OBJECTIVE Takeda G protein-coupled receptor 5(TGR5)is recognized as a promising target for type 2 diabetes and metabolic syndrome;its expression has been demonstrat⁃ed in the brain and is thought to be neuroprotec⁃tiv...OBJECTIVE Takeda G protein-coupled receptor 5(TGR5)is recognized as a promising target for type 2 diabetes and metabolic syndrome;its expression has been demonstrat⁃ed in the brain and is thought to be neuroprotec⁃tive.Here,we hypothesize that dysfunction of central TGR5 may contribute to the pathogene⁃sis of depression.METHODS In well-established chronic social defeat stress(CSDS)and chronic restraint stress(CRS)models of depression,we investigated the functional roles of TGR5 in CA3 pyramidal neurons(PyNs)and underlying mech⁃anisms of the neuronal circuit in depression(for in vivo studies,n=10;for in vitro studies,n=5-10)using fiber photometry;optogenetic,chemoge⁃netic,pharmacological,and molecular profiling techniques;and behavioral tests.RESULTS Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs.Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777,a specific agonist,protected against CSDS and CRS,exerting sig⁃nificant antidepressant-like effects that were mediated via CA3 PyN activation.Conversely,genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behav⁃iors.Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in Tgr5 knockout mice exposed to CSDS or CRS.Silencing and stimula⁃tion of CA3 PyNs→somatostatin-GABAergic(gamma-aminobutyric acidergic)neurons of the dorsolateral septum circuit bidirectionally regulat⁃ed depression-like behaviors,and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs.CON⁃CLUSION TGR5 can regulate depression via CA3 PyNs→somatostatin-GABAergic neurons of dorsolateral septum transmission,suggesting that TGR5 could be a novel target for developing antidepressants.展开更多
Limited by the tiny structure of axons,the effects of these axonal hyperpolarizing inputs on neuronal activity have not been directly elucidated.Here,we imitated these processes by simultaneously recording the activit...Limited by the tiny structure of axons,the effects of these axonal hyperpolarizing inputs on neuronal activity have not been directly elucidated.Here,we imitated these processes by simultaneously recording the activities of the somas and proximal axons of cortical pyramidal neurons.We found that spikes and subthreshold potentials propagate between somas and axons with high fidelity.Furthermore,inhibitory inputs on axons have opposite effects on neuronal activity according to their temporal integration with upstream signals.Concurrent with somatic depolarization,inhibitory inputs on axons decrease neuronal excitability and impede spike generation.In addition,following action potentials,inhibitory inputs on an axon increase neuronal spike capacity and improve spike precision.These results indicate that inhibitory inputs on proximal axons have dual regulatory functions in neuronal activity（suppression or facilitation）according to neuronal network patterns.展开更多
There is currently no treatment for effectively slowing the progression of Alzheimer＇s disease, so early prevention is very important. Numerous studies have shown that flavonoids can improve memory impairment. The pr...There is currently no treatment for effectively slowing the progression of Alzheimer＇s disease, so early prevention is very important. Numerous studies have shown that flavonoids can improve memory impairment. The present study investigated the effects of myricetin, a member of the flavonoids, on intracerebroventricular streptozotocin induced neuronal loss and memory impairment in rat models of Alzheimer＇s disease. Myricetin at 5 or 10 mg/kg was intraperitoneally injected into rats over 21 days. Control rats were treated with 10 m L/kg saline. Behavioral test（the shuttle box test） was performed on day 22 to examine learning and memory in rats. Immediately after that, hematoxylin-eosin staining was performed to observe the morphological change in hippocampal CA3 pyramidal neurons. Myricetin greatly increased the number of hippocampal CA3 pyramidal neurons and improved learning and memory impairments in rats with Alzheimer＇s disease. These findings suggest that myricetin is beneficial for treatment of Alzheimer＇s disease.展开更多
The family of voltage-gated potassium Kv2 channels consists of the Kv2.1 and Kv2.2 subtypes.Kv2.1 is constitutively highly phosphorylated in neurons and its function relies on its phosphorylation state.Whether the fun...The family of voltage-gated potassium Kv2 channels consists of the Kv2.1 and Kv2.2 subtypes.Kv2.1 is constitutively highly phosphorylated in neurons and its function relies on its phosphorylation state.Whether the function of Kv2.2 is also dependent on its phosphorylation state remains unknown.Here,we investigated whether Kv2.2 channels can be phosphorylated by protein kinase C(PKC)and examined the effects of PKC-induced phosphorylation on their activity and function.Activation of PKC inhibited Kv2.2 currents and altered their steadystate activation in HEK293 cells.Point mutations and specific antibodies against phosphorylated S481 or S488 demonstrated the importance of these residues for the PKC-dependent modulation of Kv2.2.In layer Ⅱ pyramidal neurons in cortical slices,activation of PKC similarly regulated native Kv2.2 channels and simultaneously reduced the frequency of action potentials.In conclusion,this study provides the first evidence to our knowledge that PKC-induced phosphorylation of the Kv2.2 channel controls the excitability of cortical pyramidal neurons.展开更多
Neurons can be abstractly represented as skeletons due to the filament nature of neurites.With the rapid development of imaging and image analysis techniques,an increasing amount of neuron skeleton data is being produ...Neurons can be abstractly represented as skeletons due to the filament nature of neurites.With the rapid development of imaging and image analysis techniques,an increasing amount of neuron skeleton data is being produced.In some scienti fic studies,it is necessary to dissect the axons and dendrites,which is typically done manually and is both tedious and time-consuming.To automate this process,we have developed a method that relies solely on neuronal skeletons using Geometric Deep Learning(GDL).We demonstrate the effectiveness of this method using pyramidal neurons in mammalian brains,and the results are promising for its application in neuroscience studies.展开更多
Synapse organizers are essential for the development,transmission,and plasticity of synapses.Acting as rare synapse suppressors,the MAM domain containing glycosylphosphatidylinositol anchor(MDGA)proteins contributes t...Synapse organizers are essential for the development,transmission,and plasticity of synapses.Acting as rare synapse suppressors,the MAM domain containing glycosylphosphatidylinositol anchor(MDGA)proteins contributes to synapse organization by inhibiting the formation of the synaptogenic neuroligin-neurexin complex.A previous analysis of MDGA2 mice lacking a single copy of Mdga2 revealed upregulated glutamatergic synapses and behaviors consistent with autism.However,MDGA2 is expressed in diverse cell types and is localized to both excitatory and inhibitory synapses.Differentiating the network versus cell-specific effects of MDGA2 loss-of-function requires a cell-type and brain region-selective strategy.To address this,we generated mice harboring a conditional knockout of Mdga2 restricted to CA1 pyramidal neurons.Here we report that MDGA2 suppresses the density and function of excitatory synapses selectively on pyramidal neurons in the mature hippocampus.Conditional deletion of Mdga2 in CA1 pyramidal neurons of adult mice upregulated miniature and spontaneous excitatory postsynaptic potentials,vesicular glutamate transporter 1 intensity,and neuronal excitability.These effects were limited to glutamatergic synapses as no changes were detected in miniature and spontaneous inhibitory postsynaptic potential properties or vesicular GABA transporter intensity.Functionally,evoked basal synaptic transmission and AMPAR receptor currents were enhanced at glutamatergic inputs.At a behavioral level,memory appeared to be compromised in Mdga2 cKO mice as both novel object recognition and contextual fear conditioning performance were impaired,consistent with deficits in long-term potentiation in the CA3-CA1 pathway.Social affiliation,a behavioral analog of social deficits in autism,was similarly compromised.These results demonstrate that MDGA2 confines the properties of excitatory synapses to CA1 neurons in mature hippocampal circuits,thereby optimizing this network for plasticity,cognition,and social behaviors.展开更多
