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Basal Forebrain Cholinergic Innervation Induces Depression-Like Behaviors Through Ventral subiculum Hyperactivation

Neuroscience Bulletin 2023年第4期39卷 617-630页

作者： Nana Yu Huina Song Guangpin Chu Xu Zhan Bo Liu Yangling Mu Jian-Zhi Wang Yisheng Lu Department of Physiology School of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Department of Pathophysiology Key Laboratory of Ministry of Education for Neurological DisordersSchool of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Department of Physiology and Pathophysiology Sino-UK Joint Laboratory of Brain Function and Injury of Henan ProvinceSchool of Basic MedicineXinxiang Medical UniversityXinxiang453003China Department of Neurobiology School of Basic MedicineHuazhong University of Science and TechnologyWuhan430030China Department of Otorhinolaryngology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China Institute of Brain Research Collaborative Innovation Center for Brain ScienceHuazhong University of Science and TechnologyWuhan430030China

Malfunction of the ventral subiculum(vSub),the main subregion controlling the output connections from the hippocampus,is associated with major depressive disorder(MDD).Although the vSub receives cholinergic innervation from the medial septum and diagonal band of Broca(MSDB),whether and how the MSDB-to-vSub cholinergic circuit is involved in MDD is elusive.Here,we found that chronic unpredictable mild stress(CUMS)induced depression-like behaviors with hyperactivation of vSub neurons,measured by c-fos staining and whole-cell patch-clamp recording.By retrograde and anterograde tracing,we confirmed the dense MSDB cholinergic innervation of the vSub.In addition,transient restraint stress in CUMS increased the level of ACh in the vSub.Furthermore,chemogenetic stimulation of this MSDB-vSub innervation in ChAT-Cre mice induced hyperactivation of vSub pyramidal neurons along with depression-like behaviors;and local infusion of atropine,a muscarinic receptor antagonist,into the vSub attenuated the depression-like behaviors induced by chemogenetic stimulation of this pathway and CUMS.Together,these findings suggest that activating the MSDB-vSub cholinergic pathway induces hyperactivation of vSub pyramidal neurons and depression-like behaviors,revealing a novel circuit underlying vSub pyramidal neuronal hyperactivation and its associated depression.

关键词： Depression Medial septum subiculum Acetylcholine Circuit

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Inhibition of subicular seizure-labeled c-fos+ neurons alleviates cognitive deficit in epilepsy

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中国药理学与毒理学杂志 2023年第7期37卷 482-483页

作者： YANG Lin ZHANG Qi WU Xueqing QIU Xiaoyun FEI Fan LAI Nanxi ZHENG Yuyi ZHANG Mengdi ZHANG Qingyang WANG Yu WANG Fei XU Cenglin RUAN Yeping WANG Yi CHEN Zhong Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province School of Pharmaceutical SciencesZhejiang Chinese Medical University Institute of Pharmacology&Toxicology College of Pharmaceutical SciencesZhejiang University Zhejiang Rehabilitation Medical Center the Third Affiliated HospitalZhejiang Chinese Medical University Epilepsy Center Second Affiliated HospitalSchool of MedicineZhejiang University

OBJECTIVE Cognitive deficit is a common comorbidity in temporal lobe epilepsy(TLE) and that is not well controlled by current therapeutics. Currently,how epileptic seizure affects cognitive performance remains largely unclear. The subiculum is the major output of the hippocampus, which projects to entorhinal cortex and other more distinct brain regions. Physiologically,the subiculum codes spatial working memory and navigation information including place, speed, and trajectory.Importantly, prior studies have noted the importance of the subiculum in the beginning, spreading, and generalizing process of hippocampal seizure. How seizure-activated neurons in subiculum participate in cognitive impairment remains largely elusive. METHODS In this study, we sought to label the subicular seizure-activated c-fos+neurons with a special promoter with enhanced synaptic activity-responsive element E-SARE in the subiculum,combined with chemogenetics and designer receptors exclusively activated by designer drugs(DREADDs), Ca2+fiber photometry approaches, and behavioral tasks, to reveal the role of these neurons in cognitive impairment in epilepsy. RESULTS We found that chemogenetic inhibition of subicular seizure-tagged c-fos+neurons(mainly CaMK Ⅱ α+glutamatergic neurons) alleviates seizure generalization and improves cognitive performance in the hippocampal CA3 kindling TLE model. While inhibition of seizure-labeled c-fos+GABAergic interneuron shows no effect on seizure and cognition. As a comparison, chemogenetic inhibition of the whole subicular CaMK Ⅱ α+neuron impairs cognitive function in na?ve mice in basal condition. Notably, inhibition of subicular seizure-tagged c-fos+neurons enhances the recruitment of cognitionresponsive c-fos+neurons via increasing neural excitability during cognition tasks. CONCLUSION Our results demonstrate that subicular seizure-activated c-fos+neurons contribute to cognitive impairment in TLE, suggesting seizure-tagged c-fos+neurons as the potential therapeutic target to alleviate cognitive impair

