Pain is often comorbid with emotional disorders such as anxiety and depression.Hyperexcitability of the anterior cingulate cortex has been implicated in pain and pain-related negative emotions that arise from impairme...Pain is often comorbid with emotional disorders such as anxiety and depression.Hyperexcitability of the anterior cingulate cortex has been implicated in pain and pain-related negative emotions that arise from impairments in inhibitory gamma-aminobutyric acid neurotransmission.This review primarily aims to outline the main circuitry(including the input and output connectivity)of the anterior cingulate cortex and classification and functions of different gamma-aminobutyric acidergic neurons;it also describes the neurotransmitters/neuromodulators affecting these neurons,their intercommunication with other neurons,and their importance in mental comorbidities associated with chronic pain disorders.Improving understanding on their role in pain-related mental comorbidities may facilitate the development of more effective treatments for these conditions.However,the mechanisms that regulate gamma-aminobutyric acidergic systems remain elusive.It is also unclear as to whether the mechanisms are presynaptic or postsynaptic.Further exploration of the complexities of this system may reveal new pathways for research and drug development.展开更多
Objective To explore the role of the extracellular signal-regulated kinase （ERK）/cAMP response element binding protein （CREB） pathway in the induction of long-term potentiation （LTP） in the anterior cingulate co...Objective To explore the role of the extracellular signal-regulated kinase （ERK）/cAMP response element binding protein （CREB） pathway in the induction of long-term potentiation （LTP） in the anterior cingulate cortex （ACC） that may be implicated in pain-related negative emotion. Methods LTP of field potential was recorded in ACC slice and the expressions of phospho-ERK （pERK） and phospho-CREB （pCREB） were examined using immunohistochemistry method. Results LTP could be induced stably in ACC slice by high frequency stimulation （2-train, 100 Hz, 1 s）, while APv （an antagonist of NMDA receptor） could block the induction of LTP in the ACC, indicating that LTP in this experiment was NMDA receptor-dependent. Bath application of PD98059 （50 μmol/L）, a selective MEK inhibitor, at 30 min before tetanic stimulation could completely block the induction of LTP. Moreover, the protein level of pERK in the ACC was transiently increased after LTP induction, starting at 5 rain and returning to basal at 1 h after tetanic stimulation. The protein level of pCREB was also increased after LTP induction. The up-regulation in pERK and pCREB expressions could be blocked by pretreatment of PD98059. Double immunostaining showed that after LTP induction, most pERK was co-localized with pCREB. Conclusion NMDA receptor and ERK-CREB pathway are necessary for the induction of LTP in rat ACC and may play important roles in pain emotion.展开更多
As the most common symptomatic reason to seek medical consultation,pain is a complex experience that has been classified into different categories and stages.In pain processing,noxious stimuli may activate the anterio...As the most common symptomatic reason to seek medical consultation,pain is a complex experience that has been classified into different categories and stages.In pain processing,noxious stimuli may activate the anterior cingulate cortex(ACC).But the function of ACC in the different pain conditions is not well discussed.In this review,we elaborate the commonalities and differences from accumulated evidence by a variety of pain assays for physiological pain and pathological pain including inflammatory pain,neuropathic pain,and cancer pain in the ACC,and discuss the cellular receptors and signaling molecules from animal studies.We further summarize the ACC as a new central neuromodulation target for invasive and non-invasive stimulation techniques in clinical pain management.The comprehensive understanding of pain processing in the ACC may lead to bridging the gap in translational research between basic and clinical studies and to develop new therapies.展开更多
Objective The rostral anterior cingulate cortex （rACC） is implicated in processing the emotional component of pain. N-methyl-D-aspartate receptors （NMDARs） are highly expressed in the rACC and mediate painrelated ...Objective The rostral anterior cingulate cortex （rACC） is implicated in processing the emotional component of pain. N-methyl-D-aspartate receptors （NMDARs） are highly expressed in the rACC and mediate painrelated affect by activating a signaling pathway that involves cyclic adenosine monophosphate （cAMP）/protein ki- nase A （PKA） and/or extracellular regulated kinase （ERK）/cAMP-response element-binding protein （CREB）. The present study investigated the contributions of the NMDAR glycine site and GluN2B subunit to the activation of ERK and CREB both in vitro and in vivo in rat rACC. Methods Immunohistochemistry and Western blot analy- sis were used to separately assess the expression of phospho-ERK （pERK） and phospho-CREB （pCREB） in vitro and in vivo. Double immunostaining was also used to determine the colocalization of pERK and pCREB. Results Both bath application of NMDA in brain slices in vitro and intraplantar injection of formalin into the rat hindpaw in vivo induced significant up-regulation of pERK and pCREB in the rACC, which was inhibited by the NMDAR antago- nist DL-2-amino-5-phospho-novaleric acid. Selective blockade of the NMDAR GluN2B subunit and the glycine- binding site, or degradation of endogenous D-serine, a co-agonist for the glycine site, significantly decreased the up- regulation of pERK and pCREB expression in the rACC. Further, the activated ERK predominantly colocalized with CREB. Conclusion Either the glycine site or the GluN2B subunit of NMDARs participates in the phosphorylation of ERK and CREB induced by bath application of NMDA in brain slices or hindpaw injection of 5% formalin in rats, and these might be fundamental molecular mechanisms underlying pain affect.展开更多
Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis(CP),but cortical modulation of painful CP remains elusive.Here,we examined the role of the anterior cingulate cortex(ACC)i...Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis(CP),but cortical modulation of painful CP remains elusive.Here,we examined the role of the anterior cingulate cortex(ACC)in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid(TNBS).TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats.Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii(NTS)and ACC,and some FOS-expressing neurons in the NTS projected to the ACC.In addition,a larger portion of ascending fibers from the NTS innervated pyramidal neurons,the neural subpopulation primarily expressing FOS under the condition of painful CP,rather than GABAergic neurons within the ACC.CP rats showed increased expression of vesicular glutamate transporter 1,and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor(NMDAR)subunit NR2B and theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)subunit GluR1 within the ACC.Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats,which was similar to the analgesic effect of endomorphins injected into the ACC.Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety,whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats.Taken together,these findings provide neurocircuit,biochemical,and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats,as well as novel insights into the cortical modulation of painful CP,and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.展开更多
To explore whether experiencing inflammatory pain has an impact upon intracortical synaptic organization, the planar multi-electrode array （MEA） technique and 2-dimensional current source density （2D-CSD） imaging ...To explore whether experiencing inflammatory pain has an impact upon intracortical synaptic organization, the planar multi-electrode array （MEA） technique and 2-dimensional current source density （2D-CSD） imaging were used in slice preparations of the anterior cingulate cortex （ACC） from rats. Synaptic activity across different layers of the ACC was evoked by deep layer stimulation through one electrode. The layer-localization of both local field potentials （LFPs） and the spread of current sink calculated by 2D-CSD analysis was characterized pharmacologically. Moreover, the induction of long-term potentiation （LTP） and changes in LTP magnitude were also evaluated. We found that under naive conditions, the current sink was initially generated in layer Ⅵ, then spread to layer Ⅴ and finally confined to layers Ⅱ-Ⅲ. This spatial pattern of current sink movement typically reflected changes in depolarized sites from deep layers （Ⅴ-Ⅵ） to superficial layers （Ⅱ-Ⅲ） where intra- and extra- cortical inputs terminate. In the ACC slices from rats in an inflamed state （for 2 h） caused by intraplantar bee-venom injection, the spatial profile of intra-ACC synaptic organization was significantly changed,showing an enlarged current sink distribution and a leftward shift of the stimulus-response curves relative to the naive and saline controls. The change was more distinct in the superficial layers （Ⅱ-Ⅲ） than in the deep site. In terms of temporal properties, the rate of LTP induction was significantly increased in layers Ⅱ-Ⅲ by inflammatory pain. However, the magnitude of LTP was not significantly enhanced by this treatment. Taken together, these results show that inflammatory pain results in distinct spatial and temporal plasticity of synaptic organization in the ACC, which may lead to altered synaptic transmission and modulation.展开更多
