The prelimbic cortex(PL)is actively engaged in pain modulation.The infralimbic cortex(IL)has been reported to regulate the PL.However,how this regulation affects pain remains unclear.In the present study,we recorded t...The prelimbic cortex(PL)is actively engaged in pain modulation.The infralimbic cortex(IL)has been reported to regulate the PL.However,how this regulation affects pain remains unclear.In the present study,we recorded temporary hyper-activity of PL pyramidal neurons responding to nociceptive stimuli,but a temporary hypofunction of the IL by in vivo electrophysiological recording in rats with peripheral inflammation.Manipulation of the PL or IL had opposite effects on thermal hyperalgesia.Furthermore,the functional connectivity and chemogenetic regulation between the subregions indicated an inhibitory influence of the IL on the PL.Activation of the pathway from the IL to the PL alleviated thermal hyperalgesia,whereas its inhibition exacerbated chronic pain.Overall,our results suggest a new mechanism underlying the role of the medial prefrontal cortex in chronic pain:hypo-function of the IL leads to hyperactivity of the PL,which regulates thermal hyperalgesia,and thus contributes to the chronicity of pain.展开更多
Itch is an unpleasant sensation that urges people and animals to scratch.Neuroimaging studies on itch have yielded extensive correlations with diverse cortical and subcortical regions,including the insular lobe.Howeve...Itch is an unpleasant sensation that urges people and animals to scratch.Neuroimaging studies on itch have yielded extensive correlations with diverse cortical and subcortical regions,including the insular lobe.However,the role and functional specificity of the insular cortex(IC)and its subdivisions in itch mediation remains unclear.Here,we demonstrated by immunohistochemistry and fiber photometry tests,that neurons in both the anterior insular cortex(AIC)and the posterior insular cortex(PIC)are activated during acute itch processes.Pharmacogenetic experiments revealed that nonselective inhibition of global AIC neurons,or selective inhibition of the activity of glutaminergic neurons in the AIC,reduced the scratching behaviors induced by intradermal injection of 5-hydroxytryptamine(5-HT),but not those induced by compound 48/80.However,both nonselective inhibition of global PIC neurons and selective inhibition of glutaminergic neurons in the PIC failed to affect the itching-scratching behaviors induced by either 5-HT or compound 48/80.In addition,pharmacogenetic inhibition of AIC glutaminergic neurons effectively blocked itch-associated conditioned place aversion behavior,and inhibition of AIC glutaminergic neurons projecting to the prelimbic cortex significantly suppressed 5-HT-evoked scratching.These findings provide preliminary evidence that the AIC is involved,at least partially via aversive emotion mediation,in the regulation of 5-HT-,but not compound 48/80-induced itch.展开更多
Dopaminergic neurons in the ventral tegmental area(VTA)play an important role in cognition,emergence from anesthesia,reward,and aversion,and their projection to the cortex is a crucial part of the"bottom-up"...Dopaminergic neurons in the ventral tegmental area(VTA)play an important role in cognition,emergence from anesthesia,reward,and aversion,and their projection to the cortex is a crucial part of the"bottom-up"ascending activating system.The prelimbic cortex(PrL)is one of the important projection regions of the VTA.However,the roles of dopaminergic neurons in the VTA and the VTADA–PrL pathway under sevoflurane anesthesia in rats remain unclear.In this study,we found that intraperitoneal injection and local microinjection of a dopamine D1 receptor agonist(Chloro-APB)into the PrL had an emergence-promoting effect on sevoflurane anesthesia in rats,while injection of a dopamine D1 receptor antagonist(SCH23390)deepened anesthesia.The results of chemogenetics combined with microinjection and optogenetics showed that activating the VTADA–PrL pathway prolonged the induction time and shortened the emergence time of anesthesia.These results demonstrate that the dopaminergic system in the VTA has an emergence-promoting effect and that the bottom-up VTADA–PrL pathway facilitates emergence from sevoflurane anesthesia.展开更多
Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of...Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes.The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation(CSD).We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex(PrL).We then assessed cerebral functional connectivity(FC) using resting-state functional MRI,neuron/astrocyte metabolism using a metabolic kinetics analysis;dendritic spine densities using sparse-labeling;and miniature excitato ry postsynaptic currents(mEPSCs) and action potential(AP) firing rates using whole-cell patchclamp recordings.In addition,we evaluated cognition via a comprehensive set of behavioral tests.Compared with controls,Sirt6 was significantly decreased(P<0.05) in the PrL after CSD,accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus,piriform cortex,motor co rtex,somatosensory co rtex,olfactory tubercle,insular cortex,and cerebellum.Sirt6 ove rexpression reve rsed CSD-induced cognitive impairment and reduced FC.Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4and GABA2synthesis,which could be fully restored via forced Sirt6 expression.Furthermore,Sirt6 ove rexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons.These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network,neuronal glucose metabolism,and glutamatergic neurotransmission.Thus,Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.展开更多
