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Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy

Acta Pharmaceutica Sinica B 2024年第2期14卷 667-681页

作者： Yue Zhang Jingwen Gao Na Li Peng Xu Shimeng Qu Jinqian Cheng Mingrui Wang Xueru Li Yaheng Song Fan Xiao Xinyu Yang Jihong Liu Hao Hong Ronghao Mu Xiaotian Li Youmei Wang Hui Xu Yuan Xie Tianming Gao Guangji Wang Jiye Aa Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics State Key Laboratory of Natural MedicinesResearch Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical SciencesChina Pharmaceutical UniversityNanjing 210009China Key Laboratory of Drug Monitoring and Control Drug Intelligence and Forensic CenterMinistry of Public SecurityBeijing 100193China School of Pharmacy China Pharmaceutical UniversityNanjing 211198China School of Foreign Languages China Pharmaceutical UniversityNanjing 211198China Department of Neurobiology School of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China Department of Pharmacology China Pharmaceutical UniversityNanjing 211198China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China

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.

关键词： CAMP nucleus accumbens Depression D1-MSN D2-MSN

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The nucleus accumbens CRH–CRHR1 System Mediates Early-Life Stress-Induced Sleep Disturbance and Dendritic Atrophy in the Adult Mouse

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Neuroscience Bulletin 2023年第1期39卷 41-56页

作者： Ting Wang Yu-Nu Ma Chen-Chen Zhang Xiao Liu Ya-Xin Sun Hong-Li Wang Han Wang Yu-Heng Zhong Yun-Ai Su Ji-Tao Li Tian-Mei Si Peking University Sixth Hospital Peking University Institute of Mental HealthNHC Key Laboratory of Mental Health(Peking University)National Clinical Research Center for Mental Disorders(Peking University Sixth Hospital)Beijing100191China Department of Pharmacology School of Basic Medical SciencesState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceInstitutes of Brain ScienceFudan UniversityShanghai200032China

Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood,one of which is sleep disturbance.As the corticotropin-releasing hormone(CRH)–corticotropin-releasing hormone receptor 1(CRHR1)system and nucleus accumbens(NAc)play important roles in both stress responses and sleep-wake regulation,in this study we investigated whether the NAc CRH–CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice.Using the limited nesting and bedding material paradigm from postnatal days 2 to 9,we found that early-life stress disrupted sleep-wake behaviors during adulthood,including increased wakefulness and decreased non-rapid eye movement(NREM)sleep time during the dark period and increased rapid eye movement(REM)sleep time during the light period.The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure.Importantly,Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology,whereas NAc Crhr1 knockdown reversed these effects(including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy).Together,our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc,and highlight the critical role of the NAc CRH–CRHR1 system in modulating these negative outcomes evoked by early-life stress.

关键词： Early-life stress Sleep CRH-CRHR1 nucleus accumbens Morphology

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nucleus accumbens receives gastric vagal inputs

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Acta Pharmacologica Sinica 2004年第3期25卷 17-21页

作者： Sangeeta MEHENDALE Department of Anesthesia & Critical Care IL 60637 The Pritzker School of Medicine The University of Chicago USA and Tang Center for Herbal Medicine Research

AIM: To localize and characterize the response of single accumbal neurons to electrical stimulation of the gastric vagal fibers. METHODS: Unitary responses to electrical stimulation of the ventral and dorsal gastric vagal fibers which serve the proximal stomach were recorded extracellularly in the nucleus accumbens in anesthetized cats. RESULTS: The evoked units recorded in the nucleus accumbens consisted of phasic and tonic responses, with a mean latency of (396±43) ms. Convergence of ventral and dorsal gastric vagal inputs onto single phasic and tonic accumbal units was observed. For tonic inhibitory responses, convergence was exhibited when stimulation applied to both the ventral and dorsal gastric vagal branches resulted in a significantly longer inhibitory period than did stimulation of a single gastric vagal branch. Comparing the gastric vagally evoked accumbal unitary responses to the neuronal responses recorded in the nucleus tractus solitarius, parabrachial nucleus and hypothalamus in our previous studies, our data showed a higher percentage of single spike responses and shorter response duration’s in the nucleus accumbens than in the other nuclei. This suggests that the synaptic drive from the gastric vagal inputs to the nucleus accumbens is less powerful than in the other structures. CONCLUSION: The present study localized and characterized gastric vagally evoked responses in the nucleus accumbens, which suggest that the nucleus accumbens may process gastric signals concerned with the ingestive process.

