Mapping the modulating effect of transcutaneous auricular vagus nerve stimulation on voxel-based analyses in patients with first-episode major depressive disorder: a resting-state functional magnetic resonance imaging study

Introduction: Seed-based analysis has shown that transcutaneous auricular vagus nerve stimulation (taVNS) can modulate the dysfunctional brain network in patients with major depressive disorder (MDD). However, the voxel-based neuropsychological mechanism of taVNS on patients with first-episode MDD is poorly understood. The objective of this study was to assess the effects of an 8-week course of taVNS on patients with first-episode MDD. Methods: Twenty-two patients with first-episode MDD accepted an 8-week course of taVNS treatment. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed before and after treatment. Voxel-based analyses were performed to characterize spontaneous brain activity. Healthy controls (n=23) were recruited to minimize test-retest effects. Analysis of covariance (ANCOVA) was performed to ascertain treatment-related changes. Then, correlations between changes in brain activity and the Hamilton Depression Rating Scale (HAM-D)/Hamilton Anxiety Scale (HAM-A) remission rate were estimated. Results: Significant group-by-time interactions on voxel-based analyses were observed in the inferior ventral striatum (VSi) and precuneus. Post-hoc analyses showed that taVNS inhibited higher brain activity in the VSi, while upregulating it in the precuneus. Functional connectivity (FC) between the VSi and precuneus decreased. Positive correlations were found between the HAM-D remission rate and changes in brain activity in the VSi. Conclusion: taVNS reduced the FC between VSi and precuneus by normalizing the abnormal spontaneous brain activity of VSi in first-episode MDD patients.

Guanxinning Tablet and their active substances alleviate ox-LDL-induced endothelial cell injury / 药学学报

This study investigated the intervention effect of Guanxinning Tablet on human umbilical vein endothelial cells (HUVECs) injury induced by oxidized low density lipoprotein (ox-LDL), providing experimental basis for Guanxinning Tablet in the treatment of atherosclerosis-related diseases. Under the damage of HUVECs by ox-LDL, the cell viability was detected by CCK-8 (cell counting kit-8) assay; lactate dehydrogenase (LDH) in the cell culture supernatant was detected by the corresponding kit; the cell morphology of different groups was observed by common phase contrast microscope; reactive oxygen species (ROS) and NO levels in the cells were detected by DCFH-DA and DAF-FM DA probes, respectively; monocyte adhesion assay was used to detect the recruitment of THP-1 in HUVECs, and TMRM dye was used to detect the level of mitochondrial membrane potential; interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) secretion in the cells was detected by ELISA assay. The results showed that Guanxinning Tablet had a concentration-dependent proliferative effect on HUVECs. Under the stimulation of 100 μg·mL-1 ox-LDL, the morphology of endothelial cells was significantly changed. At this time, NO level was significantly decreased, ROS level was significantly increased and accompanied by a decrease in mitochondrial membrane potential. The recruitment of THP-1 cells by endothelial cells and IL-6, ICAM-1 and MCP-1 were also significantly increased, resulting in oxidative stress and inflammatory injury. Guanxinning Tablet and its composed extracts could significantly improve cell morphology, increase NO level, decrease ROS production, and also reduce the secretion of inflammation-related proteins IL-6 and MCP-1. Salvia miltiorrhiza and Ligusticum striatum DC. have significant synergistic effects on NO. Among them, salvianolic acid B and salvianic acid A exerted the main effects, and the combined efficacy of salvianic acid A and ferulic acid was superior to that of single administration. The above results showed that Guanxinning Tablet and their active substances had the effects of improving endothelial basal function, resisting oxidative stress, and alleviating inflammatory injury, and Salvia miltiorrhiza and Ligusticum striatum DC. synergized, which may be related to their regulation of oxidative stress and inflammation and have application prospects in the treatment of atherosclerosis-related diseases.

Corticostriatal Neurons in the Anterior Auditory Field Regulate Frequency Discrimination Behavior / 神经科学通报·英文版

The anterior auditory field (AAF) is a core region of the auditory cortex and plays a vital role in discrimination tasks. However, the role of the AAF corticostriatal neurons in frequency discrimination remains unclear. Here, we used c-Fos staining, fiber photometry recording, and pharmacogenetic manipulation to investigate the function of the AAF corticostriatal neurons in a frequency discrimination task. c-Fos staining and fiber photometry recording revealed that the activity of AAF pyramidal neurons was significantly elevated during the frequency discrimination task. Pharmacogenetic inhibition of AAF pyramidal neurons significantly impaired frequency discrimination. In addition, histological results revealed that AAF pyramidal neurons send strong projections to the striatum. Moreover, pharmacogenetic suppression of the striatal projections from pyramidal neurons in the AAF significantly disrupted the frequency discrimination. Collectively, our findings show that AAF pyramidal neurons, particularly the AAF-striatum projections, play a crucial role in frequency discrimination behavior.

