Neurons in the lateral habenula (LHb) are activated by reward omission and inhibited by reward delivery-reward processing functions opposite those of midbrain dopaminergic neurons. To further explore this, we examined the role of the LHb in associating a conditioned stimulus (CS) with the absence of an unconditioned stimulus (US) in an appetitive Pavlovian-conditioning paradigm. Rats underwent training in which a CS (light) was either paired (100% CS–US contingency) or unpaired (0% CS–US contiguity and negative contingency) with an US (food). Rats in the paired group exhibited steady acquisition of conditioned food-cup behaviors, while rats in the unpaired group showed low levels of response throughout training. After training, c-Fos levels were measured in the LHb, substantia nigra pars compacta (SNc), and ventral tegmental area (VTA) of rats in all groups. c-Fos levels were higher in the SNc/VTA of the paired group and the LHb of the unpaired group compared with the group with graded excitatory conditioning due to 50% of the CSs paired with USs and a low rate of USs presented during the intertrial interval and control groups for non-associative factors. The number of c-Fos–positive signals in LHb neurons projecting to dopaminergic midbrain neurons was higher in the unpaired group than in the paired group. Excitotoxic LHb lesions did not affect the acquisition of conditioned behaviors in the association of a CS with the presence or absence of an US. Significant increases in the numbers of c-Fos–positive neurons in the unpaired group suggest that LHb neurons engage in the process that associates a CS with the absence of an US.

侧脑室（LHb）中的神经元被奖励遗忘所激活，并受到与中脑多巴胺能神经元相反的奖励交付-奖励处理功能的抑制。为了进一步探讨这一点，我们研究了在竞争性巴甫洛夫式条件范式中LHb在关联条件刺激（CS）与不存在条件刺激（US）的关联中的作用。大鼠接受了训练（CS）（轻度）与US（食物）配对（100％CS–US偶然性）或未配对（0％CS–US连续性和负性偶然性）。配对组的大鼠表现出稳定的条件性食物杯行为，而未配对组的大鼠在整个训练过程中表现出较低的反应水平。训练后，在LHb，黑质致密部（SNc）中测量c-Fos水平，各组大鼠的腹侧被盖区（VTA）。配对组的SNc / VTA和未配对组的LHb的c-Fos水平高于分级兴奋性调节的组，这是因为50％的CS与USs配对并且在试验期间出现USs的比率较低。非关联因素的区间和对照组。在未配对组中，投射到多巴胺能中脑神经元的LHb神经元中c-Fos阳性信号的数量高于配对组。兴奋性LHb病变在CS与US的存在与否之间均不影响条件行为的获得。未配对组中c-Fos阳性神经元数量的显着增加表明LHb神经元参与了将CS与US缺失相关的过程。配对组的SNc / VTA和未配对组的LHb的c-Fos水平高于分级兴奋性调节的组，这是因为50％的CS与USs配对并且在试验期间出现USs的比率较低。非关联因素的区间和对照组。在未配对组中，投射到多巴胺能中脑神经元的LHb神经元中c-Fos阳性信号的数量高于配对组。兴奋性LHb病变在CS与US的存在与否之间均不影响条件行为的获得。未配对组中c-Fos阳性神经元数量的显着增加表明LHb神经元参与了将CS与US缺失相关的过程。配对组的SNc / VTA和未配对组的LHb的c-Fos水平高于分级兴奋性调节的组，这是因为50％的CS与USs配对并且在试验期间出现USs的比率较低。非关联因素的区间和对照组。在未配对组中，投射到多巴胺能中脑神经元的LHb神经元中c-Fos阳性信号的数量高于配对组。兴奋性LHb病变在CS与US的存在与否之间均不影响条件行为的获得。未配对组中c-Fos阳性神经元数量的显着增加表明LHb神经元参与了将CS与US缺失相关的过程。