Abstract 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...Abstract 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.展开更多
Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine（DA）system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4（TLR4）, an important pattern...Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine（DA）system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4（TLR4）, an important pattern-recognition receptor in the innate immune system,can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient（TLR4^（-/-））and wild-type（WT） mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed,large spaces. We found that TLR4^（-/-）mice exhibitedreduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4^（-/-）mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approachavoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4^（-/-）mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly,the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell（NAc Sh） in TLR4^（-/-）mice than in WT mice. Partially inactivating the NAc Sh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4^（-/-）mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAc Sh may contribute to this phenomenon.展开更多
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 ...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.展开更多
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
The nucleus accumbens(NAc)is a subcortical brain structure known primarily for its roles in pleasure,reward,and addiction.Despite less focus on the NAc in pain research,it also plays a large role in the mediation of p...The nucleus accumbens(NAc)is a subcortical brain structure known primarily for its roles in pleasure,reward,and addiction.Despite less focus on the NAc in pain research,it also plays a large role in the mediation of pain and is effective as a source of analgesia.Evidence for this involvement lies in the NAc’s cortical connections,functions,pharmacology,and therapeutic targeting.The NAc projects to and receives information from notable pain structures,such as the prefrontal cortex,anterior cingulate cortex,periaqueductal gray,habenula,thalamus,etc.Additionally,the NAc and other pain-modulating structures share functions involving opioid regulation and motivational and emotional processing,which each work beyond simply the rewarding experience of pain offset.Pharmacologically speaking,the NAc responds heavily to painful stimuli,due to its high density ofμopioid receptors and the activation of several different neurotransmitter systems in the NAc,such as opioids,dopamine,calcitonin gene-related peptide,γ-aminobutyric acid,glutamate,and substance P,each of which have been shown to elicit analgesic effects.In both preclinical and clinical models,deep brain stimulation of the NAc has elicited successful analgesia.The multi-functional NAc is important in motivational behavior,and the motivation for avoiding pain is just as important to survival as the motivation for seeking pleasure.It is possible,then,that the NAc must be involved in both pleasure and pain in order to help determine the motivational salience of positive and negative events.展开更多
OBJECTIVE: To determine whether the central nervous system is involved in the effect of Chinese herbal medicine on sexual function recovery in orchidectomized rats.METHODS: Orchidectomized rats were administered intra...OBJECTIVE: To determine whether the central nervous system is involved in the effect of Chinese herbal medicine on sexual function recovery in orchidectomized rats.METHODS: Orchidectomized rats were administered intragastrically with a decoction of "kidneynourishing" Chinese herbal medicine once per day for 28 days. Accessory genital organ weight, plasma testosterone, and mating behavior were investigated. The expression of c-Fos and neuronal nitric oxide synthase(n NOS) in neuronal cells in the nucleus accumbens(NAc) was analyzed by immunohistochemistry.RESULTS: There was a decrease in accessory genital organ weight, plasma testosterone, and sexual behavior, as well as a low number of c-Fos-positive cells and a large n NOS-positive cell area in orchidectomized rats. Administration of the herbal medicine increased accessory genital organ weight, testosterone level, mating behavior, and c-Fos-positive cell number, while it decreased the n NOS-positive cell area in orchidectomized rats.CONCLUSION: An increase of plasma testosterone after administration of "kidney-nourishing" herbal medicine might contribute to the elevated sexual function and activity in orchidectomized rats. In addition, a central nervous system mechanism, such as the functional alteration of NAc, might be involved.展开更多