Major depressive disorder (MDD) is a severe, disabling pathology characterized, in addition to affective, cognitive and motor symptoms, by self-focused attention and rumination. During recursive self-focused processes...Major depressive disorder (MDD) is a severe, disabling pathology characterized, in addition to affective, cognitive and motor symptoms, by self-focused attention and rumination. During recursive self-focused processes and rumination, the posterior cingulate cortex (PCC) is activated. In vivo proton magnetic resonance spectroscopy (MRS) is a noninvasive imaging technique that can directly assess living biochemistry in localized brain regions. The aim of this study, therefore, was to use 1H-MRS as a means of analyzing brain metabolites in the PCC of a group of first-episode, unmedicated MDD patients. PCC metabolite levels were analyzed at 3-T in a single voxel located bilaterally over the PCC in 7 patients diagnosed for the first time with MDD and with no previous pharmacological treatment, as well as in 9 control subjects. Differences in metabolite levels between groups were compared using independent t-tests. Myo-inositol was significantly higher, and NAA + NAAG/Cr significantly lower, in MDD patients than in controls. The other brain metabolites showed no statistical differences. The present results suggest that alterations in PCC metabolite levels are likely involved in MDD pathophysiology, and may help to improve our understanding of MDD and the role of the PCC in some symptoms of depression.展开更多
Itch is an unpleasant sensation that provokes the desire to scratch.While acute itch serves as a protec-tive system to warn the body of external irritating agents,chronic itch is a debilitating but poorly-treated clin...Itch is an unpleasant sensation that provokes the desire to scratch.While acute itch serves as a protec-tive system to warn the body of external irritating agents,chronic itch is a debilitating but poorly-treated clinical dis-ease leading to repetitive scratching and skin lesions.How-ever,the neural mechanisms underlying the pathophysiol-ogy of chronic itch remain mysterious.Here,we identified a cell type-dependent role of the anterior cingulate cortex(ACC)in controlling chronic itch-related excessive scratch-ing behaviors in mice.Moreover,we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area(VTA)that was critically involved in chronic itch.Furthermore,we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch.Finally,the ACC neurons were shown to predomi-nantly innervate the non-dopaminergic neurons of the VTA.Taken together,our findings uncover a cortex-midbrain cir-cuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.展开更多
Stroke is a physiological alteration associated with changes in blood flow that can result in sudden-onset cognitive impairment. It has a heterogenous clinical presentation with varying degrees of severity correlated ...Stroke is a physiological alteration associated with changes in blood flow that can result in sudden-onset cognitive impairment. It has a heterogenous clinical presentation with varying degrees of severity correlated with specific central nervous system zones or areas, and its prognosis is uncertain. This case study describes a 62-year-old male patient with acquired brain damage of the anterior cingulate cortex as a result of an ischemic event in the territory of the left anterior cerebral artery. Cognitive function was assessed using the neuropsychological executive function and frontal lobe test battery (BANFE-2) as well as other neuropsychological tests. The results show a profile of higher mental functions characterized by the presence of dysexecutive syndrome with marked behavioral alteration and diencephalic amnesia. .展开更多
Background:The analgesic effects of multiple electroacupuncture(EA)sessions and single EA sessions differ significantly in pain management.Area 24b(A24b)of the anterior cingulate cortex(ACC)is crucial in pain processi...Background:The analgesic effects of multiple electroacupuncture(EA)sessions and single EA sessions differ significantly in pain management.Area 24b(A24b)of the anterior cingulate cortex(ACC)is crucial in pain processing.EA relieves pain by targeting and modulating the neuronal activity within this subregion.However,whether the cumulative effect of EA antinociception is connected to A24b mechanisms has remained unclear.Methods:In our study,we used the Complete Freund's Adjuvant(CFA)model to induce inflammatory pain and the Spared Nerve Injury(SNI)model to induce neuropathic pain,and adult male C57BL/6,FosTRAP,and FosTRAP:Ai9 mice were used as experimental subjects to investigate the cumulative effect of EA antinociception and whether multiple EA sessions and a single EA session regulate different neuronal populations in the A24b.Results:We observed that EA effectively alleviated pain in mice,with three EA sessions yielding superior analgesic effects compared to a single session.Using chemical genetics combined with FosCreER technology to activate EA-TRAPed cells in the A24b,we found that pain relief was more pronounced with three EA sessions.Moreover,chemogenetic inhibition of EA-TRAPed cells in the A24b reversed the analgesic effects of a single EA session but not those of three EA sessions.Fluorescent in situ hybridization results indicated that three EA sessions significantly increased the number of GABAergic neurons in the A24b compared with a single session.Additionally,retrograde tracing revealed that the A24b circuit that monosynaptically innervates EA-TRAPed cells included projections from the central lateral nucleus(CL),lateral mediodorsal thalamic nucleus(MDL),lateral habenula(LHb),dorsal raphe nucleus(DR),caudal linear nucleus of the raphe(CLi),dorsal tuberomamillary nucleus(DTM),periventricular hypothalamic nucleus(Pe)and hippocampal fields CA1,CA2,and CA3.These findings suggest that multiple EA sessions and single EA sessions activated different neuronal populations in the A24b.The enhanced analgesic effect of multiple EA sessions may be attributed to an increase in the proportion of GABAergic neurons within the A24b.Conclusions:Multiple and single EA sessions recruit distinct neuronal populations in A24b,with the stronger analgesic effect of repeated EA linked to a higher proportion of GABAergic neurons in this region.展开更多
The anterior cingulate cortex(ACC)has recently been proposed as a key player in the representation of itch stimuli.However,to date,little is known about the contribution of specific ACC interneuron populations to itch...The anterior cingulate cortex(ACC)has recently been proposed as a key player in the representation of itch stimuli.However,to date,little is known about the contribution of specific ACC interneuron populations to itch processing.Using c-Fos immunolabeling and in vivo Ca2+imaging,we reported that both histamine and chloroquine stimuli-induced acute itch caused a marked enhancement of vasoactive intestinal peptide(VIP)-expressing interneuron activity in the ACC.Behavioral data indicated that optogenetic and chemogenetic activation of these neurons reduced scratching responses related to histaminergic and non-histaminergic acute itch.Similar neural activity and modulatory role of these neurons were seen in mice with chronic itch induced by contact dermatitis.Together,this study highlights the importance of ACC VIP+neurons in modulating itch-related affect and behavior,which may help us to develop novel mechanism-based strategies to treat refractory chronic itch in the clinic.展开更多
The subgenual anterior cingulate cortex(sgACC)plays a central role in the pathophysiology of major depressive disorder(MDD).Its functional interactive profile with the left dorsal lateral prefrontal cortex(DLPFC)is as...The subgenual anterior cingulate cortex(sgACC)plays a central role in the pathophysiology of major depressive disorder(MDD).Its functional interactive profile with the left dorsal lateral prefrontal cortex(DLPFC)is associated with transcranial magnetic stimulation(TMS)treatment outcomes.Previous research on sgACC functional connectivity(FC)in MDD has yielded inconsistent results,partly due to small sample sizes and limited statistical power.Furthermore,calculating sgACC-FC to target TMS individually is challenging.We used a large multi-site cross-sectional sample(1660 patients with MDD vs.1341 healthy controls)from Phase Ⅱ of the Depression Imaging REsearch ConsorTium(DIRECT)to systematically delineate case-control difference maps of sgACC-FC.We explored the potential impact of group-level abnormality profiles on TMS target localization and clinical efficacy.Next,we developed an MDD big data-guided,individualized TMS targeting algorithm to integrate group-level statistical maps with individual-level brain activity to individually localize TMS targets.We found enhanced sgACCDLPFC FC in patients with MDD compared with healthy controls(HC).These group differences altered the position of the sgACC anti-correlation peak in the left DLPFC.We showed that the magnitude of case-control differences in the sgACC-FC was related to clinical improvement in two independent clinical samples.This targeting algorithm may generate targets demonstrating stronger associations with clinical efficiency than group-level targets.We reliably delineated MDD-related abnormalities of sgACC-FC profiles in a large,independently ascertained sample and demonstrated the potential impact of such casecontrol differences on FC-guided localization of TMS targets.展开更多