It was demonstrated in the Vogel conflict test (VCT) that the ventral portion of medial prefrontal cortex (vMPFC) of rats is involved with anxiety behavior. Moreover, the vMPFC local glutamatergic and nitrergic system...It was demonstrated in the Vogel conflict test (VCT) that the ventral portion of medial prefrontal cortex (vMPFC) of rats is involved with anxiety behavior. Moreover, the vMPFC local glutamatergic and nitrergic system interaction is involved in modulation of fear conditioning, a model of anxiety. To better understand the role of the MPFC-glutamatergic and nitrergic system on the VTC behavior response, male Wistar rats (250 g) were water deprived for 48 h before the VCT. After 24 h of water deprivation, they were subjected to an initial 3-min non-punished (pre-test) drinking session. Twenty-four hours later bilateral microinjections of NMDA-antagonist LY235959 (4 nmol/200 nL), the specific nNOS inhibitor N-Propyl-L-arginine (N-Propyl –0.08 nmol/200 nL), the NO scavenger Carboxi-PTIO (C-PTIO, 2 nmol/200 nL) or 200nL of vehicle were applied in the vMPFC. After 10 min, the animals were submitted to 3-min punished-licking session. LY235959 increased the number of punished licks. Similar to LY235959, both N-Propyl and C-PTIO also increased the number of punished licks. No changes were observed when LY235959, N-Propyl and C-PTIO were micro- injected into vMPFC surrounding structures such as the cingulate cortex area 1, the corpus callosum and the tenia tecta. In control experiments these drugs did not change neither the number of unpunished licks nor had any effect in the tail-flick test. The results show that NO signaling in the vMPFC can modulate anxiety-behavior in the VCT by control punished behavior. Moreover, this NO modulation could be associated with local glutamatergic activation through NMDA receptors.展开更多
基金supported by the National Natural Foundation of China(32371049,32271053,31872774,81974166,81821092,82101303,32271053,and 32000749)the Beijing Natural Science Foundation(L222016)+1 种基金the China Postdoctoral Science Foundation(2020M670061)the Tianjin Key Laboratory of Brain Science and Neuroengineering.
文摘The prelimbic cortex(PL)is actively engaged in pain modulation.The infralimbic cortex(IL)has been reported to regulate the PL.However,how this regulation affects pain remains unclear.In the present study,we recorded temporary hyper-activity of PL pyramidal neurons responding to nociceptive stimuli,but a temporary hypofunction of the IL by in vivo electrophysiological recording in rats with peripheral inflammation.Manipulation of the PL or IL had opposite effects on thermal hyperalgesia.Furthermore,the functional connectivity and chemogenetic regulation between the subregions indicated an inhibitory influence of the IL on the PL.Activation of the pathway from the IL to the PL alleviated thermal hyperalgesia,whereas its inhibition exacerbated chronic pain.Overall,our results suggest a new mechanism underlying the role of the medial prefrontal cortex in chronic pain:hypo-function of the IL leads to hyperactivity of the PL,which regulates thermal hyperalgesia,and thus contributes to the chronicity of pain.
基金supported by the National Natural Science Foundation of China(82271542)the Natural Science Foundation of Chongqing(cstc2020jcyj-msxm X0391 and cstc2019jcyj-msxm X0269)the Chongqing Medical Scientific Research Project(Joint project of Chongqing Health Commission and Science and Technology Bureau)(2023ZDXM001).
文摘Itch is an unpleasant sensation that urges people and animals to scratch.Neuroimaging studies on itch have yielded extensive correlations with diverse cortical and subcortical regions,including the insular lobe.However,the role and functional specificity of the insular cortex(IC)and its subdivisions in itch mediation remains unclear.Here,we demonstrated by immunohistochemistry and fiber photometry tests,that neurons in both the anterior insular cortex(AIC)and the posterior insular cortex(PIC)are activated during acute itch processes.Pharmacogenetic experiments revealed that nonselective inhibition of global AIC neurons,or selective inhibition of the activity of glutaminergic neurons in the AIC,reduced the scratching behaviors induced by intradermal injection of 5-hydroxytryptamine(5-HT),but not those induced by compound 48/80.However,both nonselective inhibition of global PIC neurons and selective inhibition of glutaminergic neurons in the PIC failed to affect the itching-scratching behaviors induced by either 5-HT or compound 48/80.In addition,pharmacogenetic inhibition of AIC glutaminergic neurons effectively blocked itch-associated conditioned place aversion behavior,and inhibition of AIC glutaminergic neurons projecting to the prelimbic cortex significantly suppressed 5-HT-evoked scratching.These findings provide preliminary evidence that the AIC is involved,at least partially via aversive emotion mediation,in the regulation of 5-HT-,but not compound 48/80-induced itch.