Background: Dopamine has been known to facilitate male sexual function. Methods: The effect of aqueous extract (140 mg/kg) of Phoenix dactylifera date palm pollen on sexual behavior and determining of dopamine transmi...Background: Dopamine has been known to facilitate male sexual function. Methods: The effect of aqueous extract (140 mg/kg) of Phoenix dactylifera date palm pollen on sexual behavior and determining of dopamine transmission in the nucleus accumbens was studied in male rats using in vivo microdialysis. Results: Releasing of dopamine increased significantly in the nucleus accumbens when a receptive female was introduced behind a screen (p 0.001). During copulation, dopamine increased markedly in control and treated rats. Phoenix dactylifera Date Palm Pollen enhanced the orientation of males towards females by increasing mounting and ano-genital investigatory behavior. Improving of sexual behavior and dopamine release was higher in treated rats in comparison with control (p 0.001). Conclusion: These results indicate a neurochemical basis for interaction between dopaminergic agents and male sexual behavior. Therefore, Phoenix dactylifera Date Palm Pollen seems to act as a dopamine agonist and to cure male infertility. It can be used as an aphrodisiac that leads to further increases in dopamine release.展开更多
Adolescence is a critical period for neurodevelopment. Evidence from animal studies suggests that isolated rearing can exert negative effects on behavioral and brain development. The present study aimed to investigate...Adolescence is a critical period for neurodevelopment. Evidence from animal studies suggests that isolated rearing can exert negative effects on behavioral and brain development. The present study aimed to investigate the effects of adolescent social isolation on latent inhibition and brain-derived neurotrophic factor levels in the forebrain of adult rats. Male Wistar rats were randomly divided into adolescent isolation （isolated housing, 38-51 days of age） and social groups. Latent inhibition was tested at adulthood. Brain-derived neurotrophic factor levels were measured in the medial prefrontal cortex and nucleus accumbens by an enzyme-linked immunosorbent assay. Adolescent social isolation impaired latent inhibition and increased brain-derived neurotrophic factor levels in the medial prefrontal cortex of young adult rats. These data suggest that adolescent social isolation has a profound effect on cognitive function and neurotrophin levels in adult rats and may be used as an animal model of neurodevelopmental disorders.展开更多
Background Stereotactic surgery has been used to treat heroin abstinence in China since 2000 by ablating the amygdaloid nucleus （AMY） and the nucleus accumbens （NAc）,which also provides opportunity to identify the...Background Stereotactic surgery has been used to treat heroin abstinence in China since 2000 by ablating the amygdaloid nucleus （AMY） and the nucleus accumbens （NAc）,which also provides opportunity to identify the relationship between these nuclei and addiction.Our study aimed to explore the physiological and psychological effects of electrically stimulating the AMY and the NAc in herein addicts after detoxification by observing changes of heart rate,arterial pressure and occurrence of euphoria similar to heroin induced euphoria.Methods A total of 70 heroin addicts after detoxification were recruited,and 61 of them were eligible to be given stereotactic surgery for heroin abstinence.The operation was carried out after determining the coordinates of all target nucleuses,and stimulation was performed at the AMY and the NAc solely or jointly.Heart rate,arterial pressure and occurrence of euphoria similar to heroin induced euphoria were recorded and analyzed.Results The average heat rate was （66±10） beats/min before electric stimulation,and significantly increased to （84±14） beats/min during stimulation,and changed to （73±12） beats/min 10 minutes after stimulation.There was a significant elevation of the average arterial pressure from 83 mmHg before stimulation to 98 mmHg during the stimulation,and it then decreased to 90 mmHg after stimulation.Forty-three of the 61 patients showed intense euphoria similar to heroin induced euphoria.The largest number （118/186） of euphoric responses occurred when the AMY and the NAc were stimulated at the same time.Odds ratio was 5.4 （95% CI： 2.4-11.9,P 〈0.0001） to quantify the association.Results from a Logistic regression model showed a positive correlation between unilateral stimulation of either the AMY or NAC and induction of euphoria （OR 〉1 ）,especially when the left AMY or left NAc was stimulated （P 〈0.05）.Conclusions Our data are consistent with existing results that the AMY and the NAc are related to addiction.Different roles in展开更多