关键词： nucleus accumbens unitary response,electrical stimulation vagus nerve stomach

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Brain region-specific roles of brain-derived neurotrophic factor in social stress-induced depressive-like behavior

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Neural Regeneration Research 2025年第1期20卷 159-173页

作者： Man Han Deyang Zeng Wei Tan Xingxing Chen Shuyuan Bai Qiong Wu Yushan Chen Zhen Wei Yufei Mei Yan Zeng Brain Science and Advanced Technology Institute Wuhan University of Science and TechnologyWuhanHubei ProvinceChina Geriatric Hospital Affiliated to Wuhan University of Science and Technology WuhanHubei ProvinceChina School of Public Health Wuhan University of Science and TechnologyWuhanHubei ProvinceChina

Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and hippocampus.Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology.In this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression.We focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine circuit.We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic system.Therefore,BDNF might be a biological indicator regulating stress-related processes in various brain regions.

关键词： amygdala chronic mild stress chronic social defeat stress corticolimbic system depression hippocampus medial prefrontal cortex nucleus accumbens social stress models ventral tegmental area

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Biphasic firing response of nucleus accumbens neurons elicited by THPB-18 and its correlation with DA receptor subtypes

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Acta Pharmacologica Sinica 2004年第12期25卷 31-39页

作者： Yu FU2,3,4, Zi-tao ZHU2,5, Xing-zu ZHU2, Guo-zhang JIN2,6 2State KeyLaboratory of Drug Research,Shanghai Institute ofMateria Medica, Shanghai Institutes for BiologicalSciences, ChineseAcademy of Sciences, Graduate Schoolof the Chinese Academy of Sciences, Shanghai 201203, ChinaNow in Department of Pharmacology and Toxicology, Univer-sity of Texas Medical Branch, USA.Now in Department of Physiology & Pharmacology, OregonHealth Sciences University, USA,5Now in Department of Physiology & Pharmacology, OregonHealth Sciences University, USA, 中科院上海生命科学院 State Key Laboratory of Drug ResearchChinese Academy of Sciences

AIM: To investigate the possibility whether THPB-18 (l-12-shloroscoulerine) possesses the D1 agonist-D2 antago- nist action on meso-accumbens-mPFC DA system. METHODS: Single unit spontaneous firing activity was re- corded in the nucleus accumbens (NAc) neurons of na?ve and unilateral-6-hydroxydopamine (6-OHDA)-lesioned Sprague-Dawley rats. The effects of drugs applied intravenously or iontophoretically were determined by the change of firing rates. RESULTS: Under normal conditions, the systemic administration of THPB-18 produced a decrease-increase biphasic firing pattern in the NAc neurons during cumulative doses. High dose of THPB-18 was capable of reversing the inhibition induced by both D2 agonist LY171555 and D1/D2 agonist APO on NAc firing activity. Spiperone pretreatment could not block the high dose of THPB-18-induced firing rate increase, which was reversed by the D1 selective antagonist SCH23390. The tested NAc neurons were effectively inhibited by iontophoretically applied THPB-18 in 90 % of 6-OHDA-lesioned rats, while THPB-18 caused variable effects on the firing of NAc neurons in the neurons of unlesioned rats. The inhibitory effect of THPB-18 was blocked by iontophoretic application of SCH23390, but not D2 antagonist spiperone. CONCLUSION: Similar to l-stepholidine, THPB-18 also possesses the “D1 agonistic-D2 antagonistic” dual action on the VTA-NAc DA system.4Now in Department of Pharmacology and Toxicology, Univer-sity of Texas Medical Branch, USA.5Now in Department of Physiology & Pharmacology, OregonHealth Sciences University, USA,4Now in Department of Pharmacology and Toxicology, Univer-sity of Texas Medical Branch, USA.5Now in Department of Physiology & Pharmacology, OregonHealth Sciences University, USA,5Now in Department of Physiology & Pharmacology, OregonHealth Sciences University, USA,

关键词： berberine dopamine D1 receptors dopamine D2 receptors nucleus accumbens

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CCL2/CCR2 Contributes to the Altered Excitatory-inhibitory Synaptic Balance in the nucleus accumbens Shell Following Peripheral Nerve Injury-induced Neuropathic Pain

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Neuroscience Bulletin 2021年第7期37卷 921-933页

作者： Xiao-Bo Wu Qian Zhu Yong-Jing Gao Institute of Pain Medicine and Special Environmental Medicine Nantong UniversityNantong 226019China Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226001China

The medium spiny neurons(MSNs)in the nucleus accumbens(NAc)integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output.Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation(SNL).SNL increased the frequency,but not the amplitude of spontaneous inhibitory postsynaptic currents(sIPSCs),and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents(sEPSCs)in the MSNs.SNL also decreased the paired-pulse ratio(PPR)of evoked IPSCs but increased the PPR of evoked EPSCs.Moreover,acute bath application of C–C motif chemokine ligand 2(CCL2)increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs,and especially strengthened the amplitude of N-methyl-D-aspartate receptor(NMDAR)-mediated miniature EPSCs.Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio.Finally,Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression(LTD)in the NAc after SNL.These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.

