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 药物使用障碍（SUD）的基本特征是持续的毒品寻求和滥用目的地 身体，财务和法律后果。在很大的延迟之后，批判性的厌恶后果， 例如在使用物质后的戒断，通常被低估。尽管很常见延迟 惩罚，成本/利益决策研究几乎完全集中在发生的惩罚上 选择后立即。为了解决这一差距，我们制定了延迟的惩罚决策任务 （DPDT），它表明老鼠像人类一样低估或“打折”延迟的负值 决策过程中的惩罚。使用DPDT获得的初步数据表明Orbitrontal Cortex （OFC）灭活会增加对延迟惩罚的敏感性，OFC编码有关 选择之前的惩罚延迟。尽管这些数据表明OFC在评估延迟中的作用 惩罚，这一过程的基础机制尚不清楚。 OFC活动由 来自不同中脑核的儿茶酚胺能项目，特别是来自来自的多巴胺能项目 腹侧侧瓣区域（VTA）和来自基因座（LC）的去甲肾上腺素能项目。我们的中心 假设是，多巴胺和去甲肾上腺素项目调节对延迟惩罚的敏感性 到OFC，由VTA产生的神经元释放多巴胺，影响延迟的折扣 惩罚，以及LC调节对惩罚的敏感性的神经元，无论延迟如何。我们 将使用Dreadds对LC或细胞类型的神经活动的特异性操纵来评估这一点 DPDT期间投射给OFC的VTA神经元。在AIM 1中，我们将使用注入抑制或兴奋性恐怖 进入TH-CRE大鼠的VTA，然后在DPDT之前直接刺激OFC末端中的这些受体。这 将启用OFC中多巴胺释放的选择性调制。对于AIM 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， 我们将执行控制实验，以确认操纵正在影响对立即或 延迟惩罚而不是疼痛的容忍度，奖励歧视或行为灵活性。共同 这些研究将确定OFC如何调节对延迟和延迟和的敏感性的潜在机制 立即惩罚。此外，这些实验将确定是否直接操纵两个 神经元电路具有有效的治疗方法，可以提高对SUD延迟后果的敏感性。