The nucleus accumbens shell(NAcSh) plays an important role in reward and aversion. Traditionally, NAc dopamine receptor 2-expressing(D2) neurons are assumed to function in aversion. However, this has been challenged b...The nucleus accumbens shell(NAcSh) plays an important role in reward and aversion. Traditionally, NAc dopamine receptor 2-expressing(D2) neurons are assumed to function in aversion. However, this has been challenged by recent reports which attribute positive motivational roles to D2 neurons. Using optogenetics and multiple behavioral tasks, we found that activation of D2 neurons in the dorsomedial NAcSh drives preference and increases the motivation for rewards, whereas activation of ventral NAcSh D2 neurons induces aversion. Stimulation of D2 neurons in the ventromedial NAcSh increases movement speed and stimulation of D2 neurons in the ventrolateral NAc Sh decreases movement speed. Combining retrograde tracing and in situ hybridization, we demonstrated that glutamatergic and GABAergic neurons in the ventral pallidum receive inputs differentially from the dorsomedial and ventral NAcSh. All together, these findings shed light on the controversy regarding the function of NAcSh D2 neurons, and provide new insights into understanding the heterogeneity of the NAcSh.展开更多
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 hormon...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.展开更多
Methcathinone(MCAT)belongs to the designer drugs called synthetic cathinones,which are abused worldwide for recreational purposes.It has strong stimulant effects,including enhanced euphoria,sensation,alertness,and emp...Methcathinone(MCAT)belongs to the designer drugs called synthetic cathinones,which are abused worldwide for recreational purposes.It has strong stimulant effects,including enhanced euphoria,sensation,alertness,and empathy.However,little is known about how MCAT modulates neuronal activity in vivo.Here,we evaluated the effect of MCAT on neuronal activity with a series of functional approaches.C-Fos immunostaining showed that MCAT increased the number of activated neurons by 6-fold,especially in sensory and motor cortices,striatum,and midbrain motor nuclei.In vivo single-unit recording and two-photon Ca^(2+) imaging revealed that a large proportion of neurons increased spiking activity upon MCAT administration.Notably,MCAT induced a strong de-correlation of population activity and increased trial-to-trial reliability,specifically during a natural movie stimulus.It improved the information-processing efficiency by enhancing the single-neuron coding capacity,suggesting a cortical network mechanism of the enhanced perception produced by psychoactive stimulants.展开更多
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...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.展开更多
A significant amount of evidence indicates that microRNAs （miRNAs） play an important role in drug addiction. The nucleus accumbens （NAc） is a critical part of the brain’s reward circuit and is involved in a varie...A significant amount of evidence indicates that microRNAs （miRNAs） play an important role in drug addiction. The nucleus accumbens （NAc） is a critical part of the brain’s reward circuit and is involved in a variety of psychiatric disorders, including depression, anxiety, and drug addiction. However, few studies have examined the expression of miRNAs and their functional roles in the NAc under conditions of morphine addiction. In this study, mice were intravenously infused with morphine （0.01, 0.03, 0.3, 1 and 3 mg/kg/infusion） and showed inverted U-shaped response. After morphine self-administration, NAc was used to analyze the functional networks of altered miRNAs and their putative target mRNAs in the NAc following intravenous self-administration of morphine. We utilized several bioinformatics tools, including Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway mapping and CyTargetLinker. We found that 62 miRNAs were altered and exhibited differential expression patterns. The putative targets were related to diverse regulatory functions, such as neurogenesis, neurodegeneration, and synaptic plasticity, as well as the pharmacological effects of morphine （receptor internalization/endocytosis）. The present findings provide novel insights into the regulatory mechanisms of accumbal molecules under conditions of morphine addiction and identify several novel biomarkers associated with morphine addiction.展开更多
