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Frataxin deficiency triggers hypoxia signaling:implication in pathology of Friedreich ataxia

Frataxin deficiency triggers hypoxia signaling:implication i...

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第六届亚太神经科学联合会学术会议暨中国神经科学学会第十一届全国学术会议

作者： Huihui Li Xiaoyan Sun Hongting Zhao Kuanyu Li Medical School of Nanjing University

Frataxin(FXN) is a mitochondrial protein that is involved in mitochondrial iron homeostasis and iron-sulfur cluster biogenesis. Defective expression of FXN causes an autosomal recessive mitochondrial disorder, Friedreich's ataxia(FRDA). Hypoxia-inducible factor(HIF), a transcription factor, can both activate and inhibit gene expression in response to changes of oxygen concentration. It was previously reported that HIF regulates the expression of frataxin in mouse. Here we showed that FXN deficient cells derived from FRDA patient exhibited higher levels of HIF1 a and HIF2 a proteins. Protein level of HIF1 a was not induced by hypoxia(0.5% O2) and that of HIF2 a even dropped in patient cells, whereas the positive correlation between FXN and HIIF1/2a was subsistent in control cells. When dimethyloxalyglycine(DMOG), the HIF-specific stabilizer, was used to treat the cells, the proteins of HIF1/2α in cells derived from both healthy controls and patients were stabilized, but the protein level of FXN in cells derived from healthy control did not change and even decreased in cells from the patient. The results indicate that FXN deficiency causes the loss of hypoxia-induced responses in FRDA patient cells and FXN affects HIF signaling. Interestingly, the expression of FXN in patient cells was negatively correlated with the levels of stabilized HIF2 a and iron regulatory protein 2(IRP2) under hypoxia and normoxia, which was opposite in cells derived from healthy controls. To evaluate the effect of oxygen on this alteration, we then compared the survival of cells under different oxygen concentration. The cells from patients grew better under the high oxygen concentration(21%) than under the low oxygen concentration(3%), which is within the interval of physiological O2 concentration, suggesting that FXN deficiency affects utilization of oxygen likely by electron-transfer-chain insufficiency to cause the hypoxia-like condition for cells. Taken together, our findings implicate an

关键词： Friedreich's ataxia frataxin HIF hypoxia

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TREK1/2 and HMGB1 contributed to the pre-diabetic neuropathic pain in rats

TREK1/2 and HMGB1 contributed to the pre-diabetic neuropathi...

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第六届亚太神经科学联合会学术会议暨中国神经科学学会第十一届全国学术会议

作者： Wei SUN Han FU Xiao-Liang WANG Fei YANG Yang YU Jun CHEN Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders Tangdu HospitalThe Fourth Military Medical University

Objective Peripheral neuropathy, with clinical manifestations of pain, sensory, autonomic and even motor dysfunctions, is a major common complication of both diabetes and pre-diabetes. Our previous studies have already successfully established the pre-diabetic neuropathic pain animal model. However, the cellular and molecular mechanisms under pre-diabetes and polyneuropathy are still unclear. In present research, we detected the role of two-pore potassium channels(TREK1/2) and its associated protein on the development of pre-diabetic neuropathic pain. Meanwhile, we also assayed the function of one alarming factor(HMGB1), which was a mediator of potassium channels. Methods Time courses of body weight, fasting plasma glucose(FPG), insulin, free fatty acids(FFA), homeostasis model assessment-insulin resistance index(HOMA-IR), paw withdraw mechanical threshold(PWMT) were measured in parallel. Finally, utilizing a combination of behavioral experiments, immunological methods(immunofluorescence and immunoblotting) and electrophysiological studies to explore these underlying cellular and molecular mechanisms. Results The results showed that early metabolic syndrome(hyperinsulinemia and dyslipidemia) and pre-diabetic conditions(impaired fasting glucose) could be induced by high energy diet, and these animals later developed painful polyneuropathy, which represented remarkable bilateral mechanical, but not thermal pain hypersensitivity. In this pre-diabetic condition, the expression of TREK1/2 was down-regulated. In contrast, the expression of HMGB1 and its receptor were up-regulated. During the development of this painful pre-diabetic state, both the two-pore potassium channels and alarming factors migrated the expressional location in the cellular. Additionally, administrated the opener of TREK1 or the inhibitor of HMGB1 could reverse this mechanical pain hypersensitivity. Whole-cell patch clamp recordings were obtained from the small-medium and medium-large size neurons of

关键词： pre-diabetic neuropathic pain two-pore potassium channels HMGB1 dorsal root ganglion

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Feeding the functional maps from primary visual cortex of the cat into the self-organization model:an optimal arrangement and precise prediction

Feeding the functional maps from primary visual cortex of th...