The axon initial segment(AIS)is a highly specialized axonal compartment where the action potential is initiated.The heterogeneity of AISs has been suggested to occur between interneurons and pyramidal neurons(PyNs),wh...The axon initial segment(AIS)is a highly specialized axonal compartment where the action potential is initiated.The heterogeneity of AISs has been suggested to occur between interneurons and pyramidal neurons(PyNs),which likely contributes to their unique spiking properties.However,whether the various characteristics of AISs can be linked to specific PyN subtypes remains unknown.Here,we report that in the prelimbic cortex(PL)of the mouse,two types of PyNs with axon projections either to the contralateral PL or to the ipsilateral basal lateral amygdala,possess distinct AIS properties reflected by morphology,ion channel expression,action potential initiation,and axo-axonic synaptic inputs from chandelier cells.Furthermore,projection-specific AIS diversity is more prominent in the superficial layer than in the deep layer.Thus,our study reveals the cortical layer-and axon projection-specific heterogeneity of PyN AISs,which may endow the spiking of various PyN types with exquisite modulation.展开更多
The high-order cognitive and executive functions are necessary for an individual to survive.The densely bidirectional innervations between the medial prefrontal cortex(mPFC)and the mediodorsal thalamus(MD)play a vital...The high-order cognitive and executive functions are necessary for an individual to survive.The densely bidirectional innervations between the medial prefrontal cortex(mPFC)and the mediodorsal thalamus(MD)play a vital role in regulating high-order functions.Pyramidal neurons in mPFC have been classified into several subclasses according to their morphological and electrophysi-ological properties,but the properties of the input-specific pyramidal neurons in mPFC remain poorly understood.The present study aimed to profile the morphological and electrophysiological properties of mPFC pyramidal neurons innervated by MD.In the past,the studies for characterizing the morphological and electrophysiological properties of neurons mainly relied on the electrophysiological recording of a large number of neurons and their morphologic reconstructions.But,it is a low efficient method for characterizing the circuit-specific neurons.The present study combined the advantages of traditional morphological and electrophysiological methods with machine learning to address the shortcomings of the past method,to establish a classification model for the morphological and electrophysiological properties of mPFC pyramidal neurons,and to achieve more accurate and efficient identification of the properties from a small size sample of neurons.We labeled MD-innervated pyramidal neurons of mPFC using the trans-synaptic neural circuitry tracing method and obtained their morphological properties using whole-cell patch-clamp recording and morphologic reconstructions.The results showed that the classification model established in the present study could predict the electrophysiological properties of MD-innervated pyramidal neurons based on their morphology.MD-innervated pyramidal neurons exhibit larger basal dendritic length but lower apical dendrite complexity compared to non-MD-innervated neurons in the mPFC.The morphological characteristics of the two subtypes(ET-1 and ET-2)of mPFC pyramidal neurons innervated by MD are different,with the apical dendrites of ET-1 neurons being longer and more complex than those of ET-2 neurons.These results suggest that the electrophysiological properties of MD-innervated pyramidal neurons within mPFC correlate with their morphological properties,indicating that the different roles of these two subclasses in local circuits within PFC,as well as in PFC-cortical/subcortical brain region circuits.展开更多
Hypocretins/orexins are crucial for the regulation of wakefulness by the excitatory actions on multiple subcortical arousal systems. In prefrontal cortex,
Ischemic preconditioning elicited by a non-fatal brief occlusion of blood flow has been applied for an experimental therapeutic strategy against a subsequent fatal ischemic insult. In this study, we investigated the n...Ischemic preconditioning elicited by a non-fatal brief occlusion of blood flow has been applied for an experimental therapeutic strategy against a subsequent fatal ischemic insult. In this study, we investigated the neuroprotective effects of ischemic preconditioning（2-minute transient cerebral ischemia） on calbindin D28k immunoreactivity in the gerbil hippocampal CA1 area following a subsequent fatal transient ischemic insult（5-minute transient cerebral ischemia）. A large number of pyramidal neurons in the hippocampal CA1 area died 4 days after 5-minute transient cerebral ischemia. Ischemic preconditioning reduced the death of pyramidal neurons in the hippocampal CA1 area. Calbindin D28k immunoreactivity was greatly attenuated at 2 days after 5-minute transient cerebral ischemia and it was hardly detected at 5 days post-ischemia. Ischemic preconditioning maintained calbindin D28 k immunoreactivity after transient cerebral ischemia. These findings suggest that ischemic preconditioning can attenuate transient cerebral ischemia-caused damage to the pyramidal neurons in the hippocampal CA1 area through maintaining calbindin D28k immunoreactivity.展开更多
Objective:To elucidate the modulation mechanism of Suanzaoren Decoction(SZRD)on basolateral amygdala(BLA)neuronal activity to alleviate chronic restraint stress(CRS)-related behavioral deficits.Methods:The male C57BL/...Objective:To elucidate the modulation mechanism of Suanzaoren Decoction(SZRD)on basolateral amygdala(BLA)neuronal activity to alleviate chronic restraint stress(CRS)-related behavioral deficits.Methods:The male C57BL/6J mice were assigned to 4 groups using the complete randomization method,including control(CON,n=19),CRS(n=19),SZRD(n=21),and fluoxetine(Flu,n=22)groups.Mice were restrained for 6 h per day,over a 21-d period to establish CRS models.The CON group remained in their cages without food or water during the 6-h matching period.SZRD and Flu groups received intragastric administration of SZRD(4.68 g/kg)and Flu(20 mg/kg)daily,respectively,30 min before restraint for 21 consecutive days.The therapeutic effects of SZRD were evaluated using behavioral tests including the tail suspension test,elevated plus maze test,and forced swimming test.The cellular Fletcher B.Judson murine osteosarcoma proto-oncogene(c-Fos)expression in the BLA was measured using immunofluorescence,while action potential(AP)firing and synaptic transmission in BLA pyramidal neurons were evaluated using whole-cell patch-clamp recordings.Results:SZRD administration significantly increased time spent in the open arms and open-arm entries while reducing immobility time(P<0.05or P<0.01).It downregulated CRS-induced c-Fos expression and AP firing of pyramidal neurons in the BLA(P<0.01).Additionally,SZRD selectively attenuated excitatory(P<0.01),but not inhibitory,synaptic transmission onto BLA pyramidal neurons.Conclusion:SZRD alleviated CRS-induced anxiety-and depression-like behaviors in mice by modulating the excitability and synaptic transmission of BLA pyramidal neurons.展开更多