Functional Autapses Form in Striatal Parvalbumin Interneurons but not Medium Spiny Projection Neurons / 神经科学通报·英文版

Autapses selectively form in specific cell types in many brain regions. Previous studies have also found putative autapses in principal spiny projection neurons (SPNs) in the striatum. However, it remains unclear whether these neurons indeed form physiologically functional autapses. We applied whole-cell recording in striatal slices and identified autaptic cells by the occurrence of prolonged asynchronous release (AR) of neurotransmitters after bursts of high-frequency action potentials (APs). Surprisingly, we found no autaptic AR in SPNs, even in the presence of Sr2+. However, robust autaptic AR was recorded in parvalbumin (PV)-expressing neurons. The autaptic responses were mediated by GABAA receptors and their strength was dependent on AP frequency and number. Further computer simulations suggest that autapses regulate spiking activity in PV cells by providing self-inhibition and thus shape network oscillations. Together, our results indicate that PV neurons, but not SPNs, form functional autapses, which may play important roles in striatal functions.

Electroacupuncture stimulation attenuates corpus striatum white matter injury in rats with cerebral ischemia by inhibition of Nogo-A/NgR pathway / 针灸推拿医学（英文版）

Objective:To investigate the effect and the mechanism of electroacupuncture(EA)on corpus striatum white matter injury in rats with focal cerebral ischemia(FCI).Methods:Forty-four specific-pathogen-free Sprague-Dawley rats were divided into a normal group(n=10),a sham-operation group(sham group,n=10),and a modeling group(n=24)using the random number table method.The normal group was a blank control.In the sham group,only the vessels and vagus nerve were isolated without embolization.The FCI rat model in the modeling group was replicated using the middle cerebral artery occlusion embolization method.The 20 successfully modeled rats were randomly divided into a model group and an EA group,with 10 rats in each group.Rats in the model group did not receive further treatment.Rats in the EA group received EA stimulation at Baihui(GV20)and the left Zusanli(ST36)24 h after the successful modeling,30 min each time,once a day for 14 d.On the 14th day of the experiment,rats in each group were scored for neurological deficits and then sacrificed,and brain tissues containing corpus striatum around the ischemic focus were paraffin-embedded from 5 rats in each group.Luxol fast blue(LFB)staining was used to detect damage changes in the white matter.The positive immunoreactive expression of myelin basic protein(MBP),myelin-associated growth inhibitor A(Nogo-A)and its receptor(NgR)in rat corpus striatum tissue was detected by immunohistochemistry staining,and then the protein expression of MBP,Nogo-A,and NgR in the corpus striatum tissue around the ischemic focus was determined by Western blotting.Results:Compared with the normal group and the sham group,the model group had a significantly higher neurological deficit score(P＜0.05)and fiber bundle injuries in the corpus striatum white matter,evidenced by a significantly lower mean optical density value of corpus striatum LFB staining(P＜0.05),a significantly lower MBP expression level(P＜0.05),and significantly higher Nogo-A and NgR protein expression levels(P＜0.05).Compared with the model group,the neurological deficit score was significantly lower(P＜0.05),the mean optical density value of LFB staining was significantly higher(P＜0.05),the MBP expression level was increased(P＜0.05),and the expression levels of Nogo-A and NgR proteins were decreased(P＜0.05)in the EA group.Conclusion:EA reduces the ischemia-induced corpus striatum white matter injury and improves neurological deficits.The mechanism may be related to the inhibition of Nogo-A/NgR activation.

Modelagem celular in vitro da Doença de Huntington com ácido 3-nitropropiônico e ácido quinolínico & Avaliação das funções neuroprotetoras da adenosina / In vitro cell modeling of Huntington's Disease with 3-nitropropionic acid and quinolinic acid and evaluation of the neuroprotective functions of adenosine