The human nucleus accumbens(NA), a major part of the ventral striatum, is the area of continuity between the putamen and head of the caudate nucleus. It consists of two parts, a shell laterally and a core medially. Th...The human nucleus accumbens(NA), a major part of the ventral striatum, is the area of continuity between the putamen and head of the caudate nucleus. It consists of two parts, a shell laterally and a core medially. The first is mainly connected to the limbic system and the second to the extrapyramidal motor system. The NA, a major pleasure center of the human brain, acts as a limbic-motor interface and is involved in several cognitive, emotional and psychomotor functions. It has a modulating function in the amygdala-basal gangliaprefrontal cortex circuit. It is considered as the neural interface between motivation and action. Further, it is a principal modulator of the reward circuits and supplies motor expression to emotional responses. Such a clinical significance could easily explain the intense work taking place in the respective field of basic research. Its exceptional clinical importance justifies the title of the "King of Neurosciences" for this nucleus. Purpose of this editorial is to review the "informational paths" left behind by the few researchers who tried to explore the architecture(gross anatomy) of this ‘kingdom'. The first anatomical study focused on this nucleus came from Neto et al. The most extensive study of the NA gross, imaging, stereotactic and neurosurgical anatomy so far,came from the research efforts of Mavridis et al.展开更多
Preoperative sleep loss can amplify post-operative mechanical hyperalgesia.However,the underlying mechanisms are still largely unknown.In the current study,rats were randomly allocated to a control group and an acute ...Preoperative sleep loss can amplify post-operative mechanical hyperalgesia.However,the underlying mechanisms are still largely unknown.In the current study,rats were randomly allocated to a control group and an acute sleep deprivation(ASD)group which experienced 6 h ASD before surgery.Then the variations in cerebral function and activity were investigated with multi-modal techniques,such as nuclear magnetic resonance,functional magnetic resonance imaging,c-Fos immunofluorescence,and electrophysiology.The results indicated that ASD induced hyperalgesia,and the metabolic kinetics were remarkably decreased in the striatum and midbrain.The functional connectivity(FC)between the nucleus accumbens(NAc,a subregion of the ventral striatum)and the ventrolateral periaqueductal gray(vLPAG)was significantly reduced,and the c-Fos expression in the NAc and the vLPAG was suppressed.Furthermore,the electrophysiological recordings demonstrated that both the neuronal activity in the NAc and the vLPAG,and the coherence of the NAc-vLPAG were suppressed in both resting and task states.This study showed that neuronal activity in the NAc and the vLPAG were weakened and the FC between the NAc and the vLPAG was also suppressed in rats with ASD-induced hyperalgesia.This study highlights the importance of preoperative sleep management for surgical patients.展开更多
The aim of this work was to investigate whether acamprosate modifies the expression of the enzyme responsible for neuronal NO synthesis (nNOS) in the nucleus accumbens (NAc) of mice chronically treated with morphine a...The aim of this work was to investigate whether acamprosate modifies the expression of the enzyme responsible for neuronal NO synthesis (nNOS) in the nucleus accumbens (NAc) of mice chronically treated with morphine and during the abstinence syndrome induced by naloxone. The enzyme was monitored by the NADPH diaphorase method. The number of cells stained for NADPH diaphorase in the NAc of mice was counted in 40 μm thick coronal brain slices at 40X. The intensity of the histochemical reaction of stained cells from naive morphine plus saline and morphine plus acamprosate treated mice was analyzed by Image Pro Plus 4.5.1. Morphine administered in a slow release preparation increased the stain intensity of the positive neurons. The increase in the NADPH staining persisted after naloxone was given to mice chronically treated with morphine. Acamprosate antagonized the effects induced by chronic morphine treatment in the NAc of mice. These results indicate that up-regulation of nNOS in the NAc is a consequence of the sustained effects of morphine stimulation, which, in turn, may result from an increased in glutamate release during the abstinence syndrome.展开更多
There is a growing body of evidence showing that periaqueductal gray (PAG) and nucleus accumbens (N. accumbens) play important roles in the modulation of nociception. In our previous study of the mechanisms of morphin...There is a growing body of evidence showing that periaqueductal gray (PAG) and nucleus accumbens (N. accumbens) play important roles in the modulation of nociception. In our previous study of the mechanisms of morphine analgesia we found that opioid antagonist naloxone injected into either of the two nuclei, PAG or N. accumbens, could展开更多
基金supported in part by the National Natural Science Foundation of China(81271469 and 81471350)the Natural Science Foundation of Zhejiang Province,China(Z2101211 and Y20140692)a Medical Health Project of Zhejiang Province, China(2014KYB161)
文摘Abstract 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.
