Abstract: Background：Conventional medicine has pronounced disadvantage in delayed onset in treating depression，and there was no effective drugs on treating Alzheimer’s diseases. Chinese herbal medicine has been widely used for treatment these disorders，whereas the research that test the advantageous features of TCM treatment is lacking. Aims：I will present our study on detection of the advantageous features of treatment of depression and dementia using herbal medicine，and the novel mechanism underlying the effects，focusing on repair of neural plasticity associated with depression or dementia. Results：In preclinical studies，a single dose of Yueju rapidly attenuates the depression-like symptoms in various animal models and the antidepressant
effects could last even longer than ketamine，the prototype fast-acting antidepressant. We also revealed the critical neuromolecular mechanisms involving improved neural plasticity by Yueju. Moreover，Yueju targeted more therapeutic sites，and the activation of PKA-CREB-BDNF signaling pathway or not underlies the strain-dependent differences in the lasting antidepressant effects. Furthermore，we found the brain-gut peptide PACAP is the novel target of Yueju by which the PKA signaling was triggered. Yueju was also effective in a novel model of treatment-resistant postpartum depression. Importantly，a clinical pilot study supported its fast-onset antidepressant efficacy. Our study displayed that the Gardenia jasminoids Ellis （Zhi Zi） plays the primary role in the rapid antidepressant effects of Yueju and identified the effective fractions and candidate compounds. As conventional antidepressants have a major disadvantage in delayed onset for depression treatment，the novel findings of Yueju’s unique rapid antidepressant efficacy and underlying mechanisms are of great significance both clinically and scientifically. This line of studies suggest the classic TCM formula is invaluable therapeutically for treatment of depression and may be used for treatment of the treatment-resistant depression. Following this part，I will briefly introduce another direction of our lab on treatment of memory loss using traditional Chinese medicine. So far，all chemical compounds or biological reagents to reverse or slow down the AD process have failed in clinical trials. An integrative and multi-targeted strategy is increasingly appreciated to effectively combat this devastating disease. The Amnesia Remedy Formula （ARF） was invented by the Master of TCM Sun Simiao. Here We tested the efficacy of ARF on two animal models of AD，and examine the plausible role of PKA/CREB/BDNF as well as PKA/GSK3b/Tau signaling. In the scopolamine model，ARF effectively reversed the memory in Morris water maze （MWM） test. In a battery test of MWM，novel object recognition or T maze in 5-moth-old senescence-accelerated mouse prone 8 （SAMP8） strain mice，two weeks of administration of ARF showed overall better improvement in memory loss than the anti-dementia drug donepezil，and the effect lasted for at least 1 week after termination of administration of the formula. ARF increased expression of PKA/CREB/BDNF，and reduced GSK3b/Tau signaling the hippocampus. Conclusion：our studies support that some of TCM drugs may result in advantageous features in treating depression and dementia，which are underscored by novel mechanisms.