BACKGROUND Depression is a prevalent affective disorder,but its pathophysiology remains unclear.Dysfunction in the gamma-aminobutyric acid(GABA)-ergic system may contribute to its onset.Recently,antidepressants(e.g.,b...BACKGROUND Depression is a prevalent affective disorder,but its pathophysiology remains unclear.Dysfunction in the gamma-aminobutyric acid(GABA)-ergic system may contribute to its onset.Recently,antidepressants(e.g.,brexanolone,zuranolone)targeting the GABA-A receptor were introduced.The zona incerta(ZI),an inhibitory subthalamic region mainly composed of GABAergic neurons,has been implicated in emotional regulation.Deep brain stimulation of the ZI in humans affects anxiety and depression symptoms,while activation of ZI neurons in mice can either worsen or alleviate anxiety.Currently,there is no direct evidence linking GABAergic neurons in the ZI to depression-like behaviors in rodents.AIM To explore the relationship between GABAergic neurons in the ZI and depression-like behaviors in mice.METHODS A chronic restraint stress(CRS)model was utilized to induce depression in mice.Whole-cell patch-clamp recordings assessed the excitability changes of GABAergic neurons in the ZI.Additionally,chemogenetic techniques were employed to modulate ZI GABAergic neurons.The performance of the mice in behavioral tests for depression and anxiety was observed.RESULTS The findings indicated that GABAergic neurons in the ZI were closely associated with depression-like behaviors in mice.Twenty-eight days after the CRS model was established,depression-like and anxiety-like behaviors were observed in the mice.The excitability of GABAergic neurons in the ZI was reduced.Chemogenetic activation of these neurons alleviated CRS-induced depression-like and anxiety-like behaviors.Conversely,inhibition of GABAergic neurons in the ZI led to changes in emotion-related behavioral outcomes in mice.CONCLUSION Activity of GABAergic neurons in the ZI was closely associated with depression-like phenotypes in mice,suggesting that these neurons could be a potential therapeutic target for treating depression.展开更多
The period of infancy is important for the formation of social behaviors due to the rapid postnatal development of the brain functions underlying emotions and social skills.Ilustration of the neural circuits involved ...The period of infancy is important for the formation of social behaviors due to the rapid postnatal development of the brain functions underlying emotions and social skills.Ilustration of the neural circuits involved in the developmental process of infant social behaviors could foster new therapies for some social impairments occurring in the infant period.展开更多
Parkinson’s disease(PD)is the second most common and fastest-growing neurodegenerative disorder.In recent years,it has been recognized that neurotransmitters other than dopamine and neuronal systems outside the basal...Parkinson’s disease(PD)is the second most common and fastest-growing neurodegenerative disorder.In recent years,it has been recognized that neurotransmitters other than dopamine and neuronal systems outside the basal ganglia are also related to PD pathogenesis.However,little is known about whether and how the caudal zona incerta(ZIc)regulates parkinsonian motor symptoms.Here,we showed that specific glutamatergic but not GABAergic ZIc^(VgluT2) neurons regulated these symptoms.ZIc^(VgluT2) neuronal activation induced time-locked parkinsonian motor symptoms.In mouse models of PD,the ZIc^(VgluT2) neurons were hyperactive and inhibition of their activity ameliorated the motor deficits.ZIc^(VgluT2) neurons monosynaptically projected to the substantia nigra pars reticulata.Incerta-nigral circuit activation induced parkinsonian motor symptoms.Together,our findings provide a direct link between the ZIc,its glutamatergic neurons,and parkinsonian motor symptoms for the first time,help to better understand the mechanisms of PD,and supply a new important potential therapeutic target for PD.展开更多
The zona incerta(ZI)is involved in various functions and may serve as an integrative node of the circuits for global behavioral modulation.However,the long-range connectivity of different sectors in the mouse ZI has n...The zona incerta(ZI)is involved in various functions and may serve as an integrative node of the circuits for global behavioral modulation.However,the long-range connectivity of different sectors in the mouse ZI has not been comprehensively mapped.Here,we obtained whole-brain images of the input and output connections via fluorescence micro-optical sectioning tomography and viral tracing.The principal regions in the input-output circuits of ZI GABAergic neurons were topologically organized.The 3D distribution of cortical inputs showed rostro-caudal correspondence with different ZI sectors,while the projection fibers from ZI sectors were longitudinally organized in the superior colliculus.Clustering results show that the medial and lateral ZI are two different major functional compartments,and they can be further divided into more subdomains based on projection and input connectivity.This study provides a comprehensive anatomical foundation for understanding how the ZI is involved in integrating different information,conveying motivational states,and modulating global behaviors.展开更多
Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival.The zona incerta(ZI)has been demonstrated to play important roles in fear learning...Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival.The zona incerta(ZI)has been demonstrated to play important roles in fear learning and fear memory,as well as modulating auditory-induced innate defensive behavior.However,whether the neuronal subtypes in the ZI and specific circuits can mediate the innate fear response is largely unknown.Here,we found that somatostatin(SST)-positive neurons in the rostral ZI of mice were activated by a visual innate fear stimulus.Optogenetic inhibition of SST-positive neurons in the rostral ZI resulted in reduced flight responses to an overhead looming stimulus.Optogenetic activation of SST-positive neurons in the rostral ZI induced fear-like defensive behavior including increased immobility and bradycardia.In addition,we demonstrated that manipulation of the GABAergic projections from SST-positive neurons in the rostral ZI to the downstream nucleus reuniens(Re)mediated fear-like defensive behavior.Retrograde trans-synaptic tracing also revealed looming stimulus-activated neurons in the superior colliculus(SC)that projected to the Re-projecting SST-positive neurons in the rostral ZI(SC-ZIrSST-Re pathway).Together,our study elucidates the function of SST-positive neurons in the rostral ZI and the SC-ZIrSST-Re tri-synaptic circuit in mediating the innate fear response.展开更多
AIM:To evaluate different promising magnetic resonance imaging(MRI) methods at 7.0 Tesla(T) for the pre-stereotactic visualization of the zona incerta(ZI).METHODS:Two neuroradiologists qualitatively and quantitatively...AIM:To evaluate different promising magnetic resonance imaging(MRI) methods at 7.0 Tesla(T) for the pre-stereotactic visualization of the zona incerta(ZI).METHODS:Two neuroradiologists qualitatively and quantitatively examined T2-turbo spin-echo(T2-TSE),T1-weighted gradient-echo,as well as FLASH2D-T2Star and susceptibility-weighted imaging(SWI) for the visualization of the ZI at 7.0 T MRI.Delineation and image quality for the ZI were independently examined using a 6-scale grading system.Inter-rater reliability using Cohen's kappa coefficient(κ) were assessed.Contrast-tonoise ratios(CNR),and signal-to-noise ratios(SNR) for the ZI were calculated for all sequences.Differences in delineation,SNR,and CNR between the sequences were statistically assessed using a paired t-test.For the anatomic validation the coronal FLASH2D-T2Star images were co-registered with a stereotactic atlas(Schaltenbrand-Wahren).RESULTS:The rostral part of the ZI(rZI) could easily be identified and was best and reliably visualized in the coronal FLASH2D-T2Star images.The caudal part was not definable in any of the sequences.No major artifacts in the rZI were observed in any of the scans.FLASH2D-T2Star and SWI imaging offered significant higher CNR values for the rZI compared to T2-TSE images(P > 0.05).The co-registration of the coronal FLASH2D-T2Star images with the stereotactic atlas schema(Schaltenbrand-Wahren) confirmed the correct localization of the ZI in all cases.CONCLUSION:FLASH2D-T2Star imaging(particularly coronal view) provides the reliable and currently optimal visualization of the rZI at 7.0 T.These results can facilitate a better and more precise targeting of the caudal part of the ZI than ever before.展开更多
BACKGROUND Hepatitis B cirrhosis(HBC)is a chronic disease characterized by irreversible diffuse liver damage and aggravated by intestinal microbial imbalance and metabolic dysfunction.Although the relationship between...BACKGROUND Hepatitis B cirrhosis(HBC)is a chronic disease characterized by irreversible diffuse liver damage and aggravated by intestinal microbial imbalance and metabolic dysfunction.Although the relationship between certain single probiotics and HBC has been explored,the impact of the complex ready-to-eat Lactobacillus paracasei N1115(LP N1115)supplement on patients with HBC has not been determined.AIM To compare the changes in the microbiota,inflammatory factor levels,and liver function before and after probiotic treatment in HBC patients.METHODS This study included 160 HBC patients diagnosed at the General Hospital of Ningxia Medical University between October 2018 and December 2020.Patients were randomly divided into an intervention group that received LP N1115 supplementation and routine treatment and a control group that received routine treatment only.Fecal samples were collected at the onset and conclusion