Neuropathic pain(NP)represents a considerable clinical challenge,profoundly impacting patients'quality of life.Presently,pharmacotherapy serves as a primary approach for NP alleviation,yet its efficacy often remai...Neuropathic pain(NP)represents a considerable clinical challenge,profoundly impacting patients'quality of life.Presently,pharmacotherapy serves as a primary approach for NP alleviation,yet its efficacy often remains suboptimal.Melatonin(MLT),a biologically active compound secreted by the pineal gland,has long been associated with promoting and maintaining sleep.Although recent studies suggest analgesic effects of MLT,the underlying mechanism remains largely unknown,particularly its impact on the cortex In this study,we induced an NP model in mice through spared nerve injury(SNI)and observed a considerable,dose-dependent alleviation in NP symptoms following intraperitoneal or anterior cingulate cortex(ACC)administration of MLT.Our findings further indicated that the NP management of MLT is selectively mediated by MLT-related receptor 2(MT_(2)R),rather than MT_(1)R,on neurons and microglia within the ACC.Transcriptome sequencing,complemented by bioinformatics analysis,implicated MLT in the modulation of Ga(i)and immune-inflammatory signals.Specifically,MLT inhibited the excitability level of pyramidal cells in the ACC by activating the Ga(i)signaling pathway.Simultaneously,MLT attenuated M,polarization and promoted M_(2)polarization of microglia,thereby mitigating the inflammatory response and type Il interferon response within the Acc.These findings unveil a hitherto unrecognized molecular mechanism:an MLT-mediated neuroimmune modulation pathway in the ACC mediated by MT_(2)R.This elucidation sheds light on the regulatory character of MLT in chronic nociceptive pain conditions,offering a prospective therapeutic strategy for NP management.展开更多
Background Previous animal and neuroimaging studies have demonstrated that brain function in heroin addicted users is impaired. However, the posterior cingulate cortex （PCC） has not received much attention. The purp...Background Previous animal and neuroimaging studies have demonstrated that brain function in heroin addicted users is impaired. However, the posterior cingulate cortex （PCC） has not received much attention. The purpose of this study was to investigate whether chronic heroin use is associated with craving-related changes in the functional connectivity of the PCC of heroin addicted users. Methods Fourteen male adult chronic heroin users and fifteen age and gender-matched healthy subjects participated in the present study. The participants underwent a resting-state functional magnetic resonance imaging （fMRI） scan and a cue-induced craving task fMRI scan. The activated PCC was identified in the cue-induced craving task by means of a group contrast test. Functional connectivity was analyzed based on resting-state fMRI data in order to determine the correlation between brain regions. The relationship between the connectivity of specific regions and heroin dependence was investigated. Results The activation of PCC, bilateral anterior cingulate cortex, caudate, putamen, precuneus, and thalamus was significant in the heroin group compared to the healthy group in the cue-induced craving task. The detectable functional connectivity of the heroin users was stronger between the PCC and bilateral insula, bilateral dorsal striatum, right inferior parietal Iobule （IPL） and right supramarginal gyrus （P 〈0.001） compared to that of the healthy subjects in the resting-state data analysis. The strength of the functional connectivity, both for the PCC-insula （r=0.60, P 〈0.05） and for PCC-striatum （t=0.58, P 〈0.05）, was positively correlated with the duration of heroin use. Conclusion The altered functional connectivity patterns in the PCC-insula and PCC-striatum areas may be regarded as biomarkers of brain damage severity in chronic heroin users.展开更多
Background Previous studies with animal experiments, autopsy, structural magnetic resonance imaging （MRI） and task-related functional MRI （fMRI） have confirmed that brain functional connectivity in addicts has bec...Background Previous studies with animal experiments, autopsy, structural magnetic resonance imaging （MRI） and task-related functional MRI （fMRI） have confirmed that brain functional connectivity in addicts has become impaired. The goal of this study was to investigate the alteration of resting-state functional connectivity of the ventral anterior cingulate cortex （vACC） in the heroin abusers＇ brain. Methods Fifteen heroin abusers and fifteen matched healthy volunteers were studied using vACC as the region-of interest （ROI） seed. A 3.0 T scanner with a standard head coil was the imagining apparatus. T2＊-weighted gradient-echo planar imaging （GRE-EPI） was the scanning protocol. A ROI seed based correlation analysis used a SPM5 software package as the tool for all images processing. Results This study showed a functional connection to the insula vACC in heroin abusers. Compared with controls, heroin users showed decreased functional connectivity between the nucleus accumbens （NAc） and vACC, between the parahippocampala gyrus/amgdala （PHC/amygdala） and vACC, between the thalamus and vACC, and between the posterior cingulated cortex/precuneus （PCC/pC） and vACC. Conclusion The altered resting-state functional connectivity to the vACC suggests the neural circuitry on which the addictive drug has an affect and reflects the dysfunction of the addictive brain.展开更多
The ability to detect conspecific＇s distress is crucial for animal survival. In rodent models, observational fear （OF） occurs when one animal perceives another fear related negative emotions, which may model certai...The ability to detect conspecific＇s distress is crucial for animal survival. In rodent models, observational fear （OF） occurs when one animal perceives another fear related negative emotions, which may model certain behaviors caused by witnessing traumatic experiences in humans. Anterior cingulate cortex （ACC） has been showed to play a crucial role in OF. However, cellular and neural circuit basis relating to ACC governing OF is poorly understood. Here, we used Designer Receptor Exclusively Activated by a Designer Drug （DREADD） system to investigate the cell type specific circuit mechanism of ACC in OF. Firstly, inhibitory hM4D （Gi） designer receptor together with clozapine N-oxide （CNO） injection was applied to inactivate ACC neurons in the observer mice. We found that, chemogenetic inhibition of ACC resulted in a decreased freezing response in the observer mice. Next, combining PV-ires-Cre mice and Cre-dependent DREADD system, we selectively targeted the ACC parvalbumin （PV） interneurons with the excitatory hM3D （Gq） designer receptor. Activation of ACC PV interneurons following CNO injection reduced freezing response in the observer mice, while had no effect on freezing response in the demon- strator mice. Finally, monosynaptic rabies retrograde tracing revealed that ACC PV interneurons receive inputs from the mediodorsal thalamic nucleus （MD） and the ventromedial thalamic nucleus （VM）, both known for their roles in OF. Taken together, these findings reveal that ACC activation is important for OF, during which PV interneurons in ACC play an important regulatory role. Abnormal function of ACC PV interneurons might contribute to the pathology of empathy- deficits related diseases, such as autism and schizoohrenia.展开更多
The psychostimulant methylphenidate (MPD; also called Ritalin) is a blocker of dopamine and norepi-nephrine transporter. It has been clinically used for treatment of Attention Deficit and Hyperactivity Disorder (ADHD)...The psychostimulant methylphenidate (MPD; also called Ritalin) is a blocker of dopamine and norepi-nephrine transporter. It has been clinically used for treatment of Attention Deficit and Hyperactivity Disorder (ADHD). There have been inconsistent reports regarding the effects of systemically adminis-tered MPD on learning and memory, either in animals or humans. In the present study, we investigated the effect of direct infusion of MPD into the basolateral nucleus of amygdala (BLA) or the anterior cin-gulate cortex (ACC) on conditioned fear memory. Rats were trained on a one-trial step-through inhibi-tory avoidance task. MPD was infused bilaterally into the BLA or the ACC, either at ‘0’ or 6 h post-training. Saline was administered as control. Memory retention was tested 48 h post-training. In-tra-BLA or intra-ACC infusion of MPD ‘0’ h but not 6 h post-training significantly improved 48-h memory retention: the MPD-treated rats had significant longer step-through latency than controls. The present results indicate that action of MPD in the BLA or the ACC produces a beneficial effect on the consoli-dation of inhibitory avoidance memory.展开更多