A Doença de Huntington (Huntington's disease - HD) trata-se de uma patologia neurodegenerativa hereditária caracteriza por meio da expressão das proteínas huntingtinas mutantes (mHtt), das mortes dos neurônios espinhais médios (medium spiny neurons MSNs) GABAérgicos D2-positivos do striatum e da hipercinesia. Uma hipótese se refere à função das mHtts de potencializarem os efeitos excitotóxicos das estimulações dos receptores de NMDA (NMDAR) por meio da inibição da succinato desidrogenase, resultando em desequilibrio das [Ca2+]i, estresse oxidativo e apoptose. A adenosina agonista dos receptores purinérgicos P1 tem sido descrita por conta das suas funções neuroprotetoras e neuromodulatórias. Assim, estabelecemos dois modelos in vitro da HD fundamentados nas neurodiferenciações das linhagens murinas de célula-tronco embrionárias E14-TG2a e progenitoras neurais do hipocampo HT-22; seguidas pelos tratamentos com ácido quinolínico (QA) agonista seletivo dos NMDARs , na ausência e na presença do ácido 3-nitropropiônico (3-NP) inibidor irreversível da succinato desidrogenase. Estes modelos foram utilizados nas avaliações das funções neuroprotetoras da adenosina. Os neurônios pós-mitóticos das culturas de E14-TG2a diferenciadas foram caracterizados conforme os MSNs GABAérgicos do striatum; enquanto os neurônios HT-22 diferenciados foram caracterizados de modo inespecífico. Metodologia: imunofluorescência (microscopia e citometria); PCR em tempo real; análise das variações dos potenciais das membranas plasmáticas e das variações transientes das [Ca2+]i por microfluorimetria; e quantificações das reduções do AlamarBlue® (% de sobrevida celular) e das atividades extracelulares de LDH (U/L) (necrose) por espectrometria. Avaliamos a capacidade do 3-NP de potencializar os efeitos excitotóxicos do QA comparando dois grupos de neurônios HT-22 diferenciados: QA 8mM (EC50) (controle); e 3-NP 5mM/QA 8mM. Avaliarmos o potencial neuroprotetor da adenosina comparando quatro grupos de neurônios HT-22 diferenciados: QA 8mM; adenosina 250µM/QA 8mM; 3-NP 5mM/QA 8mM; 3-NP 5mM/adenosina 250µM/QA 8mM. Os neurônios pós-mitóticos derivados das E14TG2a foram classificados como MSNsGABAérgicos do striatum integrantes de uma cultura neuronal heterogênea semelhante às conexões nigroestriatais, corticoestriatais, striatonigral e striatopallidal. Os neurônios HT-22 diferenciados perfaziam uma cultura neuronal heterogênea, não totalmente madura, composta por neurônios glutamatérgicos, dopaminérgicos, colinérgicos e GABAérgicos. Os neurônios HT-22 diferenciados 3-NP 5mM apresentaram menores % de sobrevida celular após os tratamentos com QA 8mM por 24h (p<0.05); e maiores amplitudes das variações das [Ca2+]i dependentes do QA 8mM (p<0.05) (cinética 6 minutos). Por outro lado, os neurônios HT-22 diferenciados pré- tratados com 3-NP 5mM apresentaram menores atividades extracelulares de LDH após o tratamento com QA 8mM por 24h menor proporção de necrose. Os pré-tratamentos com adenosina 250µM indicaram uma tendência dos efeitos neuroprotetores (p>0.05) maiores % de sobrevida celular; menores atividades extracelulares de LDH; e menores amplitudes das variações transientes das [Ca2+]i. Em conjunto, nossos resultados indicam que a inibição da succinato desidrogenase potencializa os efeitos excitotóxicos dos NMDARs por meio da alteração das [Ca2+]i e, provavelmente, dos mecanismos de morte celular; enquanto a adenosina apenas tendeu à neuroproteção

Huntington's disease (HD) is a hereditary neurodegenerative pathology characterized by mutant huntingtin proteins (mHtt) expression, striatum D2-positive GABAergic medium spiny neurons (MSNs) cell death and hyperkinetic motor symptoms development. One hypothesis refers to the principle that mHtt potentiates the excitotoxic effects of NMDA receptor (NMDAR) stimulation by the inhibition of mitochondrial succinate dehydrogenase, resulting in [Ca2+]i imbalance, oxidative stress and apoptosis. Adenosine P1 purinergic receptor agonist is related to neuroprotective and neuromodulatory functions. Thus, we established two in vitro HD models based on the neurodifferentiation of murine embryonic stem cell lines E14-TG2a and hippocampal neuroprogenitor cell line HT-22 followed by treatment with quinolinic acid (QA) selective agonist of NMDARs , in the absence and in the presence of 3-nitropropionic acid (3-NP) irreversible inhibitor of succinate dehydrogenase. These models were used to assess the neuroprotective functions of adenosine. Post-mitotic neurons from differentiated E14-TG2a cultures were characterized according to striatum's GABAergic MSNs; while the differentiated HT-22 neurons were characterized in a non-specific way. Methodology included immunofluorescence (microscopy and cytometry); real-time PCR; analysis of variations in the plasma membrane potentials and of transient variations in the [Ca2+]i by microfluorimetry; and quantification of AlamarBlue® reductions (% cell survival) and of extracellular LDH activity (U/L) (necrosis) by spectrometry. We evaluated the ability of 3-NP to potentiate the excitotoxic effects of QA by comparing two groups of differentiated HT-22 neurons: 8mM QA (control); and 5mM 3-NP/8mM QA. We evaluated the neuroprotective potential of adenosine comparing four groups of differentiated HT-22 neurons: QA 8mM; 250µM adenosine/8mM QA; 5mM 3-NP/8mM QA; 5mM 3-NP/250µM adenosine/8mM QA. Postmitotic neurons derived from E14TG2a were classified as striatums GABAergic MSNs that are part of a heterogeneous neuronal culture similar to nigrostriatal, corticostriatal, striatonigral, and striatopallidal connections. Differentiated HT-22 neurons consisted of a heterogeneous neuronal culture and not fully mature glutamatergic,dopaminergic, cholinergic and GABAergic neurons. Differentiated HT-22 neurons following 5mM 3-NP treatment showed lower % cell survival after treatments with 8mM QA for 24h (p<0.05); and higher amplitudes of the variations of [Ca2+]i induced by 8mM QA (p<0.05) (kinetics 6 minutes). On the other hand, differentiated HT-22 neurons 5mM 3-NP showed lower extracellular LDH activities after treatment with 8mM QA for 24h indicating a lower proportion of necrotic cells. Pretreatments with 250µM adenosine indicated a trend towards neuroprotective effects, such as higher percentages of cell survival; lower extracellular LDH activities; and lower amplitudes of transient variations of [Ca2+]i. Taken together, our results indicate that succinate dehydrogenase inhibition potentiated the excitotoxic effects of NMDARs by altering [Ca2+]i and, probably, cell death mechanisms, while adenosine only to neuroprotection