基金supported by the National Basic Research Development Program(973 Program)of China(2013CB530902)the National Natural Science Foundation of China(91132712,81571125,81221003 and 81300979)+2 种基金the Natural Science Foundation of Zhejiang Province,China(LR12C09001 and Q13C090002)the Fundamental Research Funds for the Central Universities of China(2014FZA7008)partly supported by a Chinese Postdoctoral Science Foundation grant(2015M570501)
文摘Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine（DA）system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4（TLR4）, an important pattern-recognition receptor in the innate immune system,can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient（TLR4^（-/-））and wild-type（WT） mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed,large spaces. We found that TLR4^（-/-）mice exhibitedreduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4^（-/-）mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approachavoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4^（-/-）mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly,the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell（NAc Sh） in TLR4^（-/-）mice than in WT mice. Partially inactivating the NAc Sh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4^（-/-）mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAc Sh may contribute to this phenomenon.
基金supported financially by the National Natural Science Foundation of China,No.82071272(to YZ).
文摘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.
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.
文摘The nucleus accumbens(NAc)is a subcortical brain structure known primarily for its roles in pleasure,reward,and addiction.Despite less focus on the NAc in pain research,it also plays a large role in the mediation of pain and is effective as a source of analgesia.Evidence for this involvement lies in the NAc’s cortical connections,functions,pharmacology,and therapeutic targeting.The NAc projects to and receives information from notable pain structures,such as the prefrontal cortex,anterior cingulate cortex,periaqueductal gray,habenula,thalamus,etc.Additionally,the NAc and other pain-modulating structures share functions involving opioid regulation and motivational and emotional processing,which each work beyond simply the rewarding experience of pain offset.Pharmacologically speaking,the NAc responds heavily to painful stimuli,due to its high density ofμopioid receptors and the activation of several different neurotransmitter systems in the NAc,such as opioids,dopamine,calcitonin gene-related peptide,γ-aminobutyric acid,glutamate,and substance P,each of which have been shown to elicit analgesic effects.In both preclinical and clinical models,deep brain stimulation of the NAc has elicited successful analgesia.The multi-functional NAc is important in motivational behavior,and the motivation for avoiding pain is just as important to survival as the motivation for seeking pleasure.It is possible,then,that the NAc must be involved in both pleasure and pain in order to help determine the motivational salience of positive and negative events.
基金the Natural Science Foundation of Shanxi Province(Effects and Mechanism of Electrical Stimulation of Mesolimbic Dopaminergic Pathway on Apioid Addiction,No.2012011042-1Study on Element and Properties of Common Herb Medication Administrated Through the Skin Iontophoresis,No.2008011077-4)
文摘OBJECTIVE: To determine whether the central nervous system is involved in the effect of Chinese herbal medicine on sexual function recovery in orchidectomized rats.METHODS: Orchidectomized rats were administered intragastrically with a decoction of "kidneynourishing" Chinese herbal medicine once per day for 28 days. Accessory genital organ weight, plasma testosterone, and mating behavior were investigated. The expression of c-Fos and neuronal nitric oxide synthase(n NOS) in neuronal cells in the nucleus accumbens(NAc) was analyzed by immunohistochemistry.RESULTS: There was a decrease in accessory genital organ weight, plasma testosterone, and sexual behavior, as well as a low number of c-Fos-positive cells and a large n NOS-positive cell area in orchidectomized rats. Administration of the herbal medicine increased accessory genital organ weight, testosterone level, mating behavior, and c-Fos-positive cell number, while it decreased the n NOS-positive cell area in orchidectomized rats.CONCLUSION: An increase of plasma testosterone after administration of "kidney-nourishing" herbal medicine might contribute to the elevated sexual function and activity in orchidectomized rats. In addition, a central nervous system mechanism, such as the functional alteration of NAc, might be involved.