关键词： E/I balance Synaptic transmission LTD CCL2 CCR2 nucleus accumbens Neuropathic pain

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Noninvasive ultrasound deep brain stimulation of nucleus accumbens induces behavioral avoidance

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Science China(Life Sciences) 2020年第9期63卷 1328-1336页

作者： Lili Niu Yanchen Guo Zhengrong Lin Zhe Shi Tianyuan Bian Lin Qi Long Meng Anthony AGrace Hairong Zheng Ti-Fei Yuan Paul C.Lauterbur Research Center for Biomedical Imaging Institute of Biomedical and Health EngineeringShenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Shanghai Key Laboratory of Psychotic Disorders Shanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghai 200030China Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province Hunan University of Chinese MedicineChangsha 410208China College of Medicine and Biological Information Engineering Northeastern UniversityShenyang 110016China Departments of Neuroscience Psychiatry and PsychologyUniversity of PittsburghPittsburghPA 15260USA Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226001China

Ultrasound stimulation is an emerging noninvasive option in treating neuropsychiatric disorders. The present study investigates the behavioral alterations resulting from ultrasound stimulation on the nucleus accumbens(NAc) in freely moving mice. Our results show that an acute ultrasound stimulation on the NAc, rather than the visual cortex or auditory cortex, led to a pronounced avoidance behavior, while repeated NAc ultrasound stimulation resulted in an obvious conditioned place aversion with changes in synaptic protein(Glu A1/2 subunit) expression. Notably, NAc ultrasound stimulation suppressed the morphine-induced conditioned place preference. The results provide evidence that NAc ultrasound stimulation can be applied as a potential noninvasive therapeutic option in treating psychiatric disorders.

关键词： ultrasound nucleus accumbens addiction synaptic plasticity brain stimulation

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Extracellular Signal-Regulated Kinase in nucleus accumbens Mediates Propofol Self-Administration in Rats

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Neuroscience Bulletin 2016年第6期32卷 531-537页

作者： Benfu Wang Xiaowei Yang Anna Sun Lanman Xu Sicong Wang Wenxuan Lin Miaojun Lai Huaqiang Zhu Wenhua Zhou Qingquan Lian Department of Anesthesiology and Pain Medicine the Second Affiliated Hospital of Wenzhou Medical University Laboratory of Behavioral Neuroscience Ningbo Addiction Research and Treatment CenterSchool of MedicineNingbo University Department of Infection and Liver Diseases the First Affiliated Hospital of Wenzhou Medical University

Clinical and animal studies have indicated that propofol has potential for abuse, but the specific neurobi- ological mechanism underlying propofol reward is not fully understood. The purpose of this study was to inves- tigate the role of extracellular signal-regulated kinase （ERK） signal transduction pathways in the nucleus accumbens （NAc） in propofol self-administration. We tested the expression of p-ERK in the NAc following the maintenance of propofol self-administration in rats. We also assessed the effect of administration of SCH23390, an antagonist of the D1 dopamine receptor, on the expression of p-ERK in the NAc in propofol self-administering rats, and examined the effects of intra-NAc injection of U0126, an MEK inhibitor, on propofol reinforcement in rats. The results showed that the expression of p-ERK in the NAc increased significantly in rats maintained on propofol, and pre-treatment with SCH23390 inhibited the propofol self- administration and diminished the expression of p-ERK in the NAc. Moreover, intra-NAc injection of U0126 （4 μg/ side） attenuated the propofol self-administration. The data suggest that ERK signal transduction pathways coupledwith D1 dopamine receptors in the NAc may be involved in the maintenance of propofol self-administration and its rewarding effects.