Background Previous studies demonstrated general anesthetics affect potassium ion channels, which may be one of the mechanisms of general anesthesia. Because the effect of etomidate on potassium channels in rat hippoc...Background Previous studies demonstrated general anesthetics affect potassium ion channels, which may be one of the mechanisms of general anesthesia. Because the effect of etomidate on potassium channels in rat hippocampus which is involved in memory function has not been studied, we investigated the effects of etomidate on both delayed rectifier potassium current （IK（DR）） and transient outward potassium current （I_K（A）） in acutely dissociated rat hippocampal pyramidal neurons.Methods Single rat hippocampal pyramidal neurons from male Wistar rats of 7-10 days were acutely dissociated by enzymatic digestion and mechanical dispersion according to the methods of Kay and Wong with slight modification. Voltage-clamp recordings were performed in the whole-cell patch clamp configuration. Currents were recorded with a List EPC-10 amplifier and data were stored in a computer using Pulse 8.5. Student＇s paired two-tail t test was used for data analysis. Results At the concentration of 100 μmol/L, etomidate significantly inhibited IK（DR） by 49.2% at ＋40 mV when depolarized from -110 mV （P 〈0.01, n=8）, while did not affect IK（A） （/1=8, P 〉0.05）. The IC50value of etomidate for blocking IK（DR）was calculated as 5.4 μmol/L, with a Hill slope of 2.45. At the presence of 10 μmol/L etomidate, the V1/2 of activation curve was shifted from （17.3±1.5） mV to （10.7±9.9） mV （n=8, P 〈0.05）, the V1/2 of inactivation curve was shifted from （-18.3±2.2） mV to （-45.3±9.4） mV （n=8, P 〈0.05）. Etomidate 10 μmol/L shifted both the activation curve and inactivation curve of IK（DR））to negative potential, but mainly affected the inactivation kinetics.Conclusions Etomidate potently inhibited IK（DR） but not IK（A） in rat hippocampal pyramidal neurons. IK（DR） was inhibited by etomidate in a concentration-dependent manner, while IK（A） remained unaffected.展开更多
The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not bee...The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we first compared ischemia-induced effects on p63 expression in the hippocampal regions （CA1-3） between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was significantly slow compared with that in the adult gerbils after transient global cerebral ischemia, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was significantly low compared with that in the sham-operated adult group, p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was significantly decreased at 4 days post-ischemia; however, p63 immunoreactivity in the ischemia-operated young group was significantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These findings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults.展开更多
BACKGROUND： Previous studies have demonstrated the neuroprotective effects of Xiongma drop pill （XMDP） in a mouse model of vascular dementia. Neurotrophic factors play an important role in repair and regeneration o...BACKGROUND： Previous studies have demonstrated the neuroprotective effects of Xiongma drop pill （XMDP） in a mouse model of vascular dementia. Neurotrophic factors play an important role in repair and regeneration of injured neurons. OBJECTIVE： To compare the effects of XMDP and Ginkgo leaf tablets on the appearance and number of hippocampal CA1 pyramidal neurons, as well as neurotrophic factor content in brain tissues, during vascular dementia formation to explore the neuroprotective mechanisms of XMDP. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Laboratory of Pharmacology, College of Pharmacy, Harbin University of Commerce between April 2007 and December 2008. MATERIALS： XMDP was prepared by the College of Pharmacy, Harbin University of Commerce, with each 40 mg pill containing ferulic acid （≥ 0.149 mg） and gastrodin （≥ 0.171 mg）. Ginkgo leaf tablets were purchased from Taiyuan Qianyuan Pharmacy, China. METHODS： Healthy, adult, male, Wistar rats were randomly assigned to 6 groups： sham-operation, model, XMDP （high-, middle-, and low- dose）, and Ginkgo leaf tablets. The 6 groups were subdivided into two subgroups according to administration days, i.e., 30 and 60 days, with 8 animals in each subgroup. Rats in the model, XMDP, and Ginkgo leaf tablets groups were subjected to permanent bilateral ligation of the common carotid artery to establish a vascular dementia model. At 8 days after model establishment, all groups received intragastric administration once daily of the following： 10 mL/kg normal saline in the sham-operation and model groups; 0.4, 0.2, and 0.1 g/kg XMDP in the high-, middle-, and low-dose XMDP groups, respectively; and 50 mg/kg Ginkgo leaf tablets in the Ginkgo leaf tablets group. MAIN OUTCOME MEASURES： Hematoxylin-eosin staining was used to observe appearance and to quantify the number of hippocampal CA1 pyramidal neurons. Brain-derived neurotrophic factor and nerve growth factor concentrations in brain tissues were detected by enzyme-linked immunosorbent assay. RESULTS： Following model establishment, hippocampal CA1 neurons exhibited pathological changes. Compared with the sham-operation group, the number of pyramidal neurons significantly decreased （P 〈 0.05 or P 〈 0.01）, and neurotrophic factor concentration increased in the model rats （P 〈 0.05 or P 〈 0.01）. XMDP attenuated neuronal injury in a dose-dependent manner： the number of pyramidal neurons and neurotrophic factor concentrations were significantly increased compared with the model group （P〈 0.05 or P〈 0.01）. High- and middle-dose XMDP resulted in equivalent effects to Ginkgo leaf tablets. In addition, neurotrophic factor concentrations in all XMDP groups, after 60 days of administration, were remarkably greater than corresponding concentrations at 30 days （P 〈 0.05 or P 〈 0.01 ）. CONCLUSION： Hippocampal CA1 pyramidal cells exhibited pathological injury following establishment of the vascular dementia model. Middle- and high-dose XMDP increased neurotrophic factor expression in the brain of vascular dementia rats, which suggested neuroprotection equivalent to Ginkgo leaf tablets.展开更多