文摘Background: Dopamine has been known to facilitate male sexual function. Methods: The effect of aqueous extract (140 mg/kg) of Phoenix dactylifera date palm pollen on sexual behavior and determining of dopamine transmission in the nucleus accumbens was studied in male rats using in vivo microdialysis. Results: Releasing of dopamine increased significantly in the nucleus accumbens when a receptive female was introduced behind a screen (p 0.001). During copulation, dopamine increased markedly in control and treated rats. Phoenix dactylifera Date Palm Pollen enhanced the orientation of males towards females by increasing mounting and ano-genital investigatory behavior. Improving of sexual behavior and dopamine release was higher in treated rats in comparison with control (p 0.001). Conclusion: These results indicate a neurochemical basis for interaction between dopaminergic agents and male sexual behavior. Therefore, Phoenix dactylifera Date Palm Pollen seems to act as a dopamine agonist and to cure male infertility. It can be used as an aphrodisiac that leads to further increases in dopamine release.
基金supported by the National Natural Science Foundation of China, grant No. 31070910, 91132728the Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2-EW-J-8)the Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences
文摘Adolescence is a critical period for neurodevelopment. Evidence from animal studies suggests that isolated rearing can exert negative effects on behavioral and brain development. The present study aimed to investigate the effects of adolescent social isolation on latent inhibition and brain-derived neurotrophic factor levels in the forebrain of adult rats. Male Wistar rats were randomly divided into adolescent isolation （isolated housing, 38-51 days of age） and social groups. Latent inhibition was tested at adulthood. Brain-derived neurotrophic factor levels were measured in the medial prefrontal cortex and nucleus accumbens by an enzyme-linked immunosorbent assay. Adolescent social isolation impaired latent inhibition and increased brain-derived neurotrophic factor levels in the medial prefrontal cortex of young adult rats. These data suggest that adolescent social isolation has a profound effect on cognitive function and neurotrophin levels in adult rats and may be used as an animal model of neurodevelopmental disorders.
文摘Background Stereotactic surgery has been used to treat heroin abstinence in China since 2000 by ablating the amygdaloid nucleus （AMY） and the nucleus accumbens （NAc）,which also provides opportunity to identify the relationship between these nuclei and addiction.Our study aimed to explore the physiological and psychological effects of electrically stimulating the AMY and the NAc in herein addicts after detoxification by observing changes of heart rate,arterial pressure and occurrence of euphoria similar to heroin induced euphoria.Methods A total of 70 heroin addicts after detoxification were recruited,and 61 of them were eligible to be given stereotactic surgery for heroin abstinence.The operation was carried out after determining the coordinates of all target nucleuses,and stimulation was performed at the AMY and the NAc solely or jointly.Heart rate,arterial pressure and occurrence of euphoria similar to heroin induced euphoria were recorded and analyzed.Results The average heat rate was （66±10） beats/min before electric stimulation,and significantly increased to （84±14） beats/min during stimulation,and changed to （73±12） beats/min 10 minutes after stimulation.There was a significant elevation of the average arterial pressure from 83 mmHg before stimulation to 98 mmHg during the stimulation,and it then decreased to 90 mmHg after stimulation.Forty-three of the 61 patients showed intense euphoria similar to heroin induced euphoria.The largest number （118/186） of euphoric responses occurred when the AMY and the NAc were stimulated at the same time.Odds ratio was 5.4 （95% CI： 2.4-11.9,P 〈0.0001） to quantify the association.Results from a Logistic regression model showed a positive correlation between unilateral stimulation of either the AMY or NAC and induction of euphoria （OR 〉1 ）,especially when the left AMY or left NAc was stimulated （P 〈0.05）.Conclusions Our data are consistent with existing results that the AMY and the NAc are related to addiction.Different roles in
基金supported by National Science Foundation of China grants 31571095 and 91332122a Key Scientific Technological Innovation Research project from the Ministry of Education+1 种基金a grant from Insitute Guo Qiang at Tsinghua Universityfunding from the Beijing Program on the Study of Functional Chips and Related Core Technologies of Brain-inspired Computing Systems。
文摘The nucleus accumbens shell(NAcSh) plays an important role in reward and aversion. Traditionally, NAc dopamine receptor 2-expressing(D2) neurons are assumed to function in aversion. However, this has been challenged by recent reports which attribute positive motivational roles to D2 neurons. Using optogenetics and multiple behavioral tasks, we found that activation of D2 neurons in the dorsomedial NAcSh drives preference and increases the motivation for rewards, whereas activation of ventral NAcSh D2 neurons induces aversion. Stimulation of D2 neurons in the ventromedial NAcSh increases movement speed and stimulation of D2 neurons in the ventrolateral NAc Sh decreases movement speed. Combining retrograde tracing and in situ hybridization, we demonstrated that glutamatergic and GABAergic neurons in the ventral pallidum receive inputs differentially from the dorsomedial and ventral NAcSh. All together, these findings shed light on the controversy regarding the function of NAcSh D2 neurons, and provide new insights into understanding the heterogeneity of the NAcSh.
