Circuit-specific catecholamine regulation of sensitivity to delayed punishment

摘要 物质使用障碍的一个基本特征是持续的药物寻求和滥用， 物理的、经济的和法律的后果。严重的是，严重的拖延会带来令人厌恶的后果， 例如吸毒后戒断。尽管经常发生延迟 惩罚，成本/效益决策研究几乎完全集中在惩罚发生 一个选择之后。为了解决这个问题，我们开发了延迟惩罚决策任务 （DPDT），它揭示了大鼠，像人类一样，低估或“折扣”延迟的负面价值。 决策过程中的惩罚。使用DPDT获得的初步数据显示， (OFC)失活增加了对延迟惩罚的敏感性，OFC编码了关于 选择之前的惩罚。虽然这些数据表明眶额皮层在评估延迟的 惩罚，这一过程的机制仍不清楚。眶额皮层的活动是由 来自不同中脑核团的儿茶酚胺能投射，特别是来自中脑核团的多巴胺能投射。 腹侧被盖区（VTA）和蓝斑（LC）的去甲肾上腺素能投射。我们的中央 一种假说认为，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 从腹侧被盖区引起的神经元释放多巴胺影响延迟的 惩罚，和去甲肾上腺素能神经元从LC调节敏感性的惩罚，无论延迟。我们 我将使用DREADDS评估LC中神经活动的回路和细胞类型特异性操纵， DPDT时VTA神经元向眶额皮层投射。在目标1中，我们将使用注入抑制性或兴奋性DREADDS 在DPDT前直接刺激OFC终末的这些受体。这 能够选择性调节眶额皮层多巴胺的释放。对于目标2，我们将注入兴奋或抑制 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，以确认操作是否影响对即时或 延迟惩罚，而不是疼痛容忍，奖励歧视或行为灵活性。总的来说， 这些研究将确定眶额皮层如何调节对延迟和 立即处罚。此外，这些实验将确定是否直接操纵两个未充分研究的 神经元回路作为一种潜在的治疗方法具有提高SUD对延迟后果的敏感性的功效。

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.