Our results indicated that E2 upregulates KL expression in the hippocampus of female rats that are resilient to CUMS-induced cognitive deficit, while a reduction in KL expression in the hippocampus decreases this resistance to stress in female rats and diminishes the sex differences in CUMS-induced deficit in spatial learning and memory, anhedonic-like behaviors, and anxiety-like behaviors by increasing the susceptibility of female rats to chronic stress. The gene discussed is KL; the disease is Anxiety.