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第六届亚太神经科学联合会学术会议暨中国神经科学学会第十一届全国学术会议

作者： Anqi Jin Weiao Lu Shizhen Hu Hongbo Yu Center for Brain Science Research School of Life SciencesFudan University

In the primary visual cortex of high mammals, multiple functional maps, such as retinotopic, orientation, ocular dominance(OD), and spatial frequency(SF) maps co-exist in the same piece of cortex, and their map patterns vary greatly across animals. It is almost impossible to predict these diversified organization of these maps. Although some of previous computational models could simulate the similar map patterns, the experiment and simulation were two respective manipulations-- the real experimental data could not be fed and integrate into the computational models. We obtained the multiple functional maps from the cat primary visual cortex, and then fed them into our self organization model(SOM) based on biological parameters, which successfully simulated the inter-relationship between multiple functional maps in our previous studies. The results show that the experimental maps remained highly stable during millions of iterations in SOM, suggesting a successful transplantation between experiment and simulation. On the other hand, a spatially mismatched functional map pair, or the shuffle pair from two different animals would lead to rapid and progressive re-arrangement in the SOM, until they reached a steady and optimal state. It seems that the original arrangement of functional map in animals were optimal in SOM. Furthermore, when one of the experimental functional map was manually substituted by random noise initially and then fed into the SOM, a new map would be predicted based on millions of iterations. This new map could differ greatly from the original one, and varied across different simulations, suggesting that the optimal arrangement between multiple maps was not the only one. However, if only 5% pixels of the original maps were reserved as the seeds(others were initially substituted by random values), the exact original maps would be fully restored, suggesting an optimal arrangement inherently lied in the SOM with certain local restrictions. For the first

关键词： self organization model,primary visual cortex,orientation,ocular dominance,functional map

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Stronger first-order tilt illusion reveals stronger within-“lazy eye” monocular inhibitory interactions in V1

Stronger first-order tilt illusion reveals stronger within-...

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第六届亚太神经科学联合会学术会议暨中国神经科学学会第十一届全国学术会议

作者： Jinfeng Huang Caiyuan Liu Zhongjian Liu Yifeng Zhou Tzvetomir Tzvetanov CAS Key Laboratory of Brain Function and Disease & School of Life Sciences University of Science and Technology of China Research and Treatment Center of Amblyopia and Strabismus University of Science and Technology of China

Objective: It is widely considered that amblyopia changes V1 characteristics, but the perception of first-order orientation information under contextual influence on human amblyopia is elusive. We asked whether the tilt illusion, a probe in inhibitory interaction at early visual stages, is different in anisometropic amblyopia. Methods: To investigate this issue, we measured the full-surround tilt illusion in 11 anisometropic amblyopes and 11 normal controls. We carried out all the experiment monocularly(amblyopia eye(AE), non-amblyopia eye(NAE), normal eye(NE)). First, we measured the contrast sensitivity of each eye. According to the sensitivity curve, we chose one low spatial frequency(SF)(near optimal SF) and one higher SF. Then we measured the tilt illusion for each SF(Stimulus: Gabor patch surrounded by a sinewave whose radius was two times larger than the center Gabor, and stimulus size was scaled with the spatial frequency). Results:(1) Surround orientation repulsed center orientation perception, the tilt illusion was stronger at high SFs than at low SFs, and AE showed stronger illusion from NAE and NE;(2) Adjusting for the variation of tilt illusion with SF still showed AE with strongest misperception;(3) At low SFs, only in AE the contrast sensitivity showed anticorrelation with tilt illusion, no correlations were found in NAE and NE. Conclusion:(1) Stronger tilt illusion, correlated to lower contrast sensitivities, was found within-"lazy eye" of anisometropic amblyopes;(2) According to the anticorrelation analysis between the illusion and sensitivity in AE, we suggest that stronger monocular inhibitory interactions in V1 creates the lower contrast sensitivity in AE.

关键词： tilt illusion inhibition effect amblyopia eye contrast sensitivity V1

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Single cortical neurons encode curved self-motion by subadditively integrating translation and rotation signals

Single cortical neurons encode curved self-motion by subaddi...