Acupuncture attenuates comorbid anxiety- and depressive-like behaviors of atopic dermatitis through modulating neuroadaptation in the brain reward circuit in mice

Atopic dermatitis (AD) is highly comorbid with negative emotions such as anxiety and depression. Although acupuncture has demonstrated efficacy in AD, its influence on comorbid anxiety and depression remains unclear. We sought to explore the impact and mechanisms of action of acupuncture on comorbid anxiety and depression of AD. AD-like skin lesions were induced by the topical application of MC903 to the mouse cheek. Acupuncture was performed at Gok-Ji (LI11) acupoints. AD-like phenotypes were quantified by lesion scores, scratching behavior, and histopathological changes. The effects of acupuncture on comorbid anxiety and depression-like behaviors were assessed using the elevated plus-maze (EPM), open-field tests (OFT), and tail-suspension test (TST). In addition, biochemical changes in the brain reward regions were investigated by immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine D1 receptor (D1R), phospho-dopamine and cAMP-regulated phosphoprotein-32 kDa (pDARPP-32), phospho-cAMP response element binding protein (pCREB), ΔFosB, and brain-derived neurotrophic factor (BDNF) in the nucleus accumbens, dorsolateral striatum, and ventral tegmental area. Acupuncture effectively improved the chronic itching and robust AD-like skin lesions with epidermal thickening. Additionally, it considerably reduced comorbid anxiety- and depression-like symptoms, as indicated by more time spent in the open arms of the EPM and in the center of the open field and less time spent immobile in the TST. Higher pCREB, ΔFosB, BDNF, and pDARPP-32 levels, and reduced TH and D1R protein expression in the brain reward regions of AD mice were reversed by acupuncture treatment. The beneficial effects of acupuncture on clinical symptoms (scratching behavior) and comorbid psychological distress in AD strongly correlated with dorsal striatal ΔFosB levels. Collectively, these data indicate that acupuncture had a significant, positive impact on comorbid anxiety- and depression-like behaviors by modulating neuroadaptation in the brain reward circuit in mice with AD, providing a novel perspective for the non-pharmacological management of psychiatric comorbidities of AD.

Functional magnetic resonance imaging study of drug-resistant medial temporal lobe epilepsy / 中华神经科杂志

Objective:To explore the changes of brain activity in drug-resistant or drug-controlled medial temporal lobe epilepsy patients by the method of functional connectivity density (FCD), and to analyze their correlation with the course of the disease.Methods:According to the definition of drug-resistant epilepsy by the International League Against Epilepsy in 2010, 146 patients with medial temporal lobe epilepsy who were clearly diagnosed as unilateral hippocampal sclerosis in Jinling Hospital, Nanjing University School of Medicine from July 2009 to February 2019 were divided into drug control group ( n=73) and drug-resistant group ( n=73). The 3.0 T resting state functional magnetic resonance scan was performed on all subjects to compare the difference in FCD between the two groups, and calculate the correlation between the FCD value of the brain area and the course of the disease between the two groups of patients. Results:There was significant difference between the two groups in FCD. Compared with the drug control group, the drug-resistant group had significantly lower FCD values in the insula, lenticular nucleus, thalamus, hippocampus and precentral gyrus on the side of the epileptogenic focus. The FCD value of the precuneus on the side of the epileptogenic focus in the drug-resistant group was negatively correlated with the duration ( r=-0.30, P=0.01). Conclusions:The FCD of patients with drug-resistant medial temporal lobe epilepsy was lower than that of the drug control group. In addition, there may be progressive damage to the brain. The difference is helpful for exploring the pathophysiological mechanisms related to drug resistance in patients with medial temporal lobe epilepsy, and finding reliable neuroimaging markers related to drug resistance.

