(mERC),它集成了高努力要求,延长间隔时间和选择,以实现对全身药理学的强大双向敏感性。与标准范式不同,mERC在单一任务中检测多巴胺调节剂的损害和增强作用,并揭示了间隔时间内药物敏感的预期反应——一种与间隔时间和动机活力相关的行为特征。通过神经化学和光度分析,我们发现mERC的表现与不同时间尺度上与多巴胺能信号一致的行为特征有关,并且可能受到有界动态范围的限制,超过该动态范围行为调节就会丢失。药物疗效的物种差异映射到基线多巴胺张力和消耗动力学,强调任务结构和神经化学状态之间的相互作用。总之,这些发现确立了mERC作为一种稳定和敏感的临床前检测方法,可以增强我们对基于努力的决策的理解,并筛选针对动机功能障碍的新疗法。
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来源期刊
Neuropsychopharmacology
Neuropsychopharmacology 医学-精神病学
CiteScore
15.00
自引率
2.60%
发文量
240
审稿时长
2 months
期刊介绍: Neuropsychopharmacology is a reputable international scientific journal that serves as the official publication of the American College of Neuropsychopharmacology (ACNP). The journal's primary focus is on research that enhances our knowledge of the brain and behavior, with a particular emphasis on the molecular, cellular, physiological, and psychological aspects of substances that affect the central nervous system (CNS). It also aims to identify new molecular targets for the development of future drugs. The journal prioritizes original research reports, but it also welcomes mini-reviews and perspectives, which are often solicited by the editorial office. These types of articles provide valuable insights and syntheses of current research trends and future directions in the field of neuroscience and pharmacology.
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