Studies have suggested that the nucleus accumbens(NAc)is implicated in the pathophysiology of major depression;however,the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depressi...Studies have suggested that the nucleus accumbens(NAc)is implicated in the pathophysiology of major depression;however,the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated.Here,we identified a specific reduction of cyclic adenosine monophosphate(cAMP)in the subset of dopamine D1 receptor medium spiny neurons(D1-MSNs)in the NAc that promoted stress susceptibility,while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors.Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons(D2-MSNs)of depressed mice,however,the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs.We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration,but not a lower dose.The fast onset property of crocin was verified through multicenter studies.Moreover,crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN.These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc,and provide a potential rapid antidepressant drug candidate,crocin.展开更多
Pathological anxiety is among the most difficult neuropsychiatric diseases to treat pharmacologically,and it represents a major societal problem.Studies have implicated structural changes within the prefrontal cortex(...Pathological anxiety is among the most difficult neuropsychiatric diseases to treat pharmacologically,and it represents a major societal problem.Studies have implicated structural changes within the prefrontal cortex(PFC)and functional changes in the communication of the PFC with distal brain structures in anxiety disorders.Treatments that affect the activity of the PFC,including cognitive therapies and transcranial magnetic stimulation,reverse anxiety-and fear-associated circuit abnormalities through mechanisms that remain largely unclear.While the subjective experience of a rodent cannot be precisely determined,rodent models hold great promise in dissecting well-conserved circuits.Newly developed genetic and viral tools and optogenetic and chemogenetic techniques have revealed the intricacies of neural circuits underlying anxiety and fear by allowing direct examination of hypotheses drawn from existing psychological concepts.This review focuses on studies that have used these circuit-based approaches to gain a more detailed,more comprehensive,and more integrated view on how the PFC governs anxiety and fear and orchestrates adaptive defensive behaviors to hopefully provide a roadmap for the future development of therapies for pathological anxiety.展开更多
基金supported by National Natural Science Foundation of China(No.82104278)Leading Technology Foundation Research Project of Jiangsu Province(No.BK20192005,China)+4 种基金National Key Project of Science and Technology for Innovation Drugs of China(No.2017ZX09301013)CAMS Innovation Fund for Medical Sciences(CIFMS,No.2021-I2M-5-011,China)Sanming Project of Medicine in Shenzhen(No.SZSM201801060,China)Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University(No.SKLNMKF202203,China)National Innovation and Entrepreneurship Training Program for Undergraduate,China Pharmaceutical University(Nos.2023103161381 and 2023103161287,China)。
文摘Studies have suggested that the nucleus accumbens(NAc)is implicated in the pathophysiology of major depression;however,the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated.Here,we identified a specific reduction of cyclic adenosine monophosphate(cAMP)in the subset of dopamine D1 receptor medium spiny neurons(D1-MSNs)in the NAc that promoted stress susceptibility,while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors.Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons(D2-MSNs)of depressed mice,however,the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs.We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration,but not a lower dose.The fast onset property of crocin was verified through multicenter studies.Moreover,crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN.These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc,and provide a potential rapid antidepressant drug candidate,crocin.
基金supported by grants from the National Key R&D Program of China(No.2021ZD0202704 to Tianming Gao,No.2022ZD0214300 to Yihua Chen)the National Natural Science Foundation of China(Nos.82090032 and 31830033 to Tianming Gao)+3 种基金the Key Area Research and Development Program of Guangdong Province(Nos.2018B030334001 and 2018B030340001 to Tianming Gao)the Guangdong Basic and Applied Basic Research Foundation(No.2020A1515011310 to Yihua Chen)the Guangdong−Hong Kong−Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence Fund(No.2019019 to Yihua Chen)the Science and Technology Program of Guangzhou(No.202007030013 to Tianming Gao).
文摘Pathological anxiety is among the most difficult neuropsychiatric diseases to treat pharmacologically,and it represents a major societal problem.Studies have implicated structural changes within the prefrontal cortex(PFC)and functional changes in the communication of the PFC with distal brain structures in anxiety disorders.Treatments that affect the activity of the PFC,including cognitive therapies and transcranial magnetic stimulation,reverse anxiety-and fear-associated circuit abnormalities through mechanisms that remain largely unclear.While the subjective experience of a rodent cannot be precisely determined,rodent models hold great promise in dissecting well-conserved circuits.Newly developed genetic and viral tools and optogenetic and chemogenetic techniques have revealed the intricacies of neural circuits underlying anxiety and fear by allowing direct examination of hypotheses drawn from existing psychological concepts.This review focuses on studies that have used these circuit-based approaches to gain a more detailed,more comprehensive,and more integrated view on how the PFC governs anxiety and fear and orchestrates adaptive defensive behaviors to hopefully provide a roadmap for the future development of therapies for pathological anxiety.