Neural mechanism for modulation of auditory response of the striatum by locomotion / 南方医科大学学报

OBJECTIVE@#To explore whether the characteristic responses to sound stimulations of the auditory neurons in the striatum is regulated in different behavioral states.@*METHODS@#The auditory neurons in the striatum of awake C57BL/6J mice were selected for this study. We recorded the auditory response of the striatum to noises over a long period of time by building a synchronous in vivo electrophysiological and locomotion recording system and using glass microelectrode attachment recording. By analyzing the running speed of the mice, the behavioral states of the mice were divided into the quiet state and the active state, and the spontaneous activity and evoked responses of the auditory neurons in the striatum were analyzed in these two states.@*RESULTS@#Compared with those recorded in the quiet state, the spontaneous activity of the auditory neurons in the striatum of the mice increased significantly (37.06±12.02 vs 18.51±10.91, P < 0.001) while the auditory response of the neurons decreased significantly (noise intensity=60 dB, 3.45±2.99 vs 3.04±2.76, P < 0.001) in the active state.@*CONCLUSION@#Locomotion has a significant inhibitory effect on the auditory response of the striatum, which may importantly contribute to the decline of sound information recognition ability in the active state.

Analysis of susceptibility factors and curative effect of corynebacterium striatum detected in sputum of lower respiratory tract the elderly / 中华老年医学杂志

Objective:To observe the susceptibility factors of elderly patients with corynebacterium striata in sputum of lower respiratory tract and analyze its clinical therapeutic effect.Methods:The clinical data of 192 elderly inpatients infected with corynebacterium striatum detected in sputum of lower respiratory tract were retrospectively analyzed in Quanzhou First Hospital Affiliated to Fujian Medical University from January 2019 to June 2021.The detection rate of corynebacterium striata was calculated, and the susceptibility factors and clinical efficacy were compared between the infection group(n=102)and the colonization group(n=90).Results:The detection rate of corynebacterium striata(detected cases / numbers of qualified lower respiratory tract sputum specimen)was 0.8%(72/8976)from January to December 2019, 2.3%(134/5877)from January to December 2020, and 3.0%(121/4 039)from January to June 2021, the difference was statistically significant( χ2=93.93, P<0.01). The detection rates of corynebacterium striatum during three corresponding periods in elderly patients were 0.6%(57/8 976), 1.4%(81/5 877)and 1.9%(78/4 039), respectively, with statistically significant differences( χ2=45.57, P<0.01). The incidences or values of following indexes were higher in infection group than in colonization group: age of patients, admission of intensive care unit, malnutrition, use of hormones, combined use of antibiotics, use of invasive mechanical ventilation, use of fiber bronchoscope, reduced cough reflex, other basic diseases, and so on, but the differences were not statistically significant(all P>0.05). The clinical effective rates were 41.2%(42/102)in the infection group and 48.9%(44/90)in the colonization group, respectively, and the differences was not statistically significant( P>0.05). Only 25 patients(24.5%)in the infected group were treated on corynebacterium striatum according to drug sensitivity results.Among them, the clinical effective rate of the treatment group and the untreated group was 68.0%(17/25)and 32.5%(25/77), respectively, the difference was statistically significant( χ2=9.84, P<0.01). The clinical effective rate of untreated group was lower than that of colonization group, the difference was statistically significant( χ2=4.62, P<0.05). Conclusions:The detection rate of corynebacterium striatum in elderly patients is high, and increases year by year.Patients infected with corynebacterium striatum usually has a variety of susceptibility factors, if not taking effective treatment measures, may have adverse outcomes.In clinical work, it is necessary to pay attention to and reduce the susceptibility factors of corynebacterium striatum, and to correctly interpret the etiological reports, so as to adopt a reasonable and effective therapeutic schedule.

Homeobox Gene Six3 is Required for the Differentiation of D2-Type Medium Spiny Neurons / 神经科学通报·英文版

Medium spiny neurons (MSNs) in the striatum, which can be divided into D1 and D2 MSNs, originate from the lateral ganglionic eminence (LGE). Previously, we reported that Six3 is a downstream target of Sp8/Sp9 in the transcriptional regulatory cascade of D2 MSN development and that conditionally knocking out Six3 leads to a severe loss of D2 MSNs. Here, we showed that Six3 mainly functions in D2 MSN precursor cells and gradually loses its function as D2 MSNs mature. Conditional deletion of Six3 had little effect on cell proliferation but blocked the differentiation of D2 MSN precursor cells. In addition, conditional overexpression of Six3 promoted the differentiation of precursor cells in the LGE. We measured an increase of apoptosis in the postnatal striatum of conditional Six3-knockout mice. This suggests that, in the absence of Six3, abnormally differentiated D2 MSNs are eliminated by programmed cell death. These results further identify Six3 as an important regulatory element during D2 MSN differentiation.