The sensorimotor cortex participates in diverse functions with different reciprocally connected subregions and projection-defined pyramidal neuron types therein,while the fundamental organizational logic of its circui...The sensorimotor cortex participates in diverse functions with different reciprocally connected subregions and projection-defined pyramidal neuron types therein,while the fundamental organizational logic of its circuit elements at the single-cell level is still largely unclear.Here,using mouse Cre driver lines and highresolution whole-brain imaging to selectively trace the axons and dendrites of cortical pyramidal tract(PT)and intratelencephalic(IT)neurons,we reconstructed the complete morphology of 1,023 pyramidal neurons and generated a projectome of 6 subregions within the sensorimotor cortex.Our morphological data revealed substantial hierarchical and layer differences in the axonal innervation patterns of pyramidal neurons.We found that neurons located in the medial motor cortex had more diverse projection patterns than those in the lateral motor and sensory cortices.The morphological characteristics of IT neurons in layer 5 were more complex than those in layer 2/3.Furthermore,the soma location and morphological characteristics of individual neurons exhibited topographic correspondence.Different subregions and layers were composed of different proportions of projection subtypes that innervate downstream areas differentially.While the axonal terminals of PT neuronal population in each cortical subregion were distributed in specific subdomains of the superior colliculus(SC)and zona incerta(Zl),single neurons selectively innervated a combination of these projection targets.Overall,our data provide a comprehensive list of projection types of pyramidal neurons in the sensorimotor cortex and begin to unveilthe organizational principle of these projection types in different subregions and layers.展开更多
Subjective tinnitus is the most common type of tinnitus, which is the manifestation of pathologicalactivities in the brain. It happens in a substantial portion of the general population and brings significantburden to...Subjective tinnitus is the most common type of tinnitus, which is the manifestation of pathologicalactivities in the brain. It happens in a substantial portion of the general population and brings significantburden to the society. Severe subjective tinnitus can lead to depression and insomnia and severely affectspatients’ quality of life. However, due to poor understanding of its etiology and pathogenesis, treatmentof subjective tinnitus remains challenging. In recent decades, a growing number of studies have shownthat subjective tinnitus is related to lesion-induced neural plasticity of auditory and non-auditory centralsystems. This article reviews cellular mechanisms of neural plasticity in subjective tinnitus to providefurther understanding of its pathogenesis.展开更多
In this study,we tried to verify the neuroprotective effect of Chrysanthemum indicum Linne(CIL)extract,which has been used as a botanical drug in East Asia,against ischemic damage and to explore the underlying mechani...In this study,we tried to verify the neuroprotective effect of Chrysanthemum indicum Linne(CIL)extract,which has been used as a botanical drug in East Asia,against ischemic damage and to explore the underlying mechanism involving the anti-inflammatory approach.A gerbil was given CIL extract for 7 consecutive days followed by bilateral carotid artery occlusion to make a cerebral ischemia/reperfusion model.Then,we found that CIL extracts protected pyramidal neurons in the hippocampal CA1 region(CA1)from ischemic damage using neuronal nucleus immunohistochemistry and Fluoro-Jade B histofluorescence.Accordingly,interleukin-13 immunoreactivities in the CA1 pyramidal neurons of CIL-pretreated animals were maintained or increased after cerebral ischemia/reperfusion.These findings indicate that the pre-treatment of CIL can attenuate neuronal damage/death in the brain after cerebral ischemia/reperfusion via an anti-inflammatory approach.展开更多
Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory,resistant to antiepileptic drugs,and has a high recurrence rate.The pathogenesis of temporal lobe epilepsy is complex and...Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory,resistant to antiepileptic drugs,and has a high recurrence rate.The pathogenesis of temporal lobe epilepsy is complex and is not fully understood.Intracellular calcium dynamics have been implicated in temporal lobe epilepsy.However,the effect of fluctuating calcium activity in CA1 pyramidal neurons on temporal lobe epilepsy is unknown,and no longitudinal studies have investigated calcium activity in pyramidal neurons in the hippocampal CA1 and primary motor cortex M1 of freely moving mice.In this study,we used a multichannel fiber photometry system to continuously record calcium signals in CA1 and M1 during the temporal lobe epilepsy process.We found that calcium signals varied according to the grade of temporal lobe epilepsy episodes.In particular,cortical spreading depression,which has recently been frequently used to represent the continuously and substantially increased calcium signals,was found to correspond to complex and severe behavioral characteristics of temporal lobe epilepsy ranging from gradeⅡto gradeⅤ.However,vigorous calcium oscillations and highly synchronized calcium signals in CA1 and M1 were strongly related to convulsive motor seizures.Chemogenetic inhibition of pyramidal neurons in CA1 significantly attenuated the amplitudes of the calcium signals corresponding to gradeⅠepisodes.In addition,the latency of cortical spreading depression was prolonged,and the above-mentioned abnormal calcium signals in CA1 and M1 were also significantly reduced.Intriguingly,it was possible to rescue the altered intracellular calcium dynamics.Via simultaneous analysis of calcium signals and epileptic behaviors,we found that the progression of temporal lobe epilepsy was alleviated when specific calcium signals were reduced,and that the end-point behaviors of temporal lobe epilepsy were improved.Our results indicate that the calcium dynamic between CA1 and M1 may reflect specific epileptic behaviors corresponding to different grades.Furthermore,the selective regulation of abnormal calcium signals in CA1 pyramidal neurons appears to effectively alleviate temporal lobe epilepsy,thereby providing a potential molecular mechanism for a new temporal lobe epilepsy diagnosis and treatment strategy.展开更多
文摘OBJECTIVE Takeda G protein-coupled receptor 5(TGR5)is recognized as a promising target for type 2 diabetes and metabolic syndrome;its expression has been demonstrat⁃ed in the brain and is thought to be neuroprotec⁃tive.Here,we hypothesize that dysfunction of central TGR5 may contribute to the pathogene⁃sis of depression.METHODS In well-established chronic social defeat stress(CSDS)and chronic restraint stress(CRS)models of depression,we investigated the functional roles of TGR5 in CA3 pyramidal neurons(PyNs)and underlying mech⁃anisms of the neuronal circuit in depression(for in vivo studies,n=10;for in vitro studies,n=5-10)using fiber photometry;optogenetic,chemoge⁃netic,pharmacological,and molecular profiling techniques;and behavioral tests.RESULTS Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs.Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777,a specific agonist,protected against CSDS and CRS,exerting sig⁃nificant antidepressant-like effects that were mediated via CA3 PyN activation.Conversely,genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behav⁃iors.Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in Tgr5 knockout mice exposed to CSDS or CRS.Silencing and stimula⁃tion of CA3 PyNs→somatostatin-GABAergic(gamma-aminobutyric acidergic)neurons of the dorsolateral septum circuit bidirectionally regulat⁃ed depression-like behaviors,and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs.CON⁃CLUSION TGR5 can regulate depression via CA3 PyNs→somatostatin-GABAergic neurons of dorsolateral septum transmission,suggesting that TGR5 could be a novel target for developing antidepressants.