of the 12-wk intervention period.The structure of the intestinal microbiota and the levels of serological indicators,such as liver function and inflammatory factors,were assessed.RESULTS Following LP N1115 intervention,the intestinal microbial diversity significantly increased in the intervention group(P<0.05),and the structure of the intestinal microbiota was characterized by an increase in the proportions of probiotic microbes and a reduction in harmful bacteria.Additionally,the intervention group demonstrated notable improvements in liver function indices and significantly lower levels of inflammatory factors(P<0.05).CONCLUSION LP N1115 is a promising treatment for ameliorating intestinal microbial imbalance in HBC patients by modulating the structure of the intestinal microbiota,improving liver function,and reducing inflammatory factor levels.展开更多
The functional role of glutamatergic(vGluT2)neurons in the pedunculopontine nucleus(PPN)in modulating motor activity remains controversial.Here,we demonstrated that the activity of vGluT2 neurons in the rostral PPN is...The functional role of glutamatergic(vGluT2)neurons in the pedunculopontine nucleus(PPN)in modulating motor activity remains controversial.Here,we demonstrated that the activity of vGluT2 neurons in the rostral PPN is correlated with locomotion and ipsilateral head-turning.Beyond these motor functions,we found that these rostral PPN-vGluT2 neurons remarkably respond to salient stimuli.Furthermore,we systematically traced the upstream and downstream projections of these neurons and identifed two downstream projections from these neurons to the caudal pontine reticular nucleus/anterior gigantocellular reticular nucleus(PnC/GiA)and the zona incerta(ZI).Our fndings indicate that the projections to the PnC/GiA inhibit movement,consistent with‘pause-and-play’behavior,whereas those to the ZI promote locomotion,and others respond to a new‘pause-switch-play’pattern.Collectively,these fndings elucidate the multifaceted infuence of the PPN on motor functions and provide a robust theoretical framework for understanding its physiological and potential therapeutic implications.展开更多
基金Supported by the Natural Science Foundation of Xiaogan,China,No.XGKJ2023010036.
文摘BACKGROUND Depression is a prevalent affective disorder,but its pathophysiology remains unclear.Dysfunction in the gamma-aminobutyric acid(GABA)-ergic system may contribute to its onset.Recently,antidepressants(e.g.,brexanolone,zuranolone)targeting the GABA-A receptor were introduced.The zona incerta(ZI),an inhibitory subthalamic region mainly composed of GABAergic neurons,has been implicated in emotional regulation.Deep brain stimulation of the ZI in humans affects anxiety and depression symptoms,while activation of ZI neurons in mice can either worsen or alleviate anxiety.Currently,there is no direct evidence linking GABAergic neurons in the ZI to depression-like behaviors in rodents.AIM To explore the relationship between GABAergic neurons in the ZI and depression-like behaviors in mice.METHODS A chronic restraint stress(CRS)model was utilized to induce depression in mice.Whole-cell patch-clamp recordings assessed the excitability changes of GABAergic neurons in the ZI.Additionally,chemogenetic techniques were employed to modulate ZI GABAergic neurons.The performance of the mice in behavioral tests for depression and anxiety was observed.RESULTS The findings indicated that GABAergic neurons in the ZI were closely associated with depression-like behaviors in mice.Twenty-eight days after the CRS model was established,depression-like and anxiety-like behaviors were observed in the mice.The excitability of GABAergic neurons in the ZI was reduced.Chemogenetic activation of these neurons alleviated CRS-induced depression-like and anxiety-like behaviors.Conversely,inhibition of GABAergic neurons in the ZI led to changes in emotion-related behavioral outcomes in mice.CONCLUSION Activity of GABAergic neurons in the ZI was closely associated with depression-like phenotypes in mice,suggesting that these neurons could be a potential therapeutic target for treating depression.
基金supported by grants from the National Natural Science Foundation of China(32125018,32071005,and 32171079)Zhejiang Provincial Natural Science Foundation of China(LD24H090002 and LZ24C090001)+2 种基金the Fundamental Research Funds for the Central Universities(226-2024-00133)the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20211102)the MOE Frontiers Science Center for Brain Science&Brain-Machine Integration of Zhejiang University.
文摘The period of infancy is important for the formation of social behaviors due to the rapid postnatal development of the brain functions underlying emotions and social skills.Ilustration of the neural circuits involved in the developmental process of infant social behaviors could foster new therapies for some social impairments occurring in the infant period.