Background:Pain is considered as a multidimensional conscious experience that includes a sensory component and a negative affective-motivational component.Electroacupuncture(EA)is widely used to treat pain and painind...Background:Pain is considered as a multidimensional conscious experience that includes a sensory component and a negative affective-motivational component.Electroacupuncture(EA)is widely used to treat pain and paininduced negative emotions,however,little is known about the mechanisms underlying the effect of EA.Objective:This study investigated the effect of EA on alleviating the anxiety-like behaviors in pain aversion rats and its anterior cingulate cortex(ACC)regulation mechanism.Methods:After a Freund’s complete adjuvant(CFA)-conditioned place aversion(C-CPA)model was established in rats,EA treatment(2/100 Hz,30 min,once/day,4 days totally)was applied at bilateral Zusanli(ST36)and Kunlun(BL60)acupoints.Von Frey filaments were used to measure changes of pain withdrawal threshold(PWT)at indicated time points.Elevated zero maze(EZM)was used to investigate the changes of pain-related anxiety and CPA was used to investigate the changes of pain aversion.The protein expression levels of GAD67,PV,and NPY in ACC were detected by Western blotting.Results:Compared with the control group,the staying time in the"CFA-paired compartment"was significantly reduced,and the PWT was decreased in model group.In the EZM assessment,the distance and the time in open arm,as well as the number of open arm entries of model group were significantly lower than those in the control group.In the CPA assessment,the time spent in the"CFA-paired compartment"was significantly decreased in model group compared with control group,and EA reversed the changes in pain sensation and in pain-related emotions.Western blotting showed that the NPY level,but not the levels of GAD67 and PV,was significantly increased in the ACC of the model group compared to that of the control group.The increased expression of NPY in the ACC was significantly downregulated by EA,while sham EA produced no such effect.Conclusion:EA can effectively relieve the pain and pain-related emotions,and its mechanism may be achieved by down-regulating the expression of NPY in the ACC.展开更多
Introduction: Transcranial Magnetic Stimulation (TMS) is a non-invasive technique for brain stimulation. Repetitive TMS (rTMS) over the medial Prefrontal Cortex (mPFC), Broadman Area 10 (BA10) may stimulate transynapt...Introduction: Transcranial Magnetic Stimulation (TMS) is a non-invasive technique for brain stimulation. Repetitive TMS (rTMS) over the medial Prefrontal Cortex (mPFC), Broadman Area 10 (BA10) may stimulate transynaptically perigenual Anterior Cingulate Cortex (pACC, BA 33), insula, amigdala, hypothalamus and connected branches of the Autonomic Nervous System (ANS) involved in stressorevoked cardiovascular reactivity. Stressors are associated with an increase in sympathetic cardiac control, a decrease in parasympathetic control, or both, and, consequently, an increase in systolic/stroke volume, total vascular impedance/resistance and heart rate, a decrease of baroreflex sensitivity, i.e., an increase in blood pressure/arterial tension. Objectives and Aims: The present work aims, using TMS and accordingly to Gianaros modeling, based on functional neuroimaging studies and previous neuroanatomical data from animal models, to probe the connectivity of brain systems involved in stressor-evoked cardiovascular reactivity and to explore TMS potential as a tool for detection and stratification of individual differences concerning this reactivity and hemorreological risk factors correlated with the development of Coronary Heart Disease (CHD). Methods: Both subjects, a 52 years old male and a 40 years old female with previous increased Low Frequency (LF)/High Frequency (HF) Heart Rate Variability (HRV) ratios (respectively, 4.209/3.028) without decompensated cardiorespiratory symptoms, gave informed consent, and ethico-legal issues have been observed. Electroencephalographic (EEG) monitoring has been performed for safety purposes. Immediately after administration, over the mPFC, of 15 pulses of rTMS, during 60 second, with an inductive electrical current, at the stimulating coil, of 85.9 Ampère per μsecond and 66 Ampère per μsecond, respectively, for male and female subjects (a “figure-of-eight” coil and magnetic stimulator MagLite, Dantec/Medtronic, have been used), HRV spectrum analysis (cStress software) has been performed (during 5 minutes, in supine position). Results: In both subjects, LF power, HF power and LF/HF ratio results, before and after rTMS administration, pointed towards sympathetic attenuation and parasympathetic augmentation (respectively, in male/female subject: decreased LF power—65.1 nu/69.3 nu, before rTMS;56.1 nu/41.6 nu, after rTMS;increased HF power—15.5 nu/22.9 nu, before rTMS;30.9 nu/45.5 nu, after rTMS). Conclusions: In this preliminary investigation, the existence of a link between “mind” and heart’s function has been put in evidence, through a reversible “virtual” lesion, of brain systems involved in cardiovascular control, caused by TMS. Repetitive TMS over mPFC decreased brain function involved in stressorevoked cardiovascular reactivity, suggesting the importance of TMS in the management of stress-related cardiovascular disorders.展开更多
Previous studies have demonstrated that electroacupuncture therapy is effective in the treatment of irritable bowel syndrome. However, the precise mechanism of this therapy is unknown. The present study served to inve...Previous studies have demonstrated that electroacupuncture therapy is effective in the treatment of irritable bowel syndrome. However, the precise mechanism of this therapy is unknown. The present study served to investigate the effects of electroacupuncture therapy on treatment of patients with diarrhea-predominant irritable bowel syndrome （IBS）. We compared brain activation maps based on the changes of cerebral glucose metabolism obtained by 18-fluorodeoxyglucose positron emission tomography scanning under three conditions： resting, rectal balloon distension and rectal balloon distension plus electroacupuncture. Under the resting condition, compared with healthy controls, IBS patients displayed an increasing regional cerebral metabolic rate of glucose over a wide range： bilateral superior temporal gyrus, right middle occipital gyrus, superior frontal gyrus and bilateral middle frontal gyrus. However, there was no significant activity in the visceral pain center. Compared with the resting condition, under the rectal balloon distension condition, patients with IBS had a greater regional cerebral metabolic rate of glucose in the prefrontal cortex, left anterior cingulate cortex, postcentral gyrus, precentral gyrus and temporal gyrus. Under the rectal balloon distension plus electroacupuncture condition, stimulation by electroacupuncture at Tianshu （ST 25） manifested a decreased regional cerebral metabolic rate of glucose in the left cingulate gyrus, right insula, right caudate nucleus, fusiform gyrus and hippocampal gyrus. Electroacupuncture therapy relieved abdominal pain, distension or discomfort by decreasing glucose metabolism in the brain.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82374561(to JD),82174490(to JF)the Medical and Health Science and Technology Program of Zhejiang Province,No.2021RC098(to JD)the Research Project of Zhejiang Chinese Medical University,Nos.2022JKZKTS44(to JD),2022FSYYZZ07(to JF).
文摘Pain is often comorbid with emotional disorders such as anxiety and depression.Hyperexcitability of the anterior cingulate cortex has been implicated in pain and pain-related negative emotions that arise from impairments in inhibitory gamma-aminobutyric acid neurotransmission.This review primarily aims to outline the main circuitry(including the input and output connectivity)of the anterior cingulate cortex and classification and functions of different gamma-aminobutyric acidergic neurons;it also describes the neurotransmitters/neuromodulators affecting these neurons,their intercommunication with other neurons,and their importance in mental comorbidities associated with chronic pain disorders.Improving understanding on their role in pain-related mental comorbidities may facilitate the development of more effective treatments for these conditions.However,the mechanisms that regulate gamma-aminobutyric acidergic systems remain elusive.It is also unclear as to whether the mechanisms are presynaptic or postsynaptic.Further exploration of the complexities of this system may reveal new pathways for research and drug development.
