Hwang Jaewon, Noble Pamela L, Baldwin Mary K L, Murray Elisabeth A
Section on the Neurobiology of Learning and Memory, Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurosci. 2025 Jul 28. doi: 10.1523/JNEUROSCI.0619-25.2025.
Altered arousal is characteristic of many mental health disorders, including major depressive disorder (MDD). Several studies link neural activity in orbitofrontal cortex (OFC) with anticipation of reward, including anticipatory sympathetic arousal, which is blunted in MDD. We therefore studied acquisition and consolidation of appetitive Pavlovian memories in two groups of adult male rhesus monkeys: unoperated controls (N = 4) and those with selective neurotoxic lesions of OFC (N = 4). The dependent measure was conditioned sympathetic arousal as indexed by differential pupil dilation, and the key comparison was dilation in response to a visual cue that predicted the delivery of a large fluid reward (CS+) vs. a cue that predicted no reward (CS-). Control procedures ruled out global effects of the lesion on pupil dilation. All four unoperated controls and all four monkeys with OFC lesions acquired a conditioned increase in pupil size in response to the CS+. However, three of the four monkeys in the lesion group failed to consolidate the memory underlying this response. In contrast to this impairment, monkeys with OFC lesions acquired and consolidated an operant visual discrimination for the same reward and did so at the same rate as controls. These findings point to a specialized role for OFC in consolidating memories underlying positive affective responses, which further implicates OFC dysfunction in the blunted positive affect characteristic of MDD and suggests therapeutic approaches involving enhanced consolidation and/or reconsolidation of associative memories. Blunted anticipation of positive events is characteristic of many mental health disorders, including major depressive disorder (MDD). Cortical circuits underlying anticipatory responses have been identified in rodent models, but it is likely that different mechanisms operate in anthropoid primates, the clade that includes humans and monkeys. Anthropoids have cortical areas that rats and mice lack, and here we show that-in a macaque monkey model-some of these areas are necessary for consolidating memories that produce autonomic arousal in anticipation of rewards. Specifically, the integrity of granular orbitofrontal cortex (OFC)-the part of OFC specific to primates-is essential for macaque monkeys to consistently generate arousal in response to visual cues that predict positive events.
觉醒改变是许多精神健康障碍的特征，包括重度抑郁症（MDD）。多项研究将眶额皮质（OFC）的神经活动与奖励预期联系起来，包括预期性交感神经觉醒，而这种觉醒在MDD中会减弱。因此，我们研究了两组成年雄性恒河猴对味觉性巴甫洛夫记忆的获取和巩固：未手术的对照组（N = 4）和OFC有选择性神经毒性损伤的猴子（N = 4）。因变量是通过瞳孔差异扩张来索引的条件性交感神经觉醒，关键比较是对预测会给予大量液体奖励的视觉线索（CS +）与预测无奖励的线索（CS -）做出反应时的瞳孔扩张情况。对照程序排除了损伤对瞳孔扩张的整体影响。所有四只未手术的对照组猴子和所有四只OFC损伤的猴子都获得了对CS +做出反应时瞳孔大小的条件性增加。然而，损伤组中的四只猴子中有三只未能巩固这种反应背后的记忆。与这种损伤形成对比的是，OFC损伤的猴子获得并巩固了对相同奖励的操作性视觉辨别能力，并且其速度与对照组相同。这些发现表明OFC在巩固积极情感反应背后的记忆方面具有特殊作用，这进一步暗示了OFC功能障碍与MDD特征性的积极情感减弱有关，并提示了涉及增强联想记忆巩固和/或重新巩固的治疗方法。对积极事件的预期减弱是许多精神健康障碍的特征，包括重度抑郁症（MDD）。在啮齿动物模型中已经确定了预期反应背后的皮质回路，但在类人猿灵长类动物（包括人类和猴子的进化枝）中可能存在不同的机制。类人猿具有大鼠和小鼠所没有的皮质区域，在这里我们表明——在猕猴模型中——这些区域中的一些对于巩固在预期奖励时产生自主神经觉醒的记忆是必要的。具体而言，颗粒状眶额皮质（OFC）——灵长类动物特有的OFC部分——的完整性对于猕猴持续产生对预测积极事件的视觉线索的觉醒至关重要。