基金This work was supported by Key Research and Development Program of Guangdong Province(2019B030335001)the Natural Science Foundation of China(31871070,82090031)+4 种基金Key R&D Program of Zhejiang Province(2020C03009)Science and Technology Program of Guangdong(2018B030334001)Funds for Creative Research Groups of China from the National Natural Science Foundation of China(81521062)Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2019PT310023)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-057).
文摘Parkinson’s disease(PD)is the second most common and fastest-growing neurodegenerative disorder.In recent years,it has been recognized that neurotransmitters other than dopamine and neuronal systems outside the basal ganglia are also related to PD pathogenesis.However,little is known about whether and how the caudal zona incerta(ZIc)regulates parkinsonian motor symptoms.Here,we showed that specific glutamatergic but not GABAergic ZIc^(VgluT2) neurons regulated these symptoms.ZIc^(VgluT2) neuronal activation induced time-locked parkinsonian motor symptoms.In mouse models of PD,the ZIc^(VgluT2) neurons were hyperactive and inhibition of their activity ameliorated the motor deficits.ZIc^(VgluT2) neurons monosynaptically projected to the substantia nigra pars reticulata.Incerta-nigral circuit activation induced parkinsonian motor symptoms.Together,our findings provide a direct link between the ZIc,its glutamatergic neurons,and parkinsonian motor symptoms for the first time,help to better understand the mechanisms of PD,and supply a new important potential therapeutic target for PD.
基金National Natural ScienceFoundation of China(61890953 and 31871088)the Chinese Academy of Medical Sciences Innovation Fund forMedical Sciences(2019-12M-5-014)the Director Fund of Wuhan National Laboratory for Optoelectronics.
文摘The zona incerta(ZI)is involved in various functions and may serve as an integrative node of the circuits for global behavioral modulation.However,the long-range connectivity of different sectors in the mouse ZI has not been comprehensively mapped.Here,we obtained whole-brain images of the input and output connections via fluorescence micro-optical sectioning tomography and viral tracing.The principal regions in the input-output circuits of ZI GABAergic neurons were topologically organized.The 3D distribution of cortical inputs showed rostro-caudal correspondence with different ZI sectors,while the projection fibers from ZI sectors were longitudinally organized in the superior colliculus.Clustering results show that the medial and lateral ZI are two different major functional compartments,and they can be further divided into more subdomains based on projection and input connectivity.This study provides a comprehensive anatomical foundation for understanding how the ZI is involved in integrating different information,conveying motivational states,and modulating global behaviors.
基金supported by the Science and Technology Innovation 2030-Major Project of Brain Science and Brain-like Research(2021ZD0202700,2021ZD0202702)the Key-Area Research and Development Program of Guangdong Province(2019B030335001,2018B030334001)+6 种基金the Major Program of the National Natural Science Foundation of China(82090030,82090031)the CAMS Innovation Fund for Medical Sciences(2019-12M-5-057)the Ministry of Science and Technology(2019YFA0110103)the National Natural Science Foundation of China(81870898)the Fundamental Research Funds for the Central Universities(2021FZZX001-37)the Zhejiang Provincial Natural Science Foundation(LR18H090002)the Young Scientist Program of the National Natural Science Foundation of China(82001135).
文摘Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival.The zona incerta(ZI)has been demonstrated to play important roles in fear learning and fear memory,as well as modulating auditory-induced innate defensive behavior.However,whether the neuronal subtypes in the ZI and specific circuits can mediate the innate fear response is largely unknown.Here,we found that somatostatin(SST)-positive neurons in the rostral ZI of mice were activated by a visual innate fear stimulus.Optogenetic inhibition of SST-positive neurons in the rostral ZI resulted in reduced flight responses to an overhead looming stimulus.Optogenetic activation of SST-positive neurons in the rostral ZI induced fear-like defensive behavior including increased immobility and bradycardia.In addition,we demonstrated that manipulation of the GABAergic projections from SST-positive neurons in the rostral ZI to the downstream nucleus reuniens(Re)mediated fear-like defensive behavior.Retrograde trans-synaptic tracing also revealed looming stimulus-activated neurons in the superior colliculus(SC)that projected to the Re-projecting SST-positive neurons in the rostral ZI(SC-ZIrSST-Re pathway).Together,our study elucidates the function of SST-positive neurons in the rostral ZI and the SC-ZIrSST-Re tri-synaptic circuit in mediating the innate fear response.