Single Exposure to Cocaine Impairs Reinforcement Learning by Potentiating the Activity of Neurons in the Direct Striatal Pathway in Mice / 神经科学通报·英文版

Plasticity in the glutamatergic synapses on striatal medium spiny neurons (MSNs) is not only essential for behavioral adaptation but also extremely vulnerable to drugs of abuse. Modulation on these synapses by even a single exposure to an addictive drug may interfere with the plasticity required by behavioral learning and thus produce impairment. In the present work, we found that the negative reinforcement learning, escaping mild foot-shocks by correct nose-poking, was impaired by a single in vivo exposure to 20 mg/kg cocaine 24 h before the learning in mice. Either a single exposure to cocaine or reinforcement learning potentiates the glutamatergic synapses on MSNs expressing the striatal dopamine 1 (D1) receptor (D1-MSNs). However, 24 h after the cocaine exposure, the potentiation required for reinforcement learning was disrupted. Specific manipulation of the activity of striatal D1-MSNs in D1-cre mice demonstrated that activation of these MSNs impaired reinforcement learning in normal D1-cre mice, but inhibition of these neurons reversed the reinforcement learning impairment induced by cocaine. The results suggest that cocaine potentiates the activity of direct pathway neurons in the dorsomedial striatum and this potentiation might disrupt the potentiation produced during and required for reinforcement learning.

Joint Multi-modal Parcellation of the Human Striatum: Functions and Clinical Relevance / 神经科学通报·英文版

The human striatum is essential for both low- and high-level functions and has been implicated in the pathophysiology of various prevalent disorders, including Parkinson's disease (PD) and schizophrenia (SCZ). It is known to consist of structurally and functionally divergent subdivisions. However, previous parcellations are based on a single neuroimaging modality, leaving the extent of the multi-modal organization of the striatum unknown. Here, we investigated the organization of the striatum across three modalities-resting-state functional connectivity, probabilistic diffusion tractography, and structural covariance-to provide a holistic convergent view of its structure and function. We found convergent clusters in the dorsal, dorsolateral, rostral, ventral, and caudal striatum. Functional characterization revealed the anterior striatum to be mainly associated with cognitive and emotional functions, while the caudal striatum was related to action execution. Interestingly, significant structural atrophy in the rostral and ventral striatum was common to both PD and SCZ, but atrophy in the dorsolateral striatum was specifically attributable to PD. Our study revealed a cross-modal convergent organization of the striatum, representing a fundamental topographical model that can be useful for investigating structural and functional variability in aging and in clinical conditions.

Effects of Electroacupuncture on Metabolic Changes in Motor Cortex and Striatum of 6-Hydroxydopamine-Induced Parkinsonian Rats / 中国结合医学杂志

OBJECTIVE@#To explore the possible underlying mechanism by investigating the effect of electroacupuncture (EA) treatment on the primary motor cortex and striatum in a unilateral 6-hydroxydopamine (6-OHDA) induced rat Parkinson's disease (PD) model.@*METHODS@#Male Sprague-Dawley rats were randomly divided into sham group (n=16), model group (n=14), and EA group (n=14). EA stimulation at Dazhui (GV 14) and Baihui (GV20) was applied to PD rats in the EA group for 4 weeks. Behavioral tests were conducted to evaluate the effectiveness of EA treatment. Metabolites were detected by 7.0 T proton nuclear magnetic resonance.@*RESULTS@#Following 4 weeks of EA treatment in PD model rats, the abnormal behavioral impairment induced by 6-OHDA was alleviated. In monitoring changes in metabolic activity, ratios of myoinositol/creatine (Cr) and N-acetyl aspartate (NAA)/Cr in the primary motor cortex were significantly lower at the injected side than the non-injected side in PD rats (P=0.024 and 0.020). The ratios of glutamate + glutamine (Glx)/Cr and NAA/Cr in the striatum were higher and lower, respectively, at the injected side than the non-injected side (P=0.046 and 0.008). EA treatment restored the balance of metabolic activity in the primary motor cortex and striatum. In addition, the taurine/Cr ratio and Glx/Cr ratio were elevated in the striatum of PD model rats compared to sham-lesioned rats (P=0.026 and 0.000). EA treatment alleviated the excessive glutamatergic transmission by down-regulating the striatal Glx/Cr ratio (P=0.001). The Glx/Cr ratio was negatively correlated with floor plane spontaneous locomotion in PD rats (P=0.027 and P=0.0007).@*CONCLUSIONS@#EA treatment is able to normalize the metabolic balance in the primary motor cortex and striatum of PD rats, which may contribute to its therapeutic effect on motor deficits. The striatal Glx/Cr ratio may serve as a potential indicator of PD and a therapeutic target of EA treatment.

