Circuit-specific catecholamine regulation of sensitivity to delayed punishment

电路特异性儿茶酚胺对延迟惩罚敏感性的调节

• 批准号: 10648714
• 负责人: Nicholas W Simon
• 金额: $ 19.59万
• 依托单位: UNIVERSITY OF MEMPHIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648714
• 关键词: Address; Affect; Agonist; Aversive Stimulus; Behavioral; Biological; Brain; Catecholamines; Cell Nucleus; Characteristics; Clozapine; Cognition; Costs and Benefits; Data; Decision Making; Discrimination; Dopamine; Dopamine Receptor; Economics; Evaluation; Goals; Human; Infusion procedures; Intervention; Investigation; Legal; Mediating; Midbrain structure; Neurobiology; Neurons; Neurotransmitters; Norepinephrine; Outcome; Oxides; Pain Threshold; Pharmaceutical Preparations; Prevalence; Process; Punishment; Rattus; Receptor Activation; Regulation; Research; Rewards; Role; Substance Use Disorder; System; Time; Training; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Withdrawal; addiction; cell type; designer receptors exclusively activated by designer drugs; discount; discounting; dopaminergic neuron; experimental study; flexibility; genetic approach; improved; insight; locus ceruleus structure; neural; neuromechanism; neuronal circuitry; noradrenergic; novel; pharmacologic; receptor; substance use

Abstract A fundamental characteristic of substance use disorder (SUD) is ongoing drug seeking and misuse despite physical, financial, and legal consequences. Critically, aversive consequences following a substantial delay, such as withdrawal after substance use, are often underestimated. Despite the common occurrence of delayed punishment, cost/benefit decision-making research has focused almost entirely on punishment occurring immediately after a choice. To address this gap, we developed the Delayed Punishment Decision-making Task (DPDT), which reveals that rats, like humans, underestimate or “discount” the negative value of delayed punishment during decision-making. Preliminary data obtained using DPDT reveal that orbitofrontal cortex (OFC) inactivation increases sensitivity to delayed punishment, and OFC encodes information about punishment delay prior to choice. While these data suggest a role of OFC in the assessment of delayed punishment, the mechanism underlying this process remains unclear. OFC activity is sculpted by catecholaminergic projections from distinct midbrain nuclei, specifically dopaminergic projections from the ventral tegmental area (VTA) and noradrenergic projections from the locus coeruleus (LC). Our central hypothesis is that sensitivity to delayed punishment is modulated by dopamine and norepinephrine projections to OFC, with dopamine release from neurons arising from VTA affecting the discounting of delayed punishment, and noradrenergic neurons from LC regulating sensitivity to punishment regardless of delay. We will evaluate this using DREADDS for both circuit and cell-type specific manipulation of neural activity in LC or VTA neurons projecting to OFC during DPDT. In Aim 1, we will use infuse inhibitory or excitatory DREADDS into the VTA of TH-Cre rats, then directly stimulate these receptors in the OFC terminals prior to DPDT. This will enable selective modulation of dopamine release in OFC. For Aim 2, we will infuse excitatory or inhibitory DREADDS into LC, then stimulate these receptors in OFC prior to DPDT. For all manipulations in both Aims, we will perform control experiments to confirm that manipulations are affecting sensitivity to immediate or delayed punishment rather than pain tolerance, reward discrimination, or behavioral flexibility. Collectively, these studies will determine a potential mechanism for how the OFC regulates sensitivity to both delayed and immediate punishment. Moreover, these experiments will determine if direct manipulation of two understudied neuronal circuits has efficacy as a potential treatment to improve sensitivity to delayed consequences in SUD.

抽象的 物质使用障碍 (SUD) 的一个基本特征是持续寻求药物和滥用药物，尽管 严重的后果是严重延误后的身体、财务和法律后果。 例如物质使用后的戒断，尽管经常发生延迟，但常常被低估。 惩罚、成本/收益决策研究几乎完全集中于惩罚的发生 为了解决这一差距，我们开发了延迟惩罚决策任务。 （DPDT），它揭示了老鼠像人类一样低估或“低估”了延迟的负值 使用 DPDT 获得的初步数据显示，眶额皮质会受到惩罚。 （OFC）失活增加了对延迟惩罚的敏感性，并且 OFC 对以下信息进行编码 虽然这些数据表明 OFC 在评估延迟中发挥着作用。 惩罚，这一过程背后的机制仍不清楚。 来自不同中脑核的儿茶酚胺能投射，特别是来自中脑的多巴胺能投射 腹侧被盖区（VTA）和蓝斑（LC）的去甲肾上腺素能投射。 假设是对延迟惩罚的敏感性受到多巴胺和去甲肾上腺素投射的调节 到 OFC，VTA 引起的神经元释放多巴胺影响延迟的折扣 惩罚，以及来自 LC 的去甲肾上腺素能神经元调节对惩罚的敏感性，无论延迟如何。 将使用 DREADDS 来评估这一点，以对 LC 或中的神经活动进行电路和细胞类型特定操作 在 DPDT 期间，VTA 神经元投射到 OFC 在目标 1 中，我们将使用注入抑制性或兴奋性 DREADDS。 进入 TH-Cre 大鼠的 VTA，然后在 DPDT 之前直接刺激 OFC 末端的这些受体。 将能够选择性调节 OFC 中的多巴胺释放。对于目标 2，我们将注入兴奋性或抑制性。 DREADDS 进入 LC，然后在 DPDT 之前刺激 OFC 中的这些受体 对于两个目标中的所有操作， 我们将进行对照实验，以确认操作正在影响对即时或 延迟惩罚而不是疼痛容忍、奖励歧视或行为灵活性。 这些研究将确定 OFC 如何调节对延迟和延迟的敏感性的潜在机制。 此外，这些实验将确定是否直接操纵两个被研究对象。 神经元回路作为一种潜在的治疗方法具有提高 SUD 延迟后果敏感性的功效。