文摘AIM:To evaluate different promising magnetic resonance imaging(MRI) methods at 7.0 Tesla(T) for the pre-stereotactic visualization of the zona incerta(ZI).METHODS:Two neuroradiologists qualitatively and quantitatively examined T2-turbo spin-echo(T2-TSE),T1-weighted gradient-echo,as well as FLASH2D-T2Star and susceptibility-weighted imaging(SWI) for the visualization of the ZI at 7.0 T MRI.Delineation and image quality for the ZI were independently examined using a 6-scale grading system.Inter-rater reliability using Cohen's kappa coefficient(κ) were assessed.Contrast-tonoise ratios(CNR),and signal-to-noise ratios(SNR) for the ZI were calculated for all sequences.Differences in delineation,SNR,and CNR between the sequences were statistically assessed using a paired t-test.For the anatomic validation the coronal FLASH2D-T2Star images were co-registered with a stereotactic atlas(Schaltenbrand-Wahren).RESULTS:The rostral part of the ZI(rZI) could easily be identified and was best and reliably visualized in the coronal FLASH2D-T2Star images.The caudal part was not definable in any of the sequences.No major artifacts in the rZI were observed in any of the scans.FLASH2D-T2Star and SWI imaging offered significant higher CNR values for the rZI compared to T2-TSE images(P > 0.05).The co-registration of the coronal FLASH2D-T2Star images with the stereotactic atlas schema(Schaltenbrand-Wahren) confirmed the correct localization of the ZI in all cases.CONCLUSION:FLASH2D-T2Star imaging(particularly coronal view) provides the reliable and currently optimal visualization of the rZI at 7.0 T.These results can facilitate a better and more precise targeting of the caudal part of the ZI than ever before.
基金Supported by The Health System Research Project of Ningxia Hui Autonomous Region of China,No.2022-NWKY-061.
文摘BACKGROUND Hepatitis B cirrhosis(HBC)is a chronic disease characterized by irreversible diffuse liver damage and aggravated by intestinal microbial imbalance and metabolic dysfunction.Although the relationship between certain single probiotics and HBC has been explored,the impact of the complex ready-to-eat Lactobacillus paracasei N1115(LP N1115)supplement on patients with HBC has not been determined.AIM To compare the changes in the microbiota,inflammatory factor levels,and liver function before and after probiotic treatment in HBC patients.METHODS This study included 160 HBC patients diagnosed at the General Hospital of Ningxia Medical University between October 2018 and December 2020.Patients were randomly divided into an intervention group that received LP N1115 supplementation and routine treatment and a control group that received routine treatment only.Fecal samples were collected at the onset and conclusion of the 12-wk intervention period.The structure of the intestinal microbiota and the levels of serological indicators,such as liver function and inflammatory factors,were assessed.RESULTS Following LP N1115 intervention,the intestinal microbial diversity significantly increased in the intervention group(P<0.05),and the structure of the intestinal microbiota was characterized by an increase in the proportions of probiotic microbes and a reduction in harmful bacteria.Additionally,the intervention group demonstrated notable improvements in liver function indices and significantly lower levels of inflammatory factors(P<0.05).CONCLUSION LP N1115 is a promising treatment for ameliorating intestinal microbial imbalance in HBC patients by modulating the structure of the intestinal microbiota,improving liver function,and reducing inflammatory factor levels.
基金support from the Optical Imaging Facility and the Animal Facility of the Institute of Neuroscience,Center for Excellence in Brain Science&Intelligence Technology,Chinese Academy of Sciences,supported by the STI2030-Major Projects(2022ZD0205100).
文摘The functional role of glutamatergic(vGluT2)neurons in the pedunculopontine nucleus(PPN)in modulating motor activity remains controversial.Here,we demonstrated that the activity of vGluT2 neurons in the rostral PPN is correlated with locomotion and ipsilateral head-turning.Beyond these motor functions,we found that these rostral PPN-vGluT2 neurons remarkably respond to salient stimuli.Furthermore,we systematically traced the upstream and downstream projections of these neurons and identifed two downstream projections from these neurons to the caudal pontine reticular nucleus/anterior gigantocellular reticular nucleus(PnC/GiA)and the zona incerta(ZI).Our fndings indicate that the projections to the PnC/GiA inhibit movement,consistent with‘pause-and-play’behavior,whereas those to the ZI promote locomotion,and others respond to a new‘pause-switch-play’pattern.Collectively,these fndings elucidate the multifaceted infuence of the PPN on motor functions and provide a robust theoretical framework for understanding its physiological and potential therapeutic implications.