基金supported by National Natural Science Fundation of China (No.30870835,30821002,and 30900444)National Basic Research Program of China (No. 2007CB512303,2007CB512502,and 2006CB500807)Postdoctoral Fundation of China (No.20080440578)
文摘Objective To explore the role of the extracellular signal-regulated kinase （ERK）/cAMP response element binding protein （CREB） pathway in the induction of long-term potentiation （LTP） in the anterior cingulate cortex （ACC） that may be implicated in pain-related negative emotion. Methods LTP of field potential was recorded in ACC slice and the expressions of phospho-ERK （pERK） and phospho-CREB （pCREB） were examined using immunohistochemistry method. Results LTP could be induced stably in ACC slice by high frequency stimulation （2-train, 100 Hz, 1 s）, while APv （an antagonist of NMDA receptor） could block the induction of LTP in the ACC, indicating that LTP in this experiment was NMDA receptor-dependent. Bath application of PD98059 （50 μmol/L）, a selective MEK inhibitor, at 30 min before tetanic stimulation could completely block the induction of LTP. Moreover, the protein level of pERK in the ACC was transiently increased after LTP induction, starting at 5 rain and returning to basal at 1 h after tetanic stimulation. The protein level of pCREB was also increased after LTP induction. The up-regulation in pERK and pCREB expressions could be blocked by pretreatment of PD98059. Double immunostaining showed that after LTP induction, most pERK was co-localized with pCREB. Conclusion NMDA receptor and ERK-CREB pathway are necessary for the induction of LTP in rat ACC and may play important roles in pain emotion.
基金supported by the National Key R&D Program of China(2019YFA0709504)the National Natural Science Foundation of China(31930042,31771164,31900719,and 91630314)+6 种基金the Innovative Research Team of High-level Local Universities in ShanghaiDevelopment Project of Shanghai Peak Disciplines Integrated Chinese and Western MedicineShanghai Science and Technology Committee Rising-Star Program(19QA1401400)111 Project(B18015)Key Project of Shanghai Science&Technology(16JC1420402)Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJLab。
文摘As the most common symptomatic reason to seek medical consultation,pain is a complex experience that has been classified into different categories and stages.In pain processing,noxious stimuli may activate the anterior cingulate cortex(ACC).But the function of ACC in the different pain conditions is not well discussed.In this review,we elaborate the commonalities and differences from accumulated evidence by a variety of pain assays for physiological pain and pathological pain including inflammatory pain,neuropathic pain,and cancer pain in the ACC,and discuss the cellular receptors and signaling molecules from animal studies.We further summarize the ACC as a new central neuromodulation target for invasive and non-invasive stimulation techniques in clinical pain management.The comprehensive understanding of pain processing in the ACC may lead to bridging the gap in translational research between basic and clinical studies and to develop new therapies.
基金supported by the National Natural Science Foundation of China (30900444,31070973,30870835,31121061 and 30830044)
文摘Objective The rostral anterior cingulate cortex （rACC） is implicated in processing the emotional component of pain. N-methyl-D-aspartate receptors （NMDARs） are highly expressed in the rACC and mediate painrelated affect by activating a signaling pathway that involves cyclic adenosine monophosphate （cAMP）/protein ki- nase A （PKA） and/or extracellular regulated kinase （ERK）/cAMP-response element-binding protein （CREB）. The present study investigated the contributions of the NMDAR glycine site and GluN2B subunit to the activation of ERK and CREB both in vitro and in vivo in rat rACC. Methods Immunohistochemistry and Western blot analy- sis were used to separately assess the expression of phospho-ERK （pERK） and phospho-CREB （pCREB） in vitro and in vivo. Double immunostaining was also used to determine the colocalization of pERK and pCREB. Results Both bath application of NMDA in brain slices in vitro and intraplantar injection of formalin into the rat hindpaw in vivo induced significant up-regulation of pERK and pCREB in the rACC, which was inhibited by the NMDAR antago- nist DL-2-amino-5-phospho-novaleric acid. Selective blockade of the NMDAR GluN2B subunit and the glycine- binding site, or degradation of endogenous D-serine, a co-agonist for the glycine site, significantly decreased the up- regulation of pERK and pCREB expression in the rACC. Further, the activated ERK predominantly colocalized with CREB. Conclusion Either the glycine site or the GluN2B subunit of NMDARs participates in the phosphorylation of ERK and CREB induced by bath application of NMDA in brain slices or hindpaw injection of 5% formalin in rats, and these might be fundamental molecular mechanisms underlying pain affect.
基金supported by the National Natural Science Foundations of China(81620108008 and 31971112)the Innovation Capability Support Program of Shaanxi Province,China(2021TD-57).
文摘Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis(CP),but cortical modulation of painful CP remains elusive.Here,we examined the role of the anterior cingulate cortex(ACC)in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid(TNBS).TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats.Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii(NTS)and ACC,and some FOS-expressing neurons in the NTS projected to the ACC.In addition,a larger portion of ascending fibers from the NTS innervated pyramidal neurons,the neural subpopulation primarily expressing FOS under the condition of painful CP,rather than GABAergic neurons within the ACC.CP rats showed increased expression of vesicular glutamate transporter 1,and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor(NMDAR)subunit NR2B and theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)subunit GluR1 within the ACC.Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats,which was similar to the analgesic effect of endomorphins injected into the ACC.Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety,whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats.Taken together,these findings provide neurocircuit,biochemical,and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats,as well as novel insights into the cortical modulation of painful CP,and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.
基金supported by grants from the National Basic Research Development ProgramMinistry of Science and Technology of China(2013CB835100+3 种基金2013BAI04B04)the National Natural Science Foundation of China(8107089981171049)a Military Project of China(AWS12J004)
文摘To explore whether experiencing inflammatory pain has an impact upon intracortical synaptic organization, the planar multi-electrode array （MEA） technique and 2-dimensional current source density （2D-CSD） imaging were used in slice preparations of the anterior cingulate cortex （ACC） from rats. Synaptic activity across different layers of the ACC was evoked by deep layer stimulation through one electrode. The layer-localization of both local field potentials （LFPs） and the spread of current sink calculated by 2D-CSD analysis was characterized pharmacologically. Moreover, the induction of long-term potentiation （LTP） and changes in LTP magnitude were also evaluated. We found that under naive conditions, the current sink was initially generated in layer Ⅵ, then spread to layer Ⅴ and finally confined to layers Ⅱ-Ⅲ. This spatial pattern of current sink movement typically reflected changes in depolarized sites from deep layers （Ⅴ-Ⅵ） to superficial layers （Ⅱ-Ⅲ） where intra- and extra- cortical inputs terminate. In the ACC slices from rats in an inflamed state （for 2 h） caused by intraplantar bee-venom injection, the spatial profile of intra-ACC synaptic organization was significantly changed,showing an enlarged current sink distribution and a leftward shift of the stimulus-response curves relative to the naive and saline controls. The change was more distinct in the superficial layers （Ⅱ-Ⅲ） than in the deep site. In terms of temporal properties, the rate of LTP induction was significantly increased in layers Ⅱ-Ⅲ by inflammatory pain. However, the magnitude of LTP was not significantly enhanced by this treatment. Taken together, these results show that inflammatory pain results in distinct spatial and temporal plasticity of synaptic organization in the ACC, which may lead to altered synaptic transmission and modulation.
基金Lily M.Granados-Dominguez received a grant from CONACYT for graduate studies.