关键词： cognitive deficit epilepsy seizuretagged c-fos+ neurons subiculum

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Subicular pyramidal neurons gate drug resistance in temporal lobe epilepsy

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中国药理学与毒理学杂志 2018年第9期32卷 722-723页

作者： XU Ceng-lin WANG Yi CHEN Zhong Department of Pharmacology Key Laboratory of Medical Neurobiology of the Ministry of Health of China College of Pharmaceutical Sciences School of Medicine Zhejiang University Hangzhou 310058 China

OBJECTIVE To understand the underlying mechanisms of drug resistant temporal lobe epilepsy(TLE).METHODS In vivo and vitro electrophysiology,optogenetics and chemogenetics were used in a classic multi-drug resistant TLE model.RESULTS Subicular pyramidal neuron activity was not inhibited by the anti-epileptic drug phenytoin in drug resistant rats.This phenomenon was specific to the subiculum,but did not involve surrounding temporal lobe regions.Selective inhibition of subicular pyramidal neurons by both optogenetics and chemogenetics reversed drug resistance.In contrast,selective activation of subicular pyramidal neurons directly induced drug resistance in drug responsive rats.Furthermore,long-term low frequency stimulation at the subiculum,which is clinically feasible,inhibited the activity of subicular pyramidal neurons and reversed drug resistance.CONCLUSION Subicular pyramidal neurons might be a key ″ switch″ mediating drug resistance in TLE and represent a new potential target for more precise treatment of drug resistant TLE.

关键词： temporal lobe epilepsy subiculum pyramidal neurons

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Neural Circuits Basis of Temporal Lobe Epilepsy

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神经药理学报 2019年第Z1期 11-12页

作者：陈忠中国药学会青年委员会中国药理学会神经精神药理学专业委员会中国药理学学会浙江大学癫痫中心浙江省药理学会

Temporal lobe epilepsy(TLE) is a common type of epilepsy and not well controlled by current treatments,but the underlying cellular/circuit mechanisms remain unclear. The early series of our studies have proved the success of low-frequency stimulation treatment for epilepsy,which was mainly depending on the stimulation target,the stimulation frequency and stimulation time(the therapeutic-window phenomenon). Now,by using optogenetics,multiple-channel EEG analysis,imaging,electrophysiological and molecular techniques,we are continued to investigate the circuit mechanism of therapeutic deep brain stimulation,and found that entorhinal principal neurons mediate antiepileptic "glutamatergic-GABAergic" neuronal circuit for brain stimulation treatments of epilepsy. Meanwhile,we are currently focusing on the interplay of inhibitory and excitatory network in subicular microcircuits especially that related to the generation of generalized seizures(GS) in TLE,and we found that depolarized GABAergic signaling in subicular microcircuit mediates GS in TLE. This may be of therapeutic interest in understanding the pathological neuronal circuitry and further the development of novel therapeutic approaches.

关键词： epilepsy generalized seizure optogenetics subiculum depolarized GABAergic signaling

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Satb2 is required for establishing the identity of retrosplenial cortex

Satb2 is required for establishing the identity of retrosple...

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中国神经科学学会第十二届全国学术会议

作者： Lei Zhang Qiong Zhang Xin Yu Ying Huang Jia-Yin Chen Bing Lang Ning-Ning Song Yu-Qiang Ding Key Laboratory of Arrhythmias Ministry of Education of China East Hospital Tongji University School of Medicine Department of Anatomy and Neurobiology Collaborative Innovation Center for Brain Science Tongji University School of Medicine Mental Health Institute of the Second Xiangya Hospital National Clinical Research Center on Mental Disorders National Technology Institute on Mental Disorders Key Laboratory of Psychiatry and Mental Health of Hunan Province Central South University

The retrosplenial cortex（Rsp） is a transitional cortex located between the neocortex and archicortex（hippocampal formation）, but the molecular mechanism specifying the Rsp from the archicortex remains elusive. We report here that transcription factor Satb2 is required for specifying Rsp identity during its morphogenesis. Satb2 is abundantly expressed in postmitotic Rsp neuron at embryonic day（E） 16.5. In Emx1-Cre;Satb2 flox/flox mice, the boundary between the Rsp and subiculum defined by unique cellular architecture disappears, and Rsp-thalamic projection is absent. Notably, Rspspecific gene is lost and subiculum-specific genes expand into the territory of Rsp in Satb2 CKO mice as early as E17.5. In addition, genes expressed in both Rsp and subiculum lose its unique expression patterns in the Rsp and display similar expression patterns of the subiculum in the absence of Satb2. Furthermore, cell-autonomous role of Satb2 in maintaining Rsp neuron identity is revealed by selective inactivation of Satb2 in Rsp neurons via in utero electroporation. These results indicate that Satb2 is required for the regionalization of Rsp during embryonic development.