基金supported by the National Natural Science Foundation of China,No.31500836,81671288the Natural Science Foundation of Anhui Province of China,No.1608085QH176
文摘Limited by the tiny structure of axons,the effects of these axonal hyperpolarizing inputs on neuronal activity have not been directly elucidated.Here,we imitated these processes by simultaneously recording the activities of the somas and proximal axons of cortical pyramidal neurons.We found that spikes and subthreshold potentials propagate between somas and axons with high fidelity.Furthermore,inhibitory inputs on axons have opposite effects on neuronal activity according to their temporal integration with upstream signals.Concurrent with somatic depolarization,inhibitory inputs on axons decrease neuronal excitability and impede spike generation.In addition,following action potentials,inhibitory inputs on an axon increase neuronal spike capacity and improve spike precision.These results indicate that inhibitory inputs on proximal axons have dual regulatory functions in neuronal activity（suppression or facilitation）according to neuronal network patterns.
基金funded by the Department of Biology,Faculty of Science,Arak University,Iran,No.38156-8-8349
文摘There is currently no treatment for effectively slowing the progression of Alzheimer＇s disease, so early prevention is very important. Numerous studies have shown that flavonoids can improve memory impairment. The present study investigated the effects of myricetin, a member of the flavonoids, on intracerebroventricular streptozotocin induced neuronal loss and memory impairment in rat models of Alzheimer＇s disease. Myricetin at 5 or 10 mg/kg was intraperitoneally injected into rats over 21 days. Control rats were treated with 10 m L/kg saline. Behavioral test（the shuttle box test） was performed on day 22 to examine learning and memory in rats. Immediately after that, hematoxylin-eosin staining was performed to observe the morphological change in hippocampal CA3 pyramidal neurons. Myricetin greatly increased the number of hippocampal CA3 pyramidal neurons and improved learning and memory impairments in rats with Alzheimer＇s disease. These findings suggest that myricetin is beneficial for treatment of Alzheimer＇s disease.
基金supported by the National Natural Science Foundation of China(31771282)the China Postdoctoral Science Foundation(BX20200093 and 2021M690038).
文摘The family of voltage-gated potassium Kv2 channels consists of the Kv2.1 and Kv2.2 subtypes.Kv2.1 is constitutively highly phosphorylated in neurons and its function relies on its phosphorylation state.Whether the function of Kv2.2 is also dependent on its phosphorylation state remains unknown.Here,we investigated whether Kv2.2 channels can be phosphorylated by protein kinase C(PKC)and examined the effects of PKC-induced phosphorylation on their activity and function.Activation of PKC inhibited Kv2.2 currents and altered their steadystate activation in HEK293 cells.Point mutations and specific antibodies against phosphorylated S481 or S488 demonstrated the importance of these residues for the PKC-dependent modulation of Kv2.2.In layer Ⅱ pyramidal neurons in cortical slices,activation of PKC similarly regulated native Kv2.2 channels and simultaneously reduced the frequency of action potentials.In conclusion,this study provides the first evidence to our knowledge that PKC-induced phosphorylation of the Kv2.2 channel controls the excitability of cortical pyramidal neurons.
基金supported by the Simons Foundation,the National Natural Science Foundation of China(No.NSFC61405038)the Fujian provincial fund(No.2020J01453).
文摘Neurons can be abstractly represented as skeletons due to the filament nature of neurites.With the rapid development of imaging and image analysis techniques,an increasing amount of neuron skeleton data is being produced.In some scienti fic studies,it is necessary to dissect the axons and dendrites,which is typically done manually and is both tedious and time-consuming.To automate this process,we have developed a method that relies solely on neuronal skeletons using Geometric Deep Learning(GDL).We demonstrate the effectiveness of this method using pyramidal neurons in mammalian brains,and the results are promising for its application in neuroscience studies.
基金supported by the National Natural Science Foundation of China(82001203,82173819,81871012,and 81571263)the Scientific Research Fund of Zhejiang Provincial Education Department(Y201839276)+3 种基金the Scientific Research Foundation of Zhejiang University City College(X-202103)the R&D Project of Zhejiang(2022C03034)the Natural Science Foundation of Zhejiang Province(LQ23C090001)a Canada Research Chair Award(P2018-0246).
文摘Synapse organizers are essential for the development,transmission,and plasticity of synapses.Acting as rare synapse suppressors,the MAM domain containing glycosylphosphatidylinositol anchor(MDGA)proteins contributes to synapse organization by inhibiting the formation of the synaptogenic neuroligin-neurexin complex.A previous analysis of MDGA2 mice lacking a single copy of Mdga2 revealed upregulated glutamatergic synapses and behaviors consistent with autism.However,MDGA2 is expressed in diverse cell types and is localized to both excitatory and inhibitory synapses.Differentiating the network versus cell-specific effects of MDGA2 loss-of-function requires a cell-type and brain region-selective strategy.To address this,we generated mice harboring a conditional knockout of Mdga2 restricted to CA1 pyramidal neurons.Here we report that MDGA2 suppresses the density and function of excitatory synapses selectively on pyramidal neurons in the mature hippocampus.Conditional deletion of Mdga2 in CA1 pyramidal neurons of adult mice upregulated miniature and spontaneous excitatory postsynaptic potentials,vesicular glutamate transporter 1 intensity,and neuronal excitability.These effects were limited to glutamatergic synapses as no changes were detected in miniature and spontaneous inhibitory postsynaptic potential properties or vesicular GABA transporter intensity.Functionally,evoked basal synaptic transmission and AMPAR receptor currents were enhanced at glutamatergic inputs.At a behavioral level,memory appeared to be compromised in Mdga2 cKO mice as both novel object recognition and contextual fear conditioning performance were impaired,consistent with deficits in long-term potentiation in the CA3-CA1 pathway.Social affiliation,a behavioral analog of social deficits in autism,was similarly compromised.These results demonstrate that MDGA2 confines the properties of excitatory synapses to CA1 neurons in mature hippocampal circuits,thereby optimizing this network for plasticity,cognition,and social behaviors.