文摘Major depressive disorder (MDD) is a severe, disabling pathology characterized, in addition to affective, cognitive and motor symptoms, by self-focused attention and rumination. During recursive self-focused processes and rumination, the posterior cingulate cortex (PCC) is activated. In vivo proton magnetic resonance spectroscopy (MRS) is a noninvasive imaging technique that can directly assess living biochemistry in localized brain regions. The aim of this study, therefore, was to use 1H-MRS as a means of analyzing brain metabolites in the PCC of a group of first-episode, unmedicated MDD patients. PCC metabolite levels were analyzed at 3-T in a single voxel located bilaterally over the PCC in 7 patients diagnosed for the first time with MDD and with no previous pharmacological treatment, as well as in 9 control subjects. Differences in metabolite levels between groups were compared using independent t-tests. Myo-inositol was significantly higher, and NAA + NAAG/Cr significantly lower, in MDD patients than in controls. The other brain metabolites showed no statistical differences. The present results suggest that alterations in PCC metabolite levels are likely involved in MDD pathophysiology, and may help to improve our understanding of MDD and the role of the PCC in some symptoms of depression.
基金supported by grants from the National Natural Science Foundation of China(81873787,81961128024,32170994,and 82201362)Shanghai Natural Science Foundation(18ZR1424800 and 20ZR1430000)+1 种基金a Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)the innovative research team of high-level local universities in Shanghai.
文摘Itch is an unpleasant sensation that provokes the desire to scratch.While acute itch serves as a protec-tive system to warn the body of external irritating agents,chronic itch is a debilitating but poorly-treated clinical dis-ease leading to repetitive scratching and skin lesions.How-ever,the neural mechanisms underlying the pathophysiol-ogy of chronic itch remain mysterious.Here,we identified a cell type-dependent role of the anterior cingulate cortex(ACC)in controlling chronic itch-related excessive scratch-ing behaviors in mice.Moreover,we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area(VTA)that was critically involved in chronic itch.Furthermore,we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch.Finally,the ACC neurons were shown to predomi-nantly innervate the non-dopaminergic neurons of the VTA.Taken together,our findings uncover a cortex-midbrain cir-cuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.
文摘Stroke is a physiological alteration associated with changes in blood flow that can result in sudden-onset cognitive impairment. It has a heterogenous clinical presentation with varying degrees of severity correlated with specific central nervous system zones or areas, and its prognosis is uncertain. This case study describes a 62-year-old male patient with acquired brain damage of the anterior cingulate cortex as a result of an ischemic event in the territory of the left anterior cerebral artery. Cognitive function was assessed using the neuropsychological executive function and frontal lobe test battery (BANFE-2) as well as other neuropsychological tests. The results show a profile of higher mental functions characterized by the presence of dysexecutive syndrome with marked behavioral alteration and diencephalic amnesia. .
基金The National Natural Science Fund of China(82374561,82174490,81873360)the Research Project of Zhejiang Chinese Medical University(2022JKZKTS44,2022FSYYZZ07)the Zhejiang Medical and Health Science and Technology Program(2021RC098)。
文摘Background:The analgesic effects of multiple electroacupuncture(EA)sessions and single EA sessions differ significantly in pain management.Area 24b(A24b)of the anterior cingulate cortex(ACC)is crucial in pain processing.EA relieves pain by targeting and modulating the neuronal activity within this subregion.However,whether the cumulative effect of EA antinociception is connected to A24b mechanisms has remained unclear.Methods:In our study,we used the Complete Freund's Adjuvant(CFA)model to induce inflammatory pain and the Spared Nerve Injury(SNI)model to induce neuropathic pain,and adult male C57BL/6,FosTRAP,and FosTRAP:Ai9 mice were used as experimental subjects to investigate the cumulative effect of EA antinociception and whether multiple EA sessions and a single EA session regulate different neuronal populations in the A24b.Results:We observed that EA effectively alleviated pain in mice,with three EA sessions yielding superior analgesic effects compared to a single session.Using chemical genetics combined with FosCreER technology to activate EA-TRAPed cells in the A24b,we found that pain relief was more pronounced with three EA sessions.Moreover,chemogenetic inhibition of EA-TRAPed cells in the A24b reversed the analgesic effects of a single EA session but not those of three EA sessions.Fluorescent in situ hybridization results indicated that three EA sessions significantly increased the number of GABAergic neurons in the A24b compared with a single session.Additionally,retrograde tracing revealed that the A24b circuit that monosynaptically innervates EA-TRAPed cells included projections from the central lateral nucleus(CL),lateral mediodorsal thalamic nucleus(MDL),lateral habenula(LHb),dorsal raphe nucleus(DR),caudal linear nucleus of the raphe(CLi),dorsal tuberomamillary nucleus(DTM),periventricular hypothalamic nucleus(Pe)and hippocampal fields CA1,CA2,and CA3.These findings suggest that multiple EA sessions and single EA sessions activated different neuronal populations in the A24b.The enhanced analgesic effect of multiple EA sessions may be attributed to an increase in the proportion of GABAergic neurons within the A24b.Conclusions:Multiple and single EA sessions recruit distinct neuronal populations in A24b,with the stronger analgesic effect of repeated EA linked to a higher proportion of GABAergic neurons in this region.
基金supported by grants from the National Natural Science Foundation of China(82271243 and 82101318)Shaanxi Province Key Research and Development Plan(2024SF-ZDCYL-01-13)+1 种基金the support funding from Fourth Military Medical University(2024JC005,2020AXJHHJ,and XJZT24JC27)Liaoning Provincial Joint Science and Technology Program(2023-MSLH-345).
文摘The anterior cingulate cortex(ACC)has recently been proposed as a key player in the representation of itch stimuli.However,to date,little is known about the contribution of specific ACC interneuron populations to itch processing.Using c-Fos immunolabeling and in vivo Ca2+imaging,we reported that both histamine and chloroquine stimuli-induced acute itch caused a marked enhancement of vasoactive intestinal peptide(VIP)-expressing interneuron activity in the ACC.Behavioral data indicated that optogenetic and chemogenetic activation of these neurons reduced scratching responses related to histaminergic and non-histaminergic acute itch.Similar neural activity and modulatory role of these neurons were seen in mice with chronic itch induced by contact dermatitis.Together,this study highlights the importance of ACC VIP+neurons in modulating itch-related affect and behavior,which may help us to develop novel mechanism-based strategies to treat refractory chronic itch in the clinic.
基金the Beijing Nova Program of Science and Technology(20230484465)the Beijing Natural Science Foundation(J230040)+12 种基金the National Natural Science Foundation of China(82122035,81671774,81630031,and 32300933)the Sci-Tech Innovation 2030–Major Project of Brain Science and Braininspired Intelligence Technology(2021ZD0200600)the National Key R&D Program of China(2017YFC1309902)the Key Research Program of the Chinese Academy of Sciences(ZDBS-SSW-JSC006)the Scientific Foundation of Institute of Psychology,Chinese Academy of Sciences(E2CX4425YZ,E3CX1315,and Y9CX422005)the China Postdoctoral Science Foundation(2019M660847)the China National Postdoctoral Program for Innovative Talents(BX20200360)the Special Research Assistant Program of the Chinese Academy of Sciences(E2CX0624)the Key R&D Program of Sichuan Province(2023YFS0076)the Canadian Institutes of Health Research(CIHR),the National Institutes of Health–US(NIH)the Brain Canada Foundationthe Temerty Family through the Centre for Addiction and Mental Health(CAMH)Foundation and the Campbell Family Research Institutethe China Scholarship Council(202104910248)during a visit of Xiao Chen to the Centre for Addiction and Mental Health is acknowledged.
