The ability to cope with stress is essential for emotional stability and mental health. It is also hypothesized that factors promoting resilience to stress may offer treatment strategies for maladaptive disorders such as anxiety and depression. Here, we find that physical restraint reduces the expression of type 1 adenylyl cyclase (Adcy1), a neurospecific synaptic enzyme that positively regulates the cAMP signaling cascade. Conversely, an increase of forebrain Adcy1 expression in transgenic mouse (i.e., Adcy1^tg mouse) predisposes individuals to molecular stability and behavioral resilience. Transgenic overexpression of Adcy1 prevents the physical restraint-induced down-regulation of brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY). Further, Adcy1^tg mice maintain regular locomotive activity in novelty exploration and voluntary wheel running following physical restraint. Adcy1^tg mice show higher corticosterone and lower basal glucocorticoid receptor (GR) expression, along with a higher MR (mineralocorticoid receptor) to GR ratio in the hippocampus. Further, Adcy1^tg mice show reduced immobility under acute physical stress conditions in the forced swimming test and are more sensitive to the antidepressant desipramine. Our results demonstrate a novel function of Adcy1 in stress coping and suggest Adcy1 as a potential target to antagonize stress vulnerability and promote antidepressant efficacy.

应对压力的能力对于情绪稳定和心理健康至关重要。还假设促进压力恢复的因素可能为适应不良障碍（如焦虑和抑郁）提供治疗策略。在这里，我们发现物理约束会降低 1 型腺苷酸环化酶 ( Adcy1 )的表达，这是一种神经特异性突触酶，可正向调节 cAMP 信号级联。相反，转基因小鼠（即Adcy1 ^tg小鼠）中前脑Adcy1表达的增加使个体倾向于分子稳定性和行为弹性。Adcy1 的转基因过表达阻止了身体约束诱导的脑源性神经营养因子的下调。BDNF ) 和神经肽 Y (NPY)。此外，Adcy1 ^tg小鼠在新奇探索和身体约束后自愿车轮运行中保持规律的机车活动。Adcy1 ^tg小鼠在海马中显示出更高的皮质酮和更低的基础糖皮质激素受体 (GR) 表达，以及更高的 MR（盐皮质激素受体）与 GR 的比率。此外，在强迫游泳试验中，Adcy1 ^tg小鼠在急性身体压力条件下表现出减少的不动性，并且对抗抑郁药地昔帕明更敏感。我们的结果证明了Adcy1在压力应对中的新功能，并表明Adcy1 作为对抗压力脆弱性和促进抗抑郁功效的潜在目标。