基金supported by the National Key Basic Research Program of China(973 Program,2015CB856401)the Beijing National Science Foundation(7222236)+1 种基金the Capital Medical Development Research Fund(2020-2-4113)the National Natural Science Foundation of China(81630031,81771468,82071528,and 82171529).
文摘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.
基金supported by the National Natural Science Foundation of China(31871089 and 31871028)Junior Thousand Talents Program of China,Fundamental Research Funds for the Central Universities(HUST:2172019kfyXKJC077 and HUST:2172019kfyRCPY064)Key Laboratory of Forensic Toxicology,Ministry of Public Security of China(Beijing Municipal Public Security Bureau:2020FTDWFX02 and 2019FTDWFX06).
文摘Methcathinone(MCAT)belongs to the designer drugs called synthetic cathinones,which are abused worldwide for recreational purposes.It has strong stimulant effects,including enhanced euphoria,sensation,alertness,and empathy.However,little is known about how MCAT modulates neuronal activity in vivo.Here,we evaluated the effect of MCAT on neuronal activity with a series of functional approaches.C-Fos immunostaining showed that MCAT increased the number of activated neurons by 6-fold,especially in sensory and motor cortices,striatum,and midbrain motor nuclei.In vivo single-unit recording and two-photon Ca^(2+) imaging revealed that a large proportion of neurons increased spiking activity upon MCAT administration.Notably,MCAT induced a strong de-correlation of population activity and increased trial-to-trial reliability,specifically during a natural movie stimulus.It improved the information-processing efficiency by enhancing the single-neuron coding capacity,suggesting a cortical network mechanism of the enhanced perception produced by psychoactive stimulants.
基金supported by the National Natural Science Foundation of China(81527901,81822017,11534013,11774371,31771215)Youth Innovation Promotion Association CAS(2018393)+1 种基金sponsored by the Science and Technology Commission of Shanghai Municipality(18QA1403700,18JC1420304,18140901700)Shanghai Clinical Research Center for Mental Health(19MC1911100)。
文摘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.
基金funded by the National Research Council of Science & Technology(NST)grant by the Korean government(MSIP)(No.CRC-15-04-KIST)the National Research Foundation of Korea under the grant(No.NRF-2017R1A2B200399Mid-career Researcher Program)
文摘A significant amount of evidence indicates that microRNAs （miRNAs） play an important role in drug addiction. The nucleus accumbens （NAc） is a critical part of the brain’s reward circuit and is involved in a variety of psychiatric disorders, including depression, anxiety, and drug addiction. However, few studies have examined the expression of miRNAs and their functional roles in the NAc under conditions of morphine addiction. In this study, mice were intravenously infused with morphine （0.01, 0.03, 0.3, 1 and 3 mg/kg/infusion） and showed inverted U-shaped response. After morphine self-administration, NAc was used to analyze the functional networks of altered miRNAs and their putative target mRNAs in the NAc following intravenous self-administration of morphine. We utilized several bioinformatics tools, including Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway mapping and CyTargetLinker. We found that 62 miRNAs were altered and exhibited differential expression patterns. The putative targets were related to diverse regulatory functions, such as neurogenesis, neurodegeneration, and synaptic plasticity, as well as the pharmacological effects of morphine （receptor internalization/endocytosis）. The present findings provide novel insights into the regulatory mechanisms of accumbal molecules under conditions of morphine addiction and identify several novel biomarkers associated with morphine addiction.
