Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
VA Portland Health Care System, Department of Behavioral Neuroscience and Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA.
Nat Commun. 2021 Jun 10;12(1):3539. doi: 10.1038/s41467-021-23906-2.
Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.
快感缺失（快感缺乏）是抑郁症的核心症状之一。应激体验会引发抑郁，并破坏奖赏寻求，但目前尚不清楚应激是如何导致快感缺失的。当小鼠经历应激时，我们记录了边缘脑区的同步神经活动，发现伏隔核（NAc）中存在应激诱导的 4Hz 振荡，该振荡可预测随后奖赏寻求的迟钝程度。令人惊讶的是，虽然之前关于奖赏寻求迟钝的研究集中在腹侧被盖区（VTA）到 NAc 的多巴胺（DA）传递上，但我们发现 VTA GABA 神经元，而不是 DA 神经元，介导应激诱导的奖赏寻求迟钝。抑制 VTA GABA 神经元会破坏应激诱导的 NAc 振荡，并挽救奖赏寻求。相比之下，通过以 4Hz 刺激投射到 NAc 的 VTA GABA 神经元来模拟应激的这种特征，可以重现振荡和奖赏寻求迟钝。最后，我们发现应激破坏了 VTA 对奖赏预期的 GABA 和 DA 神经编码。因此，应激引发 VTA-NAc GABA 能活动，进而导致 VTA GABA 介导的奖赏寻求迟钝。