文摘The subgenual anterior cingulate cortex(sgACC)plays a central role in the pathophysiology of major depressive disorder(MDD).Its functional interactive profile with the left dorsal lateral prefrontal cortex(DLPFC)is associated with transcranial magnetic stimulation(TMS)treatment outcomes.Previous research on sgACC functional connectivity(FC)in MDD has yielded inconsistent results,partly due to small sample sizes and limited statistical power.Furthermore,calculating sgACC-FC to target TMS individually is challenging.We used a large multi-site cross-sectional sample(1660 patients with MDD vs.1341 healthy controls)from Phase Ⅱ of the Depression Imaging REsearch ConsorTium(DIRECT)to systematically delineate case-control difference maps of sgACC-FC.We explored the potential impact of group-level abnormality profiles on TMS target localization and clinical efficacy.Next,we developed an MDD big data-guided,individualized TMS targeting algorithm to integrate group-level statistical maps with individual-level brain activity to individually localize TMS targets.We found enhanced sgACCDLPFC FC in patients with MDD compared with healthy controls(HC).These group differences altered the position of the sgACC anti-correlation peak in the left DLPFC.We showed that the magnitude of case-control differences in the sgACC-FC was related to clinical improvement in two independent clinical samples.This targeting algorithm may generate targets demonstrating stronger associations with clinical efficiency than group-level targets.We reliably delineated MDD-related abnormalities of sgACC-FC profiles in a large,independently ascertained sample and demonstrated the potential impact of such casecontrol differences on FC-guided localization of TMS targets.
基金supported by grants from the National Natural Science Foundation of China(32192410 and 32071000 to T.Chen,and 81620108008 and 82130034 to Y.L.)the National Science and Technology Innovation 2030 Major Program(2021ZD0204403 to Y.L.and 2021ZD0203200-02 to L.Zhang).
文摘Neuropathic pain(NP)represents a considerable clinical challenge,profoundly impacting patients'quality of life.Presently,pharmacotherapy serves as a primary approach for NP alleviation,yet its efficacy often remains suboptimal.Melatonin(MLT),a biologically active compound secreted by the pineal gland,has long been associated with promoting and maintaining sleep.Although recent studies suggest analgesic effects of MLT,the underlying mechanism remains largely unknown,particularly its impact on the cortex In this study,we induced an NP model in mice through spared nerve injury(SNI)and observed a considerable,dose-dependent alleviation in NP symptoms following intraperitoneal or anterior cingulate cortex(ACC)administration of MLT.Our findings further indicated that the NP management of MLT is selectively mediated by MLT-related receptor 2(MT_(2)R),rather than MT_(1)R,on neurons and microglia within the ACC.Transcriptome sequencing,complemented by bioinformatics analysis,implicated MLT in the modulation of Ga(i)and immune-inflammatory signals.Specifically,MLT inhibited the excitability level of pyramidal cells in the ACC by activating the Ga(i)signaling pathway.Simultaneously,MLT attenuated M,polarization and promoted M_(2)polarization of microglia,thereby mitigating the inflammatory response and type Il interferon response within the Acc.These findings unveil a hitherto unrecognized molecular mechanism:an MLT-mediated neuroimmune modulation pathway in the ACC mediated by MT_(2)R.This elucidation sheds light on the regulatory character of MLT in chronic nociceptive pain conditions,offering a prospective therapeutic strategy for NP management.
基金This research was supported-in part by grants from the National Natural Science Foundation of China （Nos. 30870685, 81071142, 81071143 and 81201081） and the Development Project of Science and Technology of Shaanxi Province （Nos. 2008K12-02, 2009K01-65, 2010K16-03-01 and 2010K16-03-02）.
文摘Background Previous animal and neuroimaging studies have demonstrated that brain function in heroin addicted users is impaired. However, the posterior cingulate cortex （PCC） has not received much attention. The purpose of this study was to investigate whether chronic heroin use is associated with craving-related changes in the functional connectivity of the PCC of heroin addicted users. Methods Fourteen male adult chronic heroin users and fifteen age and gender-matched healthy subjects participated in the present study. The participants underwent a resting-state functional magnetic resonance imaging （fMRI） scan and a cue-induced craving task fMRI scan. The activated PCC was identified in the cue-induced craving task by means of a group contrast test. Functional connectivity was analyzed based on resting-state fMRI data in order to determine the correlation between brain regions. The relationship between the connectivity of specific regions and heroin dependence was investigated. Results The activation of PCC, bilateral anterior cingulate cortex, caudate, putamen, precuneus, and thalamus was significant in the heroin group compared to the healthy group in the cue-induced craving task. The detectable functional connectivity of the heroin users was stronger between the PCC and bilateral insula, bilateral dorsal striatum, right inferior parietal Iobule （IPL） and right supramarginal gyrus （P 〈0.001） compared to that of the healthy subjects in the resting-state data analysis. The strength of the functional connectivity, both for the PCC-insula （r=0.60, P 〈0.05） and for PCC-striatum （t=0.58, P 〈0.05）, was positively correlated with the duration of heroin use. Conclusion The altered functional connectivity patterns in the PCC-insula and PCC-striatum areas may be regarded as biomarkers of brain damage severity in chronic heroin users.
基金This work was supported by grants from National Natural Science Foundation of China （#30870685） and Shaanxi Province Science and Technology Development Projection （#2008k12-02）.
文摘Background Previous studies with animal experiments, autopsy, structural magnetic resonance imaging （MRI） and task-related functional MRI （fMRI） have confirmed that brain functional connectivity in addicts has become impaired. The goal of this study was to investigate the alteration of resting-state functional connectivity of the ventral anterior cingulate cortex （vACC） in the heroin abusers＇ brain. Methods Fifteen heroin abusers and fifteen matched healthy volunteers were studied using vACC as the region-of interest （ROI） seed. A 3.0 T scanner with a standard head coil was the imagining apparatus. T2＊-weighted gradient-echo planar imaging （GRE-EPI） was the scanning protocol. A ROI seed based correlation analysis used a SPM5 software package as the tool for all images processing. Results This study showed a functional connection to the insula vACC in heroin abusers. Compared with controls, heroin users showed decreased functional connectivity between the nucleus accumbens （NAc） and vACC, between the parahippocampala gyrus/amgdala （PHC/amygdala） and vACC, between the thalamus and vACC, and between the posterior cingulated cortex/precuneus （PCC/pC） and vACC. Conclusion The altered resting-state functional connectivity to the vACC suggests the neural circuitry on which the addictive drug has an affect and reflects the dysfunction of the addictive brain.
基金partially sponsored by the National Natural Science Foundation of China(NSFC 81425010(L.W.),31630031(L.W.),31500861(Z.Z.),31471109(L.L.)International Partnership Program of Chinese Academy of Sciences,172644KYS820170004(L.W.)+5 种基金External Cooperation Program of the Chinese Academy of Sciences,GJHZ1508(L.W.)Guangdong Provincial Key Laboratory of Brain Connectome and Behavior,2017B030301017(L.W.)Shenzhen Governmental Grants,JCYJ20150529143500959(L.W.),JCYJ20150401150223647(Z.Z.),JCYJ20151030140325151(L.L)Shenzhen Governmental grants KQJSCX20160301144002(L.L.)Shenzhen Discipline Construction Project for Neurobiology DRCSM[2016]1379(L.W.)Ten Thousand Talent Program(L.W.)
文摘The ability to detect conspecific＇s distress is crucial for animal survival. In rodent models, observational fear （OF） occurs when one animal perceives another fear related negative emotions, which may model certain behaviors caused by witnessing traumatic experiences in humans. Anterior cingulate cortex （ACC） has been showed to play a crucial role in OF. However, cellular and neural circuit basis relating to ACC governing OF is poorly understood. Here, we used Designer Receptor Exclusively Activated by a Designer Drug （DREADD） system to investigate the cell type specific circuit mechanism of ACC in OF. Firstly, inhibitory hM4D （Gi） designer receptor together with clozapine N-oxide （CNO） injection was applied to inactivate ACC neurons in the observer mice. We found that, chemogenetic inhibition of ACC resulted in a decreased freezing response in the observer mice. Next, combining PV-ires-Cre mice and Cre-dependent DREADD system, we selectively targeted the ACC parvalbumin （PV） interneurons with the excitatory hM3D （Gq） designer receptor. Activation of ACC PV interneurons following CNO injection reduced freezing response in the observer mice, while had no effect on freezing response in the demon- strator mice. Finally, monosynaptic rabies retrograde tracing revealed that ACC PV interneurons receive inputs from the mediodorsal thalamic nucleus （MD） and the ventromedial thalamic nucleus （VM）, both known for their roles in OF. Taken together, these findings reveal that ACC activation is important for OF, during which PV interneurons in ACC play an important regulatory role. Abnormal function of ACC PV interneurons might contribute to the pathology of empathy- deficits related diseases, such as autism and schizoohrenia.