关键词： Satb2 retrosplenial cortex cortical regionalization specification subiculum

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Depolarized subicular microcircuits mediate generalized seizure in temporal lobe epilepsy

Depolarized subicular microcircuits mediate generalized seiz...

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中国神经科学学会第十二届全国学术会议

作者： Yi Wang Ceng-Lin Xu Zheng-Hao Xu Cai-Hong Ji Jiao Liang Ying Wang Bin Chen Xiao-Hua Wu Feng Gao Shuang Wang Yi Guo Xiaoming Li Jian-Hong Luo Shu-ming Duan Zhong Chen Department of Pharmacology Key Laboratory of Medical Neurobiology of the Ministry of Health of China College of Pharmaceutical Sciences School of Medicine Zhejiang University Epilepsy Center Second Affiliated Hospital School of Medicine Zhejiang University College of Basic Medical Science Zhejiang Chinese Medical University Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases First Affiliated Hospital School of Medicine Zhejiang University

Secondary generalized seizure（s GS） is a major source of disability in temporal lobe epilepsy（TLE） with unclear cellular/circuit mechanisms. Here we found that clinical TLE patients with s GS showed the reduced volume specifically in the subiculum compared with those without s GS. Further, using optogenetics and extracellular electrophysiological recording in mice models, we found that photoactivation of subicular GABAergic neurons retarded s GS acquisition by inhibiting the firing of pyramidal neurons. While once s GS had been stably acquired, photoactivation of those neurons aggravated s GS expression via depolarized GABAergic signaling. Subicular somatostatin but not parvalbumin subtype GABAergic neurons were not easily depolarized in s GS expression. Finally, photostimulation of subicular pyramidal neurons genetically targeted with proton pump Arch, rather than chloride pump Np HR3.0, alleviated s GS expression. These results demonstrated that depolarized GABAergic signaling in subicular microcircuit mediates s GS in TLE. This may be of therapeutic interest in understanding the pathological neuronal circuitry underlying s GS.

关键词： epilepsy generalized seizure optogenetics subiculum depolarized GABAergic signaling

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Abnormal resting-state functional connectivity of hippocampal subfields in patients with major depressive disorder

Abnormal resting-state functional connectivity of hippocampa...

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第二十二届全国心理学学术会议

作者： Zi Yu Hao Yuan Zhong Ning Zhang Chun Wang School of Psychology Nanjing Normal University Jiangsu Key Laboratory of Mental Health and Cognitive Science Nanjing Normal University Nanjing Brain Hospital Affiliated to Nanjing Medical University Functional Brain Imaging Institute of Nanjing Medical University Cognitive Behavioral Therapy Institute of Nanjing Medical University

Background: Many studies have found that the hippocampus plays a very important role in major depressive disorder(MDD). The hippocampus can be divided into three subfields: the cornu ammonis(CA), dentate gyrus(DG) and subiculum. Each subfield of the hippocampus has a unique function and are differentially associated with the pathological mechanisms of MDD. However, no research exists to describe the resting state functional connectivity of each hippocampal subfield in MDD. Methods: 55 patients with MDD and 25 healthy controls(HCs) matched for gender, age and years of education were obtained. A seed-based method that imposed a template on the whole brain was used to assess the resting-state functional connectivity(rsFC) of each hippocampal subfield. Results: Patients with MDD demonstrated increased connectivity in the left premotor cortex(PMC) and reduced connectivity in the right insula with the CA seed region. Increased connectivity was reported in the left orbitofrontal cortex(OFC) and left ventrolateral prefrontal cortex(vlPFC) with the DG seed region. The subiculum seed region revealed increased connectivity with the left premotor cortex(PMC), the right middle frontal gyrus(MFG), the left ventrolateral prefrontal cortex(vlPFC) and reduced connectivity with the right insula. ROC curves confirmed that the differences between groups were statistically significant. Conclusion: The results suggest that the CA, DG and subiculum have significant involvement with MDD. Specifically, the abnormal functional connectivity of the CA may be related to bias of coding and integration of information in patients with MDD. The abnormal functional connectivity of the DG may be related to the impairment of working memory in patients with MDD, and the abnormal functional connectivity of the subiculum may be related to cognitive impairment and negative emotions in patients with MDD.