文摘The human nucleus accumbens(NA), a major part of the ventral striatum, is the area of continuity between the putamen and head of the caudate nucleus. It consists of two parts, a shell laterally and a core medially. The first is mainly connected to the limbic system and the second to the extrapyramidal motor system. The NA, a major pleasure center of the human brain, acts as a limbic-motor interface and is involved in several cognitive, emotional and psychomotor functions. It has a modulating function in the amygdala-basal gangliaprefrontal cortex circuit. It is considered as the neural interface between motivation and action. Further, it is a principal modulator of the reward circuits and supplies motor expression to emotional responses. Such a clinical significance could easily explain the intense work taking place in the respective field of basic research. Its exceptional clinical importance justifies the title of the "King of Neurosciences" for this nucleus. Purpose of this editorial is to review the "informational paths" left behind by the few researchers who tried to explore the architecture(gross anatomy) of this ‘kingdom'. The first anatomical study focused on this nucleus came from Neto et al. The most extensive study of the NA gross, imaging, stereotactic and neurosurgical anatomy so far,came from the research efforts of Mavridis et al.
基金This work was supported by grants from the National Natural Science Foundation of China(82071208,81870851,31771193,and 81971775)the Outstanding Talented Young Doctor Program of Hubei Province(HB20200407)+2 种基金the Translational Medicine,and interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(ZNJC202012)the Medical Sci-Tech Innovation Platform of Zhongnan Hospital of Wuhan Universitythe Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32030200).
文摘Preoperative sleep loss can amplify post-operative mechanical hyperalgesia.However,the underlying mechanisms are still largely unknown.In the current study,rats were randomly allocated to a control group and an acute sleep deprivation(ASD)group which experienced 6 h ASD before surgery.Then the variations in cerebral function and activity were investigated with multi-modal techniques,such as nuclear magnetic resonance,functional magnetic resonance imaging,c-Fos immunofluorescence,and electrophysiology.The results indicated that ASD induced hyperalgesia,and the metabolic kinetics were remarkably decreased in the striatum and midbrain.The functional connectivity(FC)between the nucleus accumbens(NAc,a subregion of the ventral striatum)and the ventrolateral periaqueductal gray(vLPAG)was significantly reduced,and the c-Fos expression in the NAc and the vLPAG was suppressed.Furthermore,the electrophysiological recordings demonstrated that both the neuronal activity in the NAc and the vLPAG,and the coherence of the NAc-vLPAG were suppressed in both resting and task states.This study showed that neuronal activity in the NAc and the vLPAG were weakened and the FC between the NAc and the vLPAG was also suppressed in rats with ASD-induced hyperalgesia.This study highlights the importance of preoperative sleep management for surgical patients.
文摘The aim of this work was to investigate whether acamprosate modifies the expression of the enzyme responsible for neuronal NO synthesis (nNOS) in the nucleus accumbens (NAc) of mice chronically treated with morphine and during the abstinence syndrome induced by naloxone. The enzyme was monitored by the NADPH diaphorase method. The number of cells stained for NADPH diaphorase in the NAc of mice was counted in 40 μm thick coronal brain slices at 40X. The intensity of the histochemical reaction of stained cells from naive morphine plus saline and morphine plus acamprosate treated mice was analyzed by Image Pro Plus 4.5.1. Morphine administered in a slow release preparation increased the stain intensity of the positive neurons. The increase in the NADPH staining persisted after naloxone was given to mice chronically treated with morphine. Acamprosate antagonized the effects induced by chronic morphine treatment in the NAc of mice. These results indicate that up-regulation of nNOS in the NAc is a consequence of the sustained effects of morphine stimulation, which, in turn, may result from an increased in glutamate release during the abstinence syndrome.
文摘There is a growing body of evidence showing that periaqueductal gray (PAG) and nucleus accumbens (N. accumbens) play important roles in the modulation of nociception. In our previous study of the mechanisms of morphine analgesia we found that opioid antagonist naloxone injected into either of the two nuclei, PAG or N. accumbens, could