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第六届亚太神经科学联合会学术会议暨中国神经科学学会第十一届全国学术会议

作者： Zhi-Xian Cheng Yong Gu Institute of Neuroscience and Key Laboratory of Primate Neurobiology Shanghai Institutes for Biological SciencesChinese Academy of Sciences University of Chinese Academy of Sciences

Our complex motion trajectories during navigation through space could be decomposed into two variables: a linear translation and an angular acceleration signal arising from the peripheral vestibular otoliths and semicircular canals respectively in our inner ears. Previous studies have shown that the translation and rotation signals, converged in single neurons in several cortical areas. However, whether these signals could be integrated to potentially represent a curved self-motion trajectory, is still unknown. In the current study, we adopted a virtual reality system by using a 3D motion platform(MOOG Inc.) to mimic 3 types of motion trajectories:(1) Linear translation-only condition in which only otolith organs were activated;(2) Rotation-only condition in which only semicircular canals were activated in the horizontal plane;and(3) A curved motion trajectory resulted from combinations of the translation and rotation stimuli, simultaneously activating both sets of the vestibular peripherals—the otoliths and semicircular canals. We recorded extracellular activities from 308 single units in three cortical areas – MSTd(the dorsal part of Medial Superior Temporal area, VIP(Ventral Intra Parietal cortex), and VPS(Visual Posterior Sylvian fissure) in two awake, behaving monkeys. Our study revealed a few important findings. First, we found that about a third of neurons preferred curved motion during combined translation and rotation(TR cells) stimuli while another third of neurons preferred translation-only stimuli(T cells), and the rest third population preferred rotation-only movement(R cells). Second, for TR cells, translation and rotation signals were linear integrated in a subadditive way suchthat their neuronal responses during curved motion were enhanced by about 20% compared to those during the translation-only and rotation-only conditions. Third, either the category of cell groups(T, R and TR cells) or the weighted linear summation rule was analogous across all t

关键词： Self-motion,Vestibular,Macaque,Cortex

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The superior colliculus is actively involved in economic decisions during a saccade foraging task

The superior colliculus is actively involved in economic dec...

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第六届亚太神经科学联合会学术会议暨中国神经科学学会第十一届全国学术会议

作者： Beizhen Zhang Janis Ying Ying Kan Michael Christopher Dorris Institute of Neuroscience Shanghai Institutes for Biological SciencesChinese Academy of Sciences Department of Biomedical and Molecular Sciences Centre for Neuroscience StudiesQueen's University

Economic decisions require assigning values to available options and then choosing the option with the highest value. There are two competing value-based models to explain how the brain accomplishes economic decisions—the good-based model and the action-based model. According to the good-based model, values are assigned to goods(e.g., apple or orange) and compared in the prefrontal cortex(PFC) while subsequent premotor regions simply translate the decided result to action. However, in the action-based model, the decisions are not completed in the PFC rather the value signal in the PFC shapes activity across premotor maps. Decisions are made by comparing these action values, which represent the probability of making a certain action. Our goal was to test whether action value signals are present and actively involved in the decision process in premotor regions. It has been proposed that action value signal should meet following conditions:(1) neural activity must be modulated by subjective value, and(2) neural activity must not be downstream of the decision. To test the criteria, Rhesus monkeys performed a visual foraging task while we recorded the activity of single neurons in the superior colliculus(SC), which is a premotor brain region involved in generating saccade eye movements. On each trial of the visual foraging task, three different color dots represent 3 goods with different value. Monkeys harvested dot goods by fixating them for a pre-specified amount of time. All dots of the same color share same value [Value = reward magnitude/ fixation time required to harvest]. Recording experiments satisfied criterion #1 in that: neural activity across the SC was correlated with the corresponding value of the goods. Electrical microstimulation experiments satisfied criterion #2. Microstimulation was applied to the SC map at a level that could increase activity but was subthreshold for eliciting saccades directly. The choices were biased toward the sites associated with

关键词： economic decisions good-based model action-based model action value the superior colliculus

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GPCR regulation of dopamine release by action potential pattern in striatum in vivo

GPCR regulation of dopamine release by action potential patt...

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第六届亚太神经科学联合会学术会议暨中国神经科学学会第十一届全国学术会议

作者： Xiaoxuan Sun Quanfeng Zhang Li Zhou Huadong Xu Qihui Wu Bin Liu Xuanyang Chen Zhengtao Zi Changhe Wang Zhuan Zhou State Key Laboratory of Biomembrane-Center for Life Sciences-McGovern Brain Research Institute Institute of Molecular MedicinePeking University