基金Supported by the Ministry of Science and Technology of China(Grant Nos.2006CB500807 and 2006AA02Z199)the Ministry of Education of China(Program for Changjiang Scholars and Innovative Research Team in University)the National Natural Science Foundation of China(Grant Nos.30225023,30430240 and 30611120530)
文摘The psychostimulant methylphenidate (MPD; also called Ritalin) is a blocker of dopamine and norepi-nephrine transporter. It has been clinically used for treatment of Attention Deficit and Hyperactivity Disorder (ADHD). There have been inconsistent reports regarding the effects of systemically adminis-tered MPD on learning and memory, either in animals or humans. In the present study, we investigated the effect of direct infusion of MPD into the basolateral nucleus of amygdala (BLA) or the anterior cin-gulate cortex (ACC) on conditioned fear memory. Rats were trained on a one-trial step-through inhibi-tory avoidance task. MPD was infused bilaterally into the BLA or the ACC, either at ‘0’ or 6 h post-training. Saline was administered as control. Memory retention was tested 48 h post-training. In-tra-BLA or intra-ACC infusion of MPD ‘0’ h but not 6 h post-training significantly improved 48-h memory retention: the MPD-treated rats had significant longer step-through latency than controls. The present results indicate that action of MPD in the BLA or the ACC produces a beneficial effect on the consoli-dation of inhibitory avoidance memory.
基金the Zhejiang Provincial Natural Science Fund of China(No.LY20H270006)the National Natural Science Fund of China(No.81603690,81873360 and 81603692)the Zhejiang Medical and Health Science and Technology Program(No.2021RC098).
文摘Background:Pain is considered as a multidimensional conscious experience that includes a sensory component and a negative affective-motivational component.Electroacupuncture(EA)is widely used to treat pain and paininduced negative emotions,however,little is known about the mechanisms underlying the effect of EA.Objective:This study investigated the effect of EA on alleviating the anxiety-like behaviors in pain aversion rats and its anterior cingulate cortex(ACC)regulation mechanism.Methods:After a Freund’s complete adjuvant(CFA)-conditioned place aversion(C-CPA)model was established in rats,EA treatment(2/100 Hz,30 min,once/day,4 days totally)was applied at bilateral Zusanli(ST36)and Kunlun(BL60)acupoints.Von Frey filaments were used to measure changes of pain withdrawal threshold(PWT)at indicated time points.Elevated zero maze(EZM)was used to investigate the changes of pain-related anxiety and CPA was used to investigate the changes of pain aversion.The protein expression levels of GAD67,PV,and NPY in ACC were detected by Western blotting.Results:Compared with the control group,the staying time in the"CFA-paired compartment"was significantly reduced,and the PWT was decreased in model group.In the EZM assessment,the distance and the time in open arm,as well as the number of open arm entries of model group were significantly lower than those in the control group.In the CPA assessment,the time spent in the"CFA-paired compartment"was significantly decreased in model group compared with control group,and EA reversed the changes in pain sensation and in pain-related emotions.Western blotting showed that the NPY level,but not the levels of GAD67 and PV,was significantly increased in the ACC of the model group compared to that of the control group.The increased expression of NPY in the ACC was significantly downregulated by EA,while sham EA produced no such effect.Conclusion:EA can effectively relieve the pain and pain-related emotions,and its mechanism may be achieved by down-regulating the expression of NPY in the ACC.
文摘Introduction: Transcranial Magnetic Stimulation (TMS) is a non-invasive technique for brain stimulation. Repetitive TMS (rTMS) over the medial Prefrontal Cortex (mPFC), Broadman Area 10 (BA10) may stimulate transynaptically perigenual Anterior Cingulate Cortex (pACC, BA 33), insula, amigdala, hypothalamus and connected branches of the Autonomic Nervous System (ANS) involved in stressorevoked cardiovascular reactivity. Stressors are associated with an increase in sympathetic cardiac control, a decrease in parasympathetic control, or both, and, consequently, an increase in systolic/stroke volume, total vascular impedance/resistance and heart rate, a decrease of baroreflex sensitivity, i.e., an increase in blood pressure/arterial tension. Objectives and Aims: The present work aims, using TMS and accordingly to Gianaros modeling, based on functional neuroimaging studies and previous neuroanatomical data from animal models, to probe the connectivity of brain systems involved in stressor-evoked cardiovascular reactivity and to explore TMS potential as a tool for detection and stratification of individual differences concerning this reactivity and hemorreological risk factors correlated with the development of Coronary Heart Disease (CHD). Methods: Both subjects, a 52 years old male and a 40 years old female with previous increased Low Frequency (LF)/High Frequency (HF) Heart Rate Variability (HRV) ratios (respectively, 4.209/3.028) without decompensated cardiorespiratory symptoms, gave informed consent, and ethico-legal issues have been observed. Electroencephalographic (EEG) monitoring has been performed for safety purposes. Immediately after administration, over the mPFC, of 15 pulses of rTMS, during 60 second, with an inductive electrical current, at the stimulating coil, of 85.9 Ampère per μsecond and 66 Ampère per μsecond, respectively, for male and female subjects (a “figure-of-eight” coil and magnetic stimulator MagLite, Dantec/Medtronic, have been used), HRV spectrum analysis (cStress software) has been performed (during 5 minutes, in supine position). Results: In both subjects, LF power, HF power and LF/HF ratio results, before and after rTMS administration, pointed towards sympathetic attenuation and parasympathetic augmentation (respectively, in male/female subject: decreased LF power—65.1 nu/69.3 nu, before rTMS;56.1 nu/41.6 nu, after rTMS;increased HF power—15.5 nu/22.9 nu, before rTMS;30.9 nu/45.5 nu, after rTMS). Conclusions: In this preliminary investigation, the existence of a link between “mind” and heart’s function has been put in evidence, through a reversible “virtual” lesion, of brain systems involved in cardiovascular control, caused by TMS. Repetitive TMS over mPFC decreased brain function involved in stressorevoked cardiovascular reactivity, suggesting the importance of TMS in the management of stress-related cardiovascular disorders.
基金the National Basic Research Program of China (973 Program),No.2009CB522900the Leading Talents of Medical Science in Shanghai,No.LJ06019the Shanghai Leading Academic Discipline Project,No.S30304
文摘Previous studies have demonstrated that electroacupuncture therapy is effective in the treatment of irritable bowel syndrome. However, the precise mechanism of this therapy is unknown. The present study served to investigate the effects of electroacupuncture therapy on treatment of patients with diarrhea-predominant irritable bowel syndrome （IBS）. We compared brain activation maps based on the changes of cerebral glucose metabolism obtained by 18-fluorodeoxyglucose positron emission tomography scanning under three conditions： resting, rectal balloon distension and rectal balloon distension plus electroacupuncture. Under the resting condition, compared with healthy controls, IBS patients displayed an increasing regional cerebral metabolic rate of glucose over a wide range： bilateral superior temporal gyrus, right middle occipital gyrus, superior frontal gyrus and bilateral middle frontal gyrus. However, there was no significant activity in the visceral pain center. Compared with the resting condition, under the rectal balloon distension condition, patients with IBS had a greater regional cerebral metabolic rate of glucose in the prefrontal cortex, left anterior cingulate cortex, postcentral gyrus, precentral gyrus and temporal gyrus. Under the rectal balloon distension plus electroacupuncture condition, stimulation by electroacupuncture at Tianshu （ST 25） manifested a decreased regional cerebral metabolic rate of glucose in the left cingulate gyrus, right insula, right caudate nucleus, fusiform gyrus and hippocampal gyrus. Electroacupuncture therapy relieved abdominal pain, distension or discomfort by decreasing glucose metabolism in the brain.
