Hedonic processing plays an integral role in directing appropriate behavior, but disrupted hedonic processing is associated with psychiatric disorders such as depression. The infralimbic cortex (IL) is a key structure in affective processing in rodents and activation of its human homolog, the ventromedial prefrontal cortex, has been implicated in suppressing aversive states. Here, we tested whether optogenetic activation of glutamatergic projections from the IL to the nucleus accumbens shell (NAcSh) suppresses the aversive impact of sucrose devalued using the conditioned taste aversion paradigm in males and female rats. In naive rats, no significant differences in appetitive or aversive taste reactivity (TR) to sucrose was observed indicating that initial sucrose palatability was equivalent across sex. However, we found that optical activation of the IL–NAcSh pathway during intraoral infusion of devalued sucrose inhibited aversive TR in male but not female rats. Interestingly, when allowed to freely ingest water and sucrose in a two-bottle test both males and females with a history of IL–NAcSh stimulation exhibited greater preference for sucrose. Optical pathway activation failed to alter TR to innately bitter quinine in either sex. Finally, both sexes lever pressed to self-stimulate the IL–NAcSh pathway. These results indicate that the IL–NAcSh pathway plays an important role in suppressing learned aversive states selectively in males but spares hedonic processing of innately aversive tastants. Further, pathway activation is reinforcing in both sexes, indicating that suppression of conditioned aversive TR can be dissociable from the effects of unconditioned rewarding properties of IL–NAcSh pathway activation.

SIGNIFICANCE STATEMENT Negative emotional states contribute to psychiatric disorders including depression and substance use disorders. In this study, we examined whether brain circuitry previously implicated in suppressing negative emotional states in humans can inhibit learned aversion in male and female rats. We found that optical activation of the infralimbic to nucleus accumbens shell pathway attenuates learned aversive responses in male but not female rats, indicating an important sex difference in the function of this brain pathway. Furthermore, we found that pathway stimulation was reinforcing in both sexes. Collectively, these findings support the role of the infralimbic cortex and its projection to the nucleus accumbens shell in suppressing learned negative emotional states and highlight an important sex-specific function of this pathway.

享乐性加工在指导适当的行为中起着不可或缺的作用，但是享乐性加工的中断与诸如抑郁症之类的精神疾病有关。下肢皮质（IL）是啮齿动物情感加工中的关键结构，其人类同系物腹侧前额叶皮质的激活与抑制厌恶状态有关。在这里，我们测试了从条件性味觉厌恶范例对雌性大鼠的IL到伏隔核壳（NAcSh）的谷氨酸能投射的光遗传激活是否抑制了蔗糖贬值的厌恶影响。在幼稚大鼠中，对蔗糖的食性或厌恶味反应性（TR）没有观察到显着差异，表明最初的蔗糖适口性在两性之间是相同的。然而，我们发现口服降糖蔗糖期间IL-NAcSh途径的光学激活抑制了雄性大鼠而非雌性大鼠的厌恶性TR。有趣的是，在两瓶试验中允许自由摄入水和蔗糖时，有IL-NAcSh刺激史的雄性和雌性均表现出对蔗糖的更大偏好。光学通路的激活未能将TR改变为两性天生的苦奎宁。最后，男女双方都被迫自我刺激IL-NAcSh途径。这些结果表明，IL-NAcSh途径在选择性抑制男性厌恶状态中起着重要作用，但避免了先天厌恶性味觉的享乐性处理。此外，通路激活在男女双方中都在增强，

重要性声明负性情绪状态会导致精神疾病，包括抑郁症和药物滥用疾病。在这项研究中，我们检查了以前与抑制人类负面情绪状态有关的大脑电路是否可以抑制雄性和雌性大鼠的学习型厌恶。我们发现，下唇缘到伏隔核壳途径的光学激活会减弱雄性大鼠而非雌性大鼠的学习厌恶反应，这表明该脑途径的功能存在重要的性别差异。此外，我们发现通路刺激在男女中均得到加强。总的来说，这些发现支持了下唇皮层的作用及其向伏伏核壳的投射在抑制学习到的负面情绪状态方面的作用，并突出了该途径的重要的性别特异性功能。