The lateral habenula (LHb) processes information about aversive experiences that contributes to the symptoms of stress disorders. Previously, we found that chemogenetic inhibition of rat LHb neurons reduced immobility in the forced swim test, but the downstream target of these neurons was not known. Using an intersectional viral vector strategy, we selectively transduced three different output pathways from the LHb by injecting AAV8-DIO-hM4Di into the LHb and CAV2-CRE (a retrograde viral vector) into one of the three target areas as follows: dorsal raphe nucleus (DRN), ventral tegmental area (VTA), or rostromedial tegmentum (RMTg). Using the forced swim test, we found that chemogenetic inhibition of DRN-projecting LHb neurons reduced passive coping (immobility), whereas inhibition of the other pathways did not. Chemogenetic activation of DRN-projecting neurons using hM3Dq in another cohort did not further exacerbate immobility. We next examined the impact of inhibiting DRN-projecting LHb neurons on reward sensitivity, perseverative behavior, and anxiety-like behavior using saccharin preference testing, reward-omission testing, and open-field testing, respectively. There was no effect of inhibiting any of these pathways on reward sensitivity, locomotion, or anxiety-like behavior, but inhibiting DRN-projecting LHb neurons reduced perseverative licking during reward-omission testing, whereas activating these neurons increased perseverative licking. These results support the idea that inhibiting LHb projections to the DRN provides animals with resilience during highly stressful or frustrating conditions but not under low-stress circumstances, and that inhibiting these neurons may promote persistence in active coping strategies.

中文翻译：

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外侧缰核投射到中缝背核的化学遗传学抑制减少了大鼠的被动应对和持续的奖赏寻求。

外侧缰核 (LHb) 处理有关导致应激障碍症状的厌恶经历的信息。以前，我们发现大鼠 LHb 神经元的化学遗传学抑制降低了强迫游泳测试中的不动性，但这些神经元的下游目标未知。使用交叉病毒载体策略，我们通过将 AAV8-DIO-hM4Di 注入 LHb 并将 CAV2-CRE（逆行病毒载体）注入三个目标区域之一，选择性地转导 LHb 的三种不同输出途径，如下所示： (DRN)、腹侧被盖区 (VTA) 或喙内侧被盖区 (RMTg)。使用强迫游泳测试，我们发现 DRN 投射 LHb 神经元的化学遗传学抑制减少了被动应对（不动），而其他途径的抑制则没有。在另一个队列中使用 hM3Dq 对 DRN 投射神经元进行化学遗传激活并没有进一步加剧不动。接下来，我们分别使用糖精偏好测试、奖励遗漏测试和开放场测试，检查了抑制投射 DRN 的 LHb 神经元对奖励敏感性、坚持行为和焦虑样行为的影响。抑制任何这些通路对奖赏敏感性、运动或焦虑样行为没有影响，但抑制投射 DRN 的 LHb 神经元会减少奖赏遗漏测试期间的持续舔食，而激活这些神经元会增加持续舔食。这些结果支持这样一种观点，即抑制 LHb 投射到 DRN 可为动物提供在高压力或令人沮丧的条件下而非低压力情况下的恢复力，