基金supported by the National Natural Science Foundation of China(82071450,31972903,and 32000681)Shanghai Pujiang Program(20PJ1401000)+3 种基金the Natural Science Foundation of Shanghai(20ZR1405700)Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01)ZJ Lab,the Shanghai Center for Brain Science and Brain-Inspired Technologythe Fudan Undergraduate Research Opportunities Program(Wangdao 20046).
文摘The axon initial segment(AIS)is a highly specialized axonal compartment where the action potential is initiated.The heterogeneity of AISs has been suggested to occur between interneurons and pyramidal neurons(PyNs),which likely contributes to their unique spiking properties.However,whether the various characteristics of AISs can be linked to specific PyN subtypes remains unknown.Here,we report that in the prelimbic cortex(PL)of the mouse,two types of PyNs with axon projections either to the contralateral PL or to the ipsilateral basal lateral amygdala,possess distinct AIS properties reflected by morphology,ion channel expression,action potential initiation,and axo-axonic synaptic inputs from chandelier cells.Furthermore,projection-specific AIS diversity is more prominent in the superficial layer than in the deep layer.Thus,our study reveals the cortical layer-and axon projection-specific heterogeneity of PyN AISs,which may endow the spiking of various PyN types with exquisite modulation.
基金supported by the National Natural Science Foundation of China(No.31571098,32071026)Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01),ZJ Lab.and Shanghai Center for Brain Science and Brain-Inspired Technology。
文摘The high-order cognitive and executive functions are necessary for an individual to survive.The densely bidirectional innervations between the medial prefrontal cortex(mPFC)and the mediodorsal thalamus(MD)play a vital role in regulating high-order functions.Pyramidal neurons in mPFC have been classified into several subclasses according to their morphological and electrophysi-ological properties,but the properties of the input-specific pyramidal neurons in mPFC remain poorly understood.The present study aimed to profile the morphological and electrophysiological properties of mPFC pyramidal neurons innervated by MD.In the past,the studies for characterizing the morphological and electrophysiological properties of neurons mainly relied on the electrophysiological recording of a large number of neurons and their morphologic reconstructions.But,it is a low efficient method for characterizing the circuit-specific neurons.The present study combined the advantages of traditional morphological and electrophysiological methods with machine learning to address the shortcomings of the past method,to establish a classification model for the morphological and electrophysiological properties of mPFC pyramidal neurons,and to achieve more accurate and efficient identification of the properties from a small size sample of neurons.We labeled MD-innervated pyramidal neurons of mPFC using the trans-synaptic neural circuitry tracing method and obtained their morphological properties using whole-cell patch-clamp recording and morphologic reconstructions.The results showed that the classification model established in the present study could predict the electrophysiological properties of MD-innervated pyramidal neurons based on their morphology.MD-innervated pyramidal neurons exhibit larger basal dendritic length but lower apical dendrite complexity compared to non-MD-innervated neurons in the mPFC.The morphological characteristics of the two subtypes(ET-1 and ET-2)of mPFC pyramidal neurons innervated by MD are different,with the apical dendrites of ET-1 neurons being longer and more complex than those of ET-2 neurons.These results suggest that the electrophysiological properties of MD-innervated pyramidal neurons within mPFC correlate with their morphological properties,indicating that the different roles of these two subclasses in local circuits within PFC,as well as in PFC-cortical/subcortical brain region circuits.
文摘Hypocretins/orexins are crucial for the regulation of wakefulness by the excitatory actions on multiple subcortical arousal systems. In prefrontal cortex,
基金supported by Hallym University Research Fund,2016(HRF-201605-012)Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2016R1A6A3A01011698)
文摘Ischemic preconditioning elicited by a non-fatal brief occlusion of blood flow has been applied for an experimental therapeutic strategy against a subsequent fatal ischemic insult. In this study, we investigated the neuroprotective effects of ischemic preconditioning（2-minute transient cerebral ischemia） on calbindin D28k immunoreactivity in the gerbil hippocampal CA1 area following a subsequent fatal transient ischemic insult（5-minute transient cerebral ischemia）. A large number of pyramidal neurons in the hippocampal CA1 area died 4 days after 5-minute transient cerebral ischemia. Ischemic preconditioning reduced the death of pyramidal neurons in the hippocampal CA1 area. Calbindin D28k immunoreactivity was greatly attenuated at 2 days after 5-minute transient cerebral ischemia and it was hardly detected at 5 days post-ischemia. Ischemic preconditioning maintained calbindin D28 k immunoreactivity after transient cerebral ischemia. These findings suggest that ischemic preconditioning can attenuate transient cerebral ischemia-caused damage to the pyramidal neurons in the hippocampal CA1 area through maintaining calbindin D28k immunoreactivity.