Joint Multi-modal Parcellation of the Human Striatum: Functions and Clinical Relevance / 神经科学通报·英文版

The human striatum is essential for both low- and high-level functions and has been implicated in the pathophysiology of various prevalent disorders, including Parkinson's disease (PD) and schizophrenia (SCZ). It is known to consist of structurally and functionally divergent subdivisions. However, previous parcellations are based on a single neuroimaging modality, leaving the extent of the multi-modal organization of the striatum unknown. Here, we investigated the organization of the striatum across three modalities-resting-state functional connectivity, probabilistic diffusion tractography, and structural covariance-to provide a holistic convergent view of its structure and function. We found convergent clusters in the dorsal, dorsolateral, rostral, ventral, and caudal striatum. Functional characterization revealed the anterior striatum to be mainly associated with cognitive and emotional functions, while the caudal striatum was related to action execution. Interestingly, significant structural atrophy in the rostral and ventral striatum was common to both PD and SCZ, but atrophy in the dorsolateral striatum was specifically attributable to PD. Our study revealed a cross-modal convergent organization of the striatum, representing a fundamental topographical model that can be useful for investigating structural and functional variability in aging and in clinical conditions.

Metabonomics study of MCAO rats based on microdialysis technique combined with UPLC-Q/TOF-MS / 中草药

Objective: To study the brain striatum metabolomics characteristics of middle cerebral artery occlusion (MCAO) rats. Methods: The middle cerebral artery was occluded by monofilament to establish the MCAO rat model. The microdialysis probe was implanted into the striatum, and the brain microdialysis samples were collected under awake and free activity condition and were measured by UPLC-Q/TOF-MS in positive and negative ion mode respectively. Multivariate statistics were used to establish the metabobomics model. Results: Brain-targeted metabolomics studies based on microdialysis samples were successfully performed. Metabolomics models could clearly distinguish normal and model rats, and seven differential metabolites were identified. Conclusion: The brain metabolism characteristics of MCAO rats had changed significantly. The metabolomics research based on microdialysis technology enriches the research methods of metabolomics.

Neuroprotective Effects of Low-molecular-weight Chondroitin Sulfate on Dopaminergic Neurons in MPTP-induced Parkinson ’s Disease Model Mice / 中国药房

OBJECTIVE： To observe neuroprotective effects of low-molecular-weight chondroitin sulfate （CS） on dopaminergic neurons in Parkinson’s disease （PD） mice model induced by 1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine （MPTP）. METHODS： C57BL/6 mice were randomly divided into control group， MPTP injury group， low-molecular-weight CS low-dose and high-dose groups （100， 400 mg/kg）. Control group and MPTP injury group were given constant volume of normal saline intragstrically， administration groups were given relevant medicine intragastrically， once a day， for consecutive 17 d. Since 11th day after medication， except for control group， other groups were given MPTP solution （20 mg/kg） intraperitoneally to induce PD model， once a day， consecutive 5 d. After last medication， behavioral changes of mice （10 mice in each group） were evaluated by rotary rod fatigue tester. The damage of dopamine neurons （the percentage of TH positive cell and the percentage of fluorescence intensity） in substantia nigra of mice （3 mice in each group） was detected by immunohistochemistry and immunofluorescence. The content of dopamine in striatum was determined by HPLC （6 mice in each group）. The changes of oxidant stress indexes （SOD， GSH-Px， MDA） in substantia nigra of mice were determined by chemical colorimetry （6 mice in each group）. RESULTS： Compared with control group， retention time of mice on rotating rods was shortened significantly in MPTP injury group； TH positive cells of substantia nigra were decreased significantly， fluorescence intensity was obviously weakened； the percentage of positive cells and fluorescence intensity， the content of dopamine in striatum， the activities of SOD and GSH-Px in substantia nigra were decreased significantly， while the content of MDA was increased significantly （P＜0.01）. Compared with MPTP injury group， retention time of mice on the rotating rods was prolonged significantly in low-molecular-weight CS groups， the number of TH positive cells was increased significantly in substantia nigra and fluorescence intensity was increased significantly； the percentage of positive cells， the percentage of fluorescence intensity and the content of dopamine in striatum were increased significantly， while above indexes of high-dose group were significantly longer or higher than those of low-dose group （P＜0.05 or P＜0.01）. The activities of SOD and GSH-Px in substantia nigra were increased significantly in low-molecular-weight CS groups， while the content of MDA in substantia nigra was decreased significantly in low-molecular-weight CS high-dose group （P＜0.05 or P＜0.01）. CONCLUSIONS： Prophylactic administration of low-molecular-weight CS can relieve the damage of dopaminergic neurons in substantia nigra of PD model mice induced by MPTP in a dose-dependent manner， and increase the secretion of dopamine in striatum. The effect may be related to the inhibition of lipid peroxidation and the enhancement of antioxidant capacity of tissues.

