Circuit-specific catecholamine regulation of sensitivity to delayed punishment

摘要 物质使用障碍(SUD)的一个基本特征是持续寻求和滥用药物，尽管 物质、经济和法律后果。关键的是，在重大延误之后产生了令人厌恶的后果， 例如在使用药物后戒断，往往被低估。尽管经常发生延迟的情况 惩罚、成本/收益决策研究几乎完全集中在惩罚的发生上 在一次选择之后。为了解决这一差距，我们开发了延迟惩罚决策任务 (DPDT)，这表明大鼠和人类一样，低估了延迟的负值或对其打折。 在决策过程中的惩罚。DPDT获得的初步数据显示，眼眶前额叶皮质 (OFC)失活增加了对延迟惩罚的敏感度，并且OFC编码以下信息 惩罚拖延在选择之前。虽然这些数据表明OFC在评估延迟的 关于惩罚，这一过程背后的机制尚不清楚。OFC活动由 来自不同中脑核团的儿茶酚胺能投射，特别是来自 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 假设对延迟惩罚的敏感性由多巴胺和去甲肾上腺素的投射调节。 至OFC，VTA产生的神经元多巴胺释放影响延迟的折扣 来自LC的去甲肾上腺素能神经元调节对惩罚的敏感性，而不考虑延迟。我们 我将使用DREADDS对LC或 DPDT时，VTA神经元投射到OFC。在目标1中，我们将使用静脉注射抑制性或兴奋性DREADD 进入TH-CRE大鼠的VTA，然后在DPDT前直接刺激OFC终末的这些受体。这 将能够选择性地调节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。对于这两个目标的所有操纵， 我们将进行对照实验，以确认操作是否影响对即刻或 延迟惩罚，而不是疼痛容忍、奖励歧视或行为灵活性。总而言之， 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 立即给予惩罚。此外，这些实验将确定是否直接操纵两个未被研究的 神经元回路作为一种潜在的治疗方法，可以提高对SUD延迟后果的敏感性。

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.