Reward-processing impairment is a common symptomatic dimension of several psychiatric disorders. However, whether the underlying pathological mechanisms are common is unknown. Herein, we asked if the decrease in the n-3 polyunsaturated fatty acid (PUFA) lipid species, consistently described in these pathologies, could underlie reward-processing deficits. We show that reduced n-3 PUFA biostatus in mice leads to selective motivational impairments. Electrophysiological recordings revealed increased collateral inhibition of dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) onto dopamine D1 receptor-expressing MSNs in the nucleus accumbens, a main brain region for the modulation of motivation. Strikingly, transgenically preventing n-3 PUFA deficiency selectively in D2-expressing neurons normalizes MSN collateral inhibition and enhances motivation. These results constitute the first demonstration of a causal link between a behavioral deficit and n-3 PUFA decrease in a discrete neuronal population and suggest that lower n-3 PUFA biostatus in psychopathologies could participate in the etiology of reward-related symptoms.

奖励加工障碍是几种精神疾病的常见症状维度。然而，潜在的病理机制是否普遍尚不清楚。在此，我们询问了在这些病理中一致描述的 n-3 多不饱和脂肪酸 (PUFA) 脂质种类的减少是否会导致奖励处理缺陷。我们表明，小鼠 n-3 PUFA 生物状态降低会导致选择性动机障碍。电生理记录显示，表达多巴胺 D2 受体的中型多刺神经元 (D2-MSN) 对伏隔核中表达多巴胺 D1 受体的 MSN 的附带抑制增加，伏隔核是调节动机的主要大脑区域。引人注目的是，在表达 D2 的神经元中选择性地通过转基因预防 n-3 PUFA 缺乏使 MSN 侧支抑制正常化并增强动机。这些结果首次证明了离散神经元群体中行为缺陷与 n-3 PUFA 减少之间存在因果关系，并表明精神病理学中较低的 n-3 PUFA 生物状态可能参与奖励相关症状的病因学。