Altered Local Field Potential Relationship Between the Parafascicular Thalamic Nucleus and Dorsal Striatum in Hemiparkinsonian Rats / 神经科学通报·英文版

The thalamostriatal pathway is implicated in Parkinson's disease (PD); however, PD-related changes in the relationship between oscillatory activity in the centromedian-parafascicular complex (CM/Pf, or the Pf in rodents) and the dorsal striatum (DS) remain unclear. Therefore, we simultaneously recorded local field potentials (LFPs) in both the Pf and DS of hemiparkinsonian and control rats during epochs of rest or treadmill walking. The dopamine-lesioned rats showed increased LFP power in the beta band (12 Hz-35 Hz) in the Pf and DS during both epochs, but decreased LFP power in the delta (0.5 Hz-3 Hz) band in the Pf during rest epochs and in the DS during both epochs, compared to control rats. In addition, exaggerated low gamma (35 Hz-70 Hz) oscillations after dopamine loss were restricted to the Pf regardless of the behavioral state. Furthermore, enhanced synchronization of LFP oscillations was found between the Pf and DS after the dopamine lesion. Significant increases occurred in the mean coherence in both theta (3 Hz-7 Hz) and beta bands, and a significant increase was also noted in the phase coherence in the beta band between the Pf and DS during rest epochs. During the treadmill walking epochs, significant increases were found in both the alpha (7 Hz-12 Hz) and beta bands for two coherence measures. Collectively, dramatic changes in the relative LFP power and coherence in the thalamostriatal pathway may underlie the dysfunction of the basal ganglia-thalamocortical network circuits in PD, contributing to some of the motor and non-motor symptoms of the disease.

Early-Life Stress in D2 Heterozygous Mice Promotes Autistic-like Behaviors through the Downregulation of the BDNF-TrkB Pathway in the Dorsal Striatum

A number of specific genetic variants including gene mutations and single nucleotide variations have been identified in genomewide association studies of autism spectrum disorder (ASD). ASD phenotypes in individuals carrying specific genetic variations are manifest mostly in a heterozygous state. Furthermore, individuals with most genetic variants show incomplete penetrance and phenotypic variability, suggesting that non-genetic factors are also involved in developing ASD. However, the mechanisms of how genetic and environmental factors interactively promote ASD are not clearly understood. In the present study, we investigated whether early-life stress (ELS) in D2 dopamine receptor heterozygous knockout (D2(+/−)) mice induces ASD-like symptoms. To address that, we exposed D2 heterozygous pups to maternal separation stress for 3 h daily for 13 days beginning on postnatal day 2. D2(+/−) adult mice that had experienced ELS exhibited impaired sociability in the three-chamber test and home-cage social interaction test and increased grooming behavior, whereas wildtype littermates exposed to ELS did not show those phenotypes. ELS-exposed D2(+/−) mice had decreased levels of BDNF, TrkB, phospho-ERK1/2 and phospho-CREB in the dorsal striatum. Administration of the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) to ELS-exposed D2(+/−) mice rescued the sociability deficits and repetitive behavior. In contrast, behavioral rescue by 7,8-DHF in ELS-exposed D2(+/−) mice was blocked when TrkB expression in the dorsal striatum was locally inhibited by the injection of TrkB-siRNA. Together, our results suggest that the interaction between ELS and defective D2 gene function promotes autistic-like behaviors by downregulating the BDNF-TrkB pathway in the dorsal striatum.

Effect of rgs4 overexpression on related protein expression of mglur5-mediated signaling pathway in methamphetamine-dependent rat striatum / 中国药理学通报

Aim To investigate the effect of the regulator of G-protein signaling 4(RGS4) overexpression in rat striatum on the related protein expression of metabolic glutamate receptor 5(mGluR5) signaling pathway and the conditioned place preference(CPP) behavior in rats, by establishing the METH-dependent CPP model. Methods Rats were divided into five groups: Normal, normal saline(NS), METH, Ad5-RGS4-EGFP and Ad5-EGFP group. Normal group was without any administration, while the striatum of the other groups were respectively stereotactic injected with phosphate buffer methamphetamine (METH)-depardent soline (PBS), PBS, overexpressed adenovirus vector Ad5-RGS4-EGFP and negative control adenovirus vector Ad5-EGFP. The CPP behavior of rats in each group was analyzed. The expression of RGS4, mGluR5, Gαq, PLC1 was measured in rat striatum tissue by Western blot. Results The difference of CPP in Ad5-RGS4-EGFP group decreased compared with that in METH group and Ad5-EGFP group(P 0.05). PLCβ1 expression changed with no significant difference. Conclusions RGS4 overexpression in striatum is able to alleviate the CPP behavior in METH-dependent rats, and its mechanism may be associated with the overexpression of RGS4 in METH-dependent rat striatum, which could down-regulate the mGluR5-mediated Gαq and PLCβ1 signaling pathway.