Chronic stress is a major risk factor for psychiatric disorders, including depression. Although depression is a highly heterogeneous syndrome, it remains unclear how chronic stress drives individual differences in behavioral responses. In this study, we developed a subtyping-based approach wherein stressed male mice were divided into four subtypes based on their behavioral patterns of social interaction deficits and anhedonia, the core symptoms of psychiatric disorders. We identified three prefrontal cortical neuronal projections that regulate repeated stress-induced behavioral phenotypes. Among them, the medial prefrontal cortex (mPFC)→anterior paraventricular thalamus (aPVT) pathway determines the specific behavioral subtype that exhibits both social deficits and anhedonia. Additionally, we identified the circuit-level molecular mechanism underlying this subtype: KDM5C-mediated epigenetic repression of Shisa2 transcription in aPVT projectors in the mPFC led to social deficits and anhedonia. Thus, we provide a set of biological aspects at the cellular, molecular, and epigenetic levels that determine distinctive stress-induced behavioral phenotypes.

慢性压力是精神疾病（包括抑郁症）的主要危险因素。尽管抑郁症是一种高度异质性的综合征，但慢性压力如何导致行为反应的个体差异仍不清楚。在这项研究中，我们开发了一种基于亚型的方法，其中根据社交互动缺陷和快感缺失（精神疾病的核心症状）的行为模式，将受到压力的雄性小鼠分为四种亚型。我们确定了三种调节重复压力诱发的行为表型的前额皮质神经元投射。其中，内侧前额叶皮层（mPFC）→前室旁丘脑（aPVT）通路决定了同时表现出社交缺陷和快感缺乏的特定行为亚型。此外，我们还确定了该亚型背后的电路水平分子机制：KDM5C 介导的mPFC 中 aPVT 投影仪中Shisa2转录的表观遗传抑制导致社交缺陷和快感缺失。因此，我们在细胞、分子和表观遗传水平上提供了一系列生物学方面的信息，这些方面决定了独特的应激诱导的行为表型。