In humans and rodents, stress promotes habit-based behaviors that can interfere with action—outcome decision-making. Further, developmental stressor exposure confers long-term habit biases across rodent—primate species. Despite these homologies, mechanisms remain unclear. We first report that exposure to the primary glucocorticoid corticosterone (CORT) in adolescent mice recapitulates multiple neurobehavioral consequences of stressor exposure, including long-lasting biases towards habit-based responding in a food-reinforced operant conditioning task. In both adolescents and adults, CORT also caused a shift in the balance between full-length tyrosine kinase receptor B (trkB) and a truncated form of this neurotrophin receptor, favoring the inactive form throughout multiple corticolimbic brain regions. In adolescents, phosphorylation of the trkB substrate extracellular signal-regulated kinase 42/44 (ERK42/44) in the ventral hippocampus was also diminished, a long-term effect that persisted for at least 12 wk. Administration of the trkB agonist 7,8-dihydroxyflavone (7,8-DHF) during adolescence at doses that stimulated ERK42/44 corrected long-lasting corticosterone-induced behavioral abnormalities. Meanwhile, viral-mediated overexpression of truncated trkB in the ventral hippocampus reduced local ERK42/44 phosphorylation and was sufficient to induce habit-based and depression-like behaviors. Together, our findings indicate that ventral hippocampal trkB is essential to goal-directed action selection, countering habit-based behavior otherwise facilitated by developmental stress hormone exposure. They also reveal an early-life sensitive period during which trkB—ERK42/44 tone determines long-term behavioral outcomes.

在人类和啮齿动物中，压力会促进基于习惯的行为，这种行为会干扰行动，从而影响决策。此外，发育应激源的暴露会给啮齿动物-灵长类物种带来长期的习惯偏见。尽管存在这些同源性，但机制仍不清楚。我们首先报道，在青春期小鼠中暴露于初级糖皮质激素皮质酮（CORT）可以概括应激暴露的多种神经行为后果，包括对食物强化的操作者调节任务中基于习惯的反应的长期偏见。在青少年和成年人中，CORT还导致全长酪氨酸激酶受体B（trkB）和该神经营养蛋白受体的截短形式之间的平衡发生转变，从而促进了整个多个皮质小脑区的非活性形式。在青少年时期，腹侧海马中trkB底物细胞外信号调节激酶42/44（ERK42 / 44）的磷酸化也被减弱，这种长期作用至少持续了12周。在青春期以刺激ERK42 / 44的剂量服用trkB激动剂7,8-二羟基黄酮（7,8-DHF）可纠正长期皮质类固醇诱发的行为异常。同时，病毒介导的trkB在腹侧海马中的过度表达减少了局部ERK42 / 44磷酸化，足以诱导基于习惯和抑郁的行为。在一起，我们的研究结果表明腹侧海马trkB对于目标导向的行动选择至关重要，以应对习惯性行为，否则发育应激激素暴露会促进这种行为。