关键词： Keywords Dopamine receptor Drug reward ERK Anesthesiology nucleus accumbens

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Reduced Firing of nucleus accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice

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Neuroscience Bulletin 2021年第9期37卷 1325-1338页

作者： Xinyi Zhou Bifeng Wu Wenhao Liu Qian Xiao Wei He Ying Zhou Pengfei Wei Xu Zhang Yue Liu Jie Wang Jufang He Zhigang Zhang Weidong Li Liping Wang Jie Tu Guangdong Provincial Key Laboratory of Brain Connectome and Behavior CAS Key Laboratory of Brain Connectome and Manipulationthe Brain Cognition and Brain Disease InstituteShenzhen-Hong Kong Institute of Brain ScienceShenzhen Fundamental Research InstitutionsShenzhen Institute of Advanced TechnologyChinese Academy of Sciences518055 ShenzhenChina University of Chinese of Academy of Sciences Beijing 100049China Department of Information Technology and Electrical Engineering Zurich Swiss Federal Institute of Technology Zurich8092 ZurichSwitzerland Department of Biomedical Sciences City University of Hong KongKowloon TongHong Kong Virginia Polytechnic Institute and State University BlacksburgVirginia 24061USA Department of Psychiatry and Behavioral Sciences Emory University School of MedicineAtlanta 30322USA Bio-X Institutes Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders(Ministry of Education)Shanghai Key Laboratory of Psychotic Disordersand Brain Science and Technology Research CenterShanghai Jiao Tong UniversityShanghai 200240China Center of Brain Science State Key Laboratory of Magnetic Resonance and Atomic and Molecular PhysicsInnovation Academy for Precision Measurement Science and TechnologyNational Center for Magnetic Resonance in WuhanKey Laboratory of Magnetic Resonance in Biological SystemsWuhan Institute of Physics and MathematicsChinese Academy of Sciences430071 WuhanChina Department of Neuroscience City University of Hong KongKowloon TongHong Kong City University of Hong Kong Shenzhen Research Institute Shenzhen 518057China

A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk.In humans,a large proportion of mental disorders are accompanied by impairments in risk avoidance.One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1(DISC1),and animal models in which this gene has some level of dysfunction show emotion-related impairments.However,it is not known whether DISC1 mouse models have an impairment in avoiding potential risks.In the present study,we used DISC1-N terminal truncation(DISC1-N^(TM))mice to investigate risk avoidance and found that these mice were impaired in risk avoidance on the elevated plus maze(EPM)and showed reduced social preference in a three-chamber social interaction test.Following EPM tests,c-Fos expression levels indicated that the nucleus accumbens(NAc)was associated with risk-avoidance behavior in DISC1-N^(TM)mice.In addition,in vivo electrophysiological recordings following tamoxifen administration showed that the firing rates of fast-spiking neurons(FS)in the NAc were significantly lower in DISC1-N^(TM)mice than in wild-type(WT)mice.In addition,in vitro patch clamp recording revealed that the frequency of action potentials stimulated by current injection was lower in parvalbumin(PV)neurons in the NAc of DISC1-N^(TM)mice than in WT controls.The impairment of risk avoidance in DISC1-N^(TM)mice was rescued using optogenetic tools that activated NAcPV neurons.Finally,inhibition of the activity of NAcPV neurons in PV-Cre mice mimicked the risk-avoidance impairment found in DISC1-N^(TM)mice during tests on the elevated zero maze.Taken together,our findings confirm an impairment in risk avoidance in DISC1-N^(TM)mice and suggest that reduced excitability of NAc^(PV) neurons is responsible.

关键词： DISC1 Risk avoidance Parvalbumin nucleus accumbens

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Framework for internal sensation of pleasure using constraints from disparate findings in nucleus accumbens

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World Journal of Psychiatry 2021年第10期11卷 681-695页

作者： Kunjumon Ittira Vadakkan Division of Neuroscience Neurosearch CenterToronto M5S2M3OntarioCanada

It is necessary to find a mechanism that generates first-person inner sensation of pleasure to understand what causes addiction and associated behaviour by drugs of abuse.The actual mechanism is expected to explain several disparate findings in nucleus accumbens(NAc),a brain region associated with pleasure,in an interconnected manner.Previously,it was possible to derive a mechanism for natural learning and explain:(1)Generation of inner sensation of memory using changes generated by learning;and(2)Long-term potentiation as an experimental delayed scaled-up change by the same mechanism that occur during natural learning.By extending these findings and by using disparate third person observations in NAc from several studies,present work provides a framework of a mechanism that generates internal sensation of pleasure that can provide interconnected explanations for:(1)Ability to induce robust long-term depression(LTD)in NAc from naïve animals;(2)Impaired ability to induce LTD in“addicted”state;(3)Attenuation of postsynaptic potentials by cocaine;and(4)Reduced firing of medium spiny neurons in response to cocaine or dopamine.Findings made by this work are testable.

关键词： Pleasure Internal sensation Mind Memory Long-term potentiation Longterm depression nucleus accumbens Drug addiction

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