基金Supported by the Natural Science Foundation of Anhui Province(Nos.2108085QH332,2408085MH189)the CHEN Hao's Famous Traditional Chinese Pharmacist Studio of Anhui Province,the Scientific Research Project of Colleges and Universities in Anhui Province(Nos.2024AH051017,KJ2021A0202)+2 种基金the Education Department of Anhui Province Young and Middle-Aged Talent Cultivation Project(No.YQYB2024031)the Students'Innovation and Entrepreneurship Training Program of Anhui Province(No.S202410366078)the Scientific Research Platform and Base Upgrading Plan of Anhui Medical University(No.2021xkjT048)。
文摘Objective:To elucidate the modulation mechanism of Suanzaoren Decoction(SZRD)on basolateral amygdala(BLA)neuronal activity to alleviate chronic restraint stress(CRS)-related behavioral deficits.Methods:The male C57BL/6J mice were assigned to 4 groups using the complete randomization method,including control(CON,n=19),CRS(n=19),SZRD(n=21),and fluoxetine(Flu,n=22)groups.Mice were restrained for 6 h per day,over a 21-d period to establish CRS models.The CON group remained in their cages without food or water during the 6-h matching period.SZRD and Flu groups received intragastric administration of SZRD(4.68 g/kg)and Flu(20 mg/kg)daily,respectively,30 min before restraint for 21 consecutive days.The therapeutic effects of SZRD were evaluated using behavioral tests including the tail suspension test,elevated plus maze test,and forced swimming test.The cellular Fletcher B.Judson murine osteosarcoma proto-oncogene(c-Fos)expression in the BLA was measured using immunofluorescence,while action potential(AP)firing and synaptic transmission in BLA pyramidal neurons were evaluated using whole-cell patch-clamp recordings.Results:SZRD administration significantly increased time spent in the open arms and open-arm entries while reducing immobility time(P<0.05or P<0.01).It downregulated CRS-induced c-Fos expression and AP firing of pyramidal neurons in the BLA(P<0.01).Additionally,SZRD selectively attenuated excitatory(P<0.01),but not inhibitory,synaptic transmission onto BLA pyramidal neurons.Conclusion:SZRD alleviated CRS-induced anxiety-and depression-like behaviors in mice by modulating the excitability and synaptic transmission of BLA pyramidal neurons.
基金This study was supported by a grant from the National Nature Science Foundation of China （No. 30672030）.
文摘Background Previous studies demonstrated general anesthetics affect potassium ion channels, which may be one of the mechanisms of general anesthesia. Because the effect of etomidate on potassium channels in rat hippocampus which is involved in memory function has not been studied, we investigated the effects of etomidate on both delayed rectifier potassium current （IK（DR）） and transient outward potassium current （I_K（A）） in acutely dissociated rat hippocampal pyramidal neurons.Methods Single rat hippocampal pyramidal neurons from male Wistar rats of 7-10 days were acutely dissociated by enzymatic digestion and mechanical dispersion according to the methods of Kay and Wong with slight modification. Voltage-clamp recordings were performed in the whole-cell patch clamp configuration. Currents were recorded with a List EPC-10 amplifier and data were stored in a computer using Pulse 8.5. Student＇s paired two-tail t test was used for data analysis. Results At the concentration of 100 μmol/L, etomidate significantly inhibited IK（DR） by 49.2% at ＋40 mV when depolarized from -110 mV （P 〈0.01, n=8）, while did not affect IK（A） （/1=8, P 〉0.05）. The IC50value of etomidate for blocking IK（DR）was calculated as 5.4 μmol/L, with a Hill slope of 2.45. At the presence of 10 μmol/L etomidate, the V1/2 of activation curve was shifted from （17.3±1.5） mV to （10.7±9.9） mV （n=8, P 〈0.05）, the V1/2 of inactivation curve was shifted from （-18.3±2.2） mV to （-45.3±9.4） mV （n=8, P 〈0.05）. Etomidate 10 μmol/L shifted both the activation curve and inactivation curve of IK（DR））to negative potential, but mainly affected the inactivation kinetics.Conclusions Etomidate potently inhibited IK（DR） but not IK（A） in rat hippocampal pyramidal neurons. IK（DR） was inhibited by etomidate in a concentration-dependent manner, while IK（A） remained unaffected.
基金supported by 2013 Research Grant from Kangwon National University(120131480)Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2014R1A6A3A01056005)
文摘The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we first compared ischemia-induced effects on p63 expression in the hippocampal regions （CA1-3） between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was significantly slow compared with that in the adult gerbils after transient global cerebral ischemia, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was significantly low compared with that in the sham-operated adult group, p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was significantly decreased at 4 days post-ischemia; however, p63 immunoreactivity in the ischemia-operated young group was significantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These findings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults.
基金Natural Science Foundation of Heilongjiang Province, No.D200916the Youth Science Foundation of Heilongjiang Province. No. QC2009C65
文摘BACKGROUND： Previous studies have demonstrated the neuroprotective effects of Xiongma drop pill （XMDP） in a mouse model of vascular dementia. Neurotrophic factors play an important role in repair and regeneration of injured neurons. OBJECTIVE： To compare the effects of XMDP and Ginkgo leaf tablets on the appearance and number of hippocampal CA1 pyramidal neurons, as well as neurotrophic factor content in brain tissues, during vascular dementia formation to explore the neuroprotective mechanisms of XMDP. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Laboratory of Pharmacology, College of Pharmacy, Harbin University of Commerce between April 2007 and December 2008. MATERIALS： XMDP was prepared by the College of Pharmacy, Harbin University of Commerce, with each 40 mg pill containing ferulic acid （≥ 0.149 mg） and gastrodin （≥ 0.171 mg）. Ginkgo leaf tablets were purchased from Taiyuan Qianyuan Pharmacy, China. METHODS： Healthy, adult, male, Wistar rats were randomly assigned to 6 groups： sham-operation, model, XMDP （high-, middle-, and low- dose）, and Ginkgo leaf tablets. The 6 groups were subdivided into two subgroups according to administration days, i.e., 30 and 60 days, with 8 animals in each subgroup. Rats in the model, XMDP, and Ginkgo leaf tablets groups were subjected to permanent bilateral ligation of the common carotid artery to establish a vascular dementia model. At 8 days after model establishment, all groups received intragastric administration once daily of the following： 10 mL/kg normal saline in the sham-operation and model groups; 0.4, 0.2, and 0.1 g/kg XMDP in the high-, middle-, and low-dose XMDP groups, respectively; and 50 mg/kg Ginkgo leaf tablets in the Ginkgo leaf tablets group. MAIN OUTCOME MEASURES： Hematoxylin-eosin staining was used to observe appearance and to quantify the number of hippocampal CA1 pyramidal neurons. Brain-derived neurotrophic factor and nerve growth factor concentrations in brain tissues were detected by enzyme-linked immunosorbent assay. RESULTS： Following model establishment, hippocampal CA1 neurons exhibited pathological changes. Compared with the sham-operation group, the number of pyramidal neurons significantly decreased （P 〈 0.05 or P 〈 0.01）, and neurotrophic factor concentration increased in the model rats （P 〈 0.05 or P 〈 0.01）. XMDP attenuated neuronal injury in a dose-dependent manner： the number of pyramidal neurons and neurotrophic factor concentrations were significantly increased compared with the model group （P〈 0.05 or P〈 0.01）. High- and middle-dose XMDP resulted in equivalent effects to Ginkgo leaf tablets. In addition, neurotrophic factor concentrations in all XMDP groups, after 60 days of administration, were remarkably greater than corresponding concentrations at 30 days （P 〈 0.05 or P 〈 0.01 ）. CONCLUSION： Hippocampal CA1 pyramidal cells exhibited pathological injury following establishment of the vascular dementia model. Middle- and high-dose XMDP increased neurotrophic factor expression in the brain of vascular dementia rats, which suggested neuroprotection equivalent to Ginkgo leaf tablets.
