Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey; Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey.
Biol Psychiatry. 2022 Dec 1;92(11):836-844. doi: 10.1016/j.biopsych.2022.06.027. Epub 2022 Jul 3.
In 2014, we proposed that orexin signaling transformed motivationally relevant states into adaptive behavior directed toward exploiting an opportunity or managing a threat, a process we referred to as motivational activation. Advancements in animal models since then have permitted higher-resolution measurements of motivational states; in particular, the behavioral economics approach for studying drug demand characterizes conditions that lead to the enhanced motivation that underlies addiction. This motivational plasticity is paralleled by persistently increased orexin expression in a topographically specific manner-a finding confirmed across species, including in humans. Normalization of orexin levels also reduces drug motivation in addiction models. These new advancements lead us to update our proposed framework for the orexin function. We now propose that the capacity of orexin neurons to exhibit dynamic shifts in peptide production contributes to their role in adaptive motivational regulation and that this is achieved via a pool of reserve orexin neurons. This reserve is normally bidirectionally recruited to permit motivational plasticity that promotes flexible, adaptive behavior. In pathological states such as addiction, however, we propose that the orexin system loses capacity to adaptively adjust peptide production, resulting in focused hypermotivation for drug, driven by aberrantly and persistently high expression in the orexin reserve pool. This mechanistic framework has implications for the understanding and treatment of several psychiatric disorders beyond addiction, particularly those characterized by motivational dysfunction.
2014 年，我们提出，食欲素信号将动机相关状态转化为指向利用机会或应对威胁的适应性行为，我们将这一过程称为动机激活。此后，动物模型的进步使得对动机状态进行更高分辨率的测量成为可能；特别是，研究药物需求的行为经济学方法描述了导致成瘾基础上增强动机的条件。这种动机可塑性与食欲素表达以特定的拓扑方式持续增加平行——这一发现已在包括人类在内的多种物种中得到证实。食欲素水平的正常化也会降低成瘾模型中的药物动机。这些新的进展促使我们更新我们提出的食欲素功能框架。我们现在提出，食欲素神经元表现出肽产生动态变化的能力有助于它们在适应性动机调节中的作用，并且这是通过储备食欲素神经元池来实现的。这个储备通常被双向招募，以促进灵活的、适应性的行为。然而，在成瘾等病理状态下，我们提出，食欲素系统失去了适应性调整肽产生的能力，导致对药物的过度关注和持久的高表达，从而驱动了异常和持久的高表达。这种机械框架对于理解和治疗除成瘾以外的几种精神障碍具有重要意义，特别是那些以动机功能障碍为特征的障碍。