基金supported by the National Natural Science Foundation of China(81801366 and 82001453)and the National Key R&D Program of China(2018YFC2001901).
文摘Dopaminergic neurons in the ventral tegmental area(VTA)play an important role in cognition,emergence from anesthesia,reward,and aversion,and their projection to the cortex is a crucial part of the"bottom-up"ascending activating system.The prelimbic cortex(PrL)is one of the important projection regions of the VTA.However,the roles of dopaminergic neurons in the VTA and the VTADA–PrL pathway under sevoflurane anesthesia in rats remain unclear.In this study,we found that intraperitoneal injection and local microinjection of a dopamine D1 receptor agonist(Chloro-APB)into the PrL had an emergence-promoting effect on sevoflurane anesthesia in rats,while injection of a dopamine D1 receptor antagonist(SCH23390)deepened anesthesia.The results of chemogenetics combined with microinjection and optogenetics showed that activating the VTADA–PrL pathway prolonged the induction time and shortened the emergence time of anesthesia.These results demonstrate that the dopaminergic system in the VTA has an emergence-promoting effect and that the bottom-up VTADA–PrL pathway facilitates emergence from sevoflurane anesthesia.
基金National Natural Science Foundation of China,Nos.81771160 (to ZZ),81671060 (to CC),31970973 (to JW),21921004 (to FX)Translational Medicine and In terdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University,No.ZNJC201934 (to ZZ)。
文摘Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes.The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation(CSD).We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex(PrL).We then assessed cerebral functional connectivity(FC) using resting-state functional MRI,neuron/astrocyte metabolism using a metabolic kinetics analysis;dendritic spine densities using sparse-labeling;and miniature excitato ry postsynaptic currents(mEPSCs) and action potential(AP) firing rates using whole-cell patchclamp recordings.In addition,we evaluated cognition via a comprehensive set of behavioral tests.Compared with controls,Sirt6 was significantly decreased(P<0.05) in the PrL after CSD,accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus,piriform cortex,motor co rtex,somatosensory co rtex,olfactory tubercle,insular cortex,and cerebellum.Sirt6 ove rexpression reve rsed CSD-induced cognitive impairment and reduced FC.Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4and GABA2synthesis,which could be fully restored via forced Sirt6 expression.Furthermore,Sirt6 ove rexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons.These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network,neuronal glucose metabolism,and glutamatergic neurotransmission.Thus,Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.
基金a PhD fellowship from FAPESP(07/06999-9)supported by a grant from FAPESP(2009/03187-9)+1 种基金CNPq(470042/2009-5 and 305996/2008-8)FAEPA
文摘It was demonstrated in the Vogel conflict test (VCT) that the ventral portion of medial prefrontal cortex (vMPFC) of rats is involved with anxiety behavior. Moreover, the vMPFC local glutamatergic and nitrergic system interaction is involved in modulation of fear conditioning, a model of anxiety. To better understand the role of the MPFC-glutamatergic and nitrergic system on the VTC behavior response, male Wistar rats (250 g) were water deprived for 48 h before the VCT. After 24 h of water deprivation, they were subjected to an initial 3-min non-punished (pre-test) drinking session. Twenty-four hours later bilateral microinjections of NMDA-antagonist LY235959 (4 nmol/200 nL), the specific nNOS inhibitor N-Propyl-L-arginine (N-Propyl –0.08 nmol/200 nL), the NO scavenger Carboxi-PTIO (C-PTIO, 2 nmol/200 nL) or 200nL of vehicle were applied in the vMPFC. After 10 min, the animals were submitted to 3-min punished-licking session. LY235959 increased the number of punished licks. Similar to LY235959, both N-Propyl and C-PTIO also increased the number of punished licks. No changes were observed when LY235959, N-Propyl and C-PTIO were micro- injected into vMPFC surrounding structures such as the cingulate cortex area 1, the corpus callosum and the tenia tecta. In control experiments these drugs did not change neither the number of unpunished licks nor had any effect in the tail-flick test. The results show that NO signaling in the vMPFC can modulate anxiety-behavior in the VCT by control punished behavior. Moreover, this NO modulation could be associated with local glutamatergic activation through NMDA receptors.