基金supported by the STI2030-Major Projects(nos.2021ZD0201001 and 2021ZD0201002)the National Natural Science Foundation of China(no.32192412)the CAMS Innovation Fund for Medical Sciences(no.2019-12M-5-014).
文摘The sensorimotor cortex participates in diverse functions with different reciprocally connected subregions and projection-defined pyramidal neuron types therein,while the fundamental organizational logic of its circuit elements at the single-cell level is still largely unclear.Here,using mouse Cre driver lines and highresolution whole-brain imaging to selectively trace the axons and dendrites of cortical pyramidal tract(PT)and intratelencephalic(IT)neurons,we reconstructed the complete morphology of 1,023 pyramidal neurons and generated a projectome of 6 subregions within the sensorimotor cortex.Our morphological data revealed substantial hierarchical and layer differences in the axonal innervation patterns of pyramidal neurons.We found that neurons located in the medial motor cortex had more diverse projection patterns than those in the lateral motor and sensory cortices.The morphological characteristics of IT neurons in layer 5 were more complex than those in layer 2/3.Furthermore,the soma location and morphological characteristics of individual neurons exhibited topographic correspondence.Different subregions and layers were composed of different proportions of projection subtypes that innervate downstream areas differentially.While the axonal terminals of PT neuronal population in each cortical subregion were distributed in specific subdomains of the superior colliculus(SC)and zona incerta(Zl),single neurons selectively innervated a combination of these projection targets.Overall,our data provide a comprehensive list of projection types of pyramidal neurons in the sensorimotor cortex and begin to unveilthe organizational principle of these projection types in different subregions and layers.
基金This work was supported by the National Natural Science Foundation of China under Grant[81820108009]Beijing Municipal Science and Technology Commission under Grant[Z161100000116038]+3 种基金Beijing Municipal Health Commission under Grant[2016-1-5014]Beijing Nova Program[Z201100006820133]the National Key Research and Development Project[2019YFC0121302]the National Key Research and Development Project[2019YFC0840707].
文摘Subjective tinnitus is the most common type of tinnitus, which is the manifestation of pathologicalactivities in the brain. It happens in a substantial portion of the general population and brings significantburden to the society. Severe subjective tinnitus can lead to depression and insomnia and severely affectspatients’ quality of life. However, due to poor understanding of its etiology and pathogenesis, treatmentof subjective tinnitus remains challenging. In recent decades, a growing number of studies have shownthat subjective tinnitus is related to lesion-induced neural plasticity of auditory and non-auditory centralsystems. This article reviews cellular mechanisms of neural plasticity in subjective tinnitus to providefurther understanding of its pathogenesis.
基金supported by Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT and Future Planning(NRF-2013R1A2A2A01068190)Hallym University Specialization Fund(HRF-S-13)
文摘In this study,we tried to verify the neuroprotective effect of Chrysanthemum indicum Linne(CIL)extract,which has been used as a botanical drug in East Asia,against ischemic damage and to explore the underlying mechanism involving the anti-inflammatory approach.A gerbil was given CIL extract for 7 consecutive days followed by bilateral carotid artery occlusion to make a cerebral ischemia/reperfusion model.Then,we found that CIL extracts protected pyramidal neurons in the hippocampal CA1 region(CA1)from ischemic damage using neuronal nucleus immunohistochemistry and Fluoro-Jade B histofluorescence.Accordingly,interleukin-13 immunoreactivities in the CA1 pyramidal neurons of CIL-pretreated animals were maintained or increased after cerebral ischemia/reperfusion.These findings indicate that the pre-treatment of CIL can attenuate neuronal damage/death in the brain after cerebral ischemia/reperfusion via an anti-inflammatory approach.
基金supported by the National Natural Science Foundation of China,Nos.62027812(to HS),81771470(to HS),and 82101608(to YL)Tianjin Postgraduate Research and Innovation Project,No.2020YJSS122(to XD)。
文摘Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory,resistant to antiepileptic drugs,and has a high recurrence rate.The pathogenesis of temporal lobe epilepsy is complex and is not fully understood.Intracellular calcium dynamics have been implicated in temporal lobe epilepsy.However,the effect of fluctuating calcium activity in CA1 pyramidal neurons on temporal lobe epilepsy is unknown,and no longitudinal studies have investigated calcium activity in pyramidal neurons in the hippocampal CA1 and primary motor cortex M1 of freely moving mice.In this study,we used a multichannel fiber photometry system to continuously record calcium signals in CA1 and M1 during the temporal lobe epilepsy process.We found that calcium signals varied according to the grade of temporal lobe epilepsy episodes.In particular,cortical spreading depression,which has recently been frequently used to represent the continuously and substantially increased calcium signals,was found to correspond to complex and severe behavioral characteristics of temporal lobe epilepsy ranging from gradeⅡto gradeⅤ.However,vigorous calcium oscillations and highly synchronized calcium signals in CA1 and M1 were strongly related to convulsive motor seizures.Chemogenetic inhibition of pyramidal neurons in CA1 significantly attenuated the amplitudes of the calcium signals corresponding to gradeⅠepisodes.In addition,the latency of cortical spreading depression was prolonged,and the above-mentioned abnormal calcium signals in CA1 and M1 were also significantly reduced.Intriguingly,it was possible to rescue the altered intracellular calcium dynamics.Via simultaneous analysis of calcium signals and epileptic behaviors,we found that the progression of temporal lobe epilepsy was alleviated when specific calcium signals were reduced,and that the end-point behaviors of temporal lobe epilepsy were improved.Our results indicate that the calcium dynamic between CA1 and M1 may reflect specific epileptic behaviors corresponding to different grades.Furthermore,the selective regulation of abnormal calcium signals in CA1 pyramidal neurons appears to effectively alleviate temporal lobe epilepsy,thereby providing a potential molecular mechanism for a new temporal lobe epilepsy diagnosis and treatment strategy.