关键词： major depressive disorder hippocampal subfields cornu ammonis dentate gyrus subiculum resting-state functional connectivity

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Theta-frequency membrane resonance and its ionic mechanisms in rat subicular pyramidal neurons

Theta-frequency membrane resonance and its ionic mechanisms ...

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中国神经科学学会第四次会员代表大会暨第七届全国学术会议

作者： W.-T.WANG,Y.-H.WAN,J.-L.ZHU,G.-S.LEI,Y.-Y.WANG,P.ZHANG AND S.-J.HU~* Institute of Neuroscience,The Fourth Military Medical University,Xi’an,710033,China

The neuron population of the hippocampal formation exhibits oscillatory activity within the theta frequency band (4-10 Hz),and the intrinsic resonance properties of individual hippocampal neurons contribute to this network oscillation. The subiculum is the pivotal output region of the hippocampal formation and it is involved in many of the physiological and pathological functions of the limbic system.To study the characteristics and underlying mechanisms of resonance activity in subicular pyramidal neurons,we performed whole-cell patch-clamp recordings from these neurons in rat horizontal brain slices.We applied sinusoidal currents with constant amplitudes and linearly increasing frequencies to measure the resonance frequency of subicular pyramidal neurons.We found that the resonance frequency of subicular pyramidal neurons was about 2 Hz at room temperature and 4-6 Hz at 32-35℃.The resonance frequency increased at hyperpolarized membrane potentials and decreased at depolarized membrane potentials.We also investigated three sub-threshold currents involved in the resonance:a slow hyperpolarization-activated cation current;an instantaneously activating,inwardly rectifying potassium current;and an inwardly persistent sodium current.The application of ZD7288 abolished the resonance hump,indicating that hyperpolarization-activated cation current generated resonance.The application of Ba enlarged the resonance hump at hyperpolarized potentials below -80 mV,indicating that inwardly rectifying potassium current attenuated resonance.The application of TTX suppressed the resonance at depolarized potentials,indicating that persistent sodium current amplified resonance when neurons were depolarized.Thus,there is a theta-frequency resonance mediated by hyperpolarizationactivated cation current in subicular pyramidal neurons.This theta-frequency resonance of individual subicular pyramidal neurons may participate in the population’s theta oscillation and contribute to the functions of the subiculum.

关键词： subiculum oscillation hyperpolarization-activated cation current frequency preference.

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Depolarized subicular microcircuitsmediate generalized seizure in temporal lobe epilepsy

Depolarized subicular microcircuitsmediate generalized seizu...

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长三角地区神经科学论坛2017

作者： Yi Wang Cenglin Xu Zhenghao Xu Caihong Ji Jiao Liang Ying Wang Bin Chen Xiaohua Wu Feng Gao Shuang Wang Yi Guo Xiaoming Li Jianhong Luo Shuming Duan Zhong Chen Department of Pharmacology Key Laboratory of Medical Neurobiology of the Ministry of Health of China College of Pharmaceutical Sciences School of Medicine Zhejiang University Epilepsy Center Second Affiliated Hospital School of Medicine Zhejiang University College of Basic Medical Science Zhejiang Chinese Medical University Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases First Affiliated HospitalSchool of Medicine Zhejiang University

Secondary generalized seizure（s GS）is a major source of disability in temporal lobe epilepsy（TLE）with unclear cellular/circuit mechanisms.Here we found that clinical TLE patients with s GS showed the reduced volume specifically in the subiculum compared with those without s GS.Further,using optogeneticsand extracellular electrophysiological recording in mice models,we found that photoactivation of subicular GABA ergic neurons retarded s GS acquisition by inhibiting the firing of pyramidal neurons.While once s GS had been stably acquired,photoactivation of those neurons aggravated s GS expression viadepolarized GABAergic signaling.Subicularsomatostatinbut not parvalbumin subtype GABAergic neuronswere not easily depolarized in s GS expression.Finally,photostimulation of subicularpyramidal neurons genetically targeted with proton pump Arch,rather than chloride pump Np HR3.0,alleviated s GS expression.These results demonstrated that depolarized GABAergic signaling in subicular microcircuit mediatess GS in TLE.This may be oftherapeutic interest in understanding the pathological neuronal circuitry underlying s GS.

关键词： epilepsy generalized seizure optogenetics subiculum depolarized GABAergic signaling

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