Dopamine(DA) is critical in mental physiology(rewards, learning and memory) and diseases(depression, addiction, PD). DA receptor D2 R is a Gi-sensitive GPCR. Strength of membrane depolarization is either dependent on depolarization amplitude/duration, or action potential(AP) frequency(Artalejo et al., 1992). Following electric pulses at medial forebrain bundle to trigger APs in DA neurons, DA release from striatum is recorded by electrochemical carbon fiber electrode(CFE) in vivo. D2 R blocker haloperidol(0.37mg/kg) enhances AP-induced DA overflow. Interestingly, the relative haloperidol enhancement, ?(f), was strongly dependent on AP-frequency: ?(20Hz) > 10*?(80Hz) in WT-mice. The f-dependence was abolished in D2R-KO mice, indicating D2 R is responsible for the f-dependence of ?(f). This implicated that D2 R is voltage dependent, because AP-frequency is equivalent to membrane-depolarization strength. Thus, we examined voltage dependence of D2R-Gi(vG i) in cultured Hela cells expressing D2R2. vG i-D2 R was measured by co-expression of D2R-G?iq-GCa MP3, as GCa MP3 reported Ca2+-release from ER following activating D2 R. This in-vitro system showed, depolarization significantly inhibited D2R-mediated Ca2+ signal, indicating D2R-activation is indeed sensitive to voltage per se. We thus conclude that membrane-depolarization per se can regulate D2 R and D2R-dependent DA-release in striatum in vivo.

关键词： GPCR regulation of dopamine release by action potential pattern in striatum in vivo

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Optic tectal superficial interneurons detect motion in larval zebrafish

Optic tectal superficial interneurons detect motion in larva...

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第六届亚太神经科学联合会学术会议暨中国神经科学学会第十一届全国学术会议

作者： Chen Yin Xiaoquan Li Jiulin Du Institute of Neuroscience State Key Laboratory of NeuroscienceCAS Center for Excellence in Brain ScienceShanghai Institutes for Biological SciencesChinese Academy of Sciences

Background Animals discriminate preys, predators and conspecifics in the constantly changing world through combing multiple objective features, among which motion is an essential one. In visual brain areas, local neural circuits integrate visual inputs for extracting motion information. In teleosts, the visual center optic tectum(OT) receives visual signal from retinal ganglion cells(RGCs) and transmits behavior-relevant information to downstream pre-motor circuits for generating relevant behavior. Thus, the processing of motion information within the OT is critical for visual perception and visuomotor transformation. With regard to motion detection, an important feature that can be extracted is the direction of a moving object. Direction information may signal physiological meaning such as food resources and threatening and thus is under fine processing. Method We performed in vivo whole-cell recording and calcium imaging to examine the role of superficial interneurons(SINs), a specific type of tectal cells, in motion detection in larval zebrafish. Results First, SINs exhibit sustained high frequency firing with current injection, transient ON and OFF responses evoked by visual stimuli, large receptive field(RF) and mainly receive excitatory inputs. Second, we identify two subsets of direction selective(DS) SINs. Third, SINs show size-dependent responses to moving dots. Further characterization reveals that SINs are activated by a moving object but not a static one, capable of showing sustained responses to a moving object and have less visual adaptation than that of tectal principle neurons, the periventricular neurons(PVNs). At the circuit level, manipulation of activities of single SINs affected PVN activities. Behaviorally, ablation of SINs impairs prey capture, which requires fine local motion detection, but do not affect global looming-evoked escape. Finally, starvation enhances gain of SIN motion responses while maintaining their size tuning and DS. Conclusi

关键词： optic tectum motion direction selectivity size tuning visual adaptation prey capture

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BACE1 and Cerebral Amyloid Angiopathy

BACE1 and Cerebral Amyloid Angiopathy

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第六届亚太神经科学联合会学术会议暨中国神经科学学会第十一届全国学术会议

作者： Xiao-Xin Yan Yan Cai Zhi-Qin Xue Wen-Ying Qiu Xue-Gang Luo Chao Ma Department of Anatomy and Neurobiology Central South University School of Basic Medical Science Department of Anatomy Xinjiang Medical University Institute of Basic Medical Sciences Neuroscience CenterChinese Academy of Medical Sciences Department of Human Anatomy Histology & EmbryologySchool of Basic MedicinePeking Union Medical College

Cerebral amyloid angiopathy(CAA) refers to the deposition of β-amyloid(Aβ) peptides in the wall of brain vasculature, commonly involving capillaries and arterioles. Also being considered a part of CAA is the Aβ deposition in leptomeninge. The pathogenic mechanism underlying CAA has been conceptualized largely in context of an abnormal Aβ conveyance around the neurovascular interface. Many studies explored the role of reduced brain-to-blood efflux and/or increased periphery-to-central transportation of Aβ in cerebral amyloidosis. However, the cellular origin of angiopathic Aβ and the pathogenic course of CAA remain incompletely understood. We speculated that BACE1 elevation could occur at sites of amyloid angiopathy in the human brain. As such, identifying the cellular elements showing increased BACE1 expression could help reveal the origin of pathologically important Aβ products in the development of CAA. In the present study we choose a cohort of postmortem brains from our recently established human brain banks. BACE1 alteration relative to Aβ and other labeling was determined anatomically and biochemically, with a focus on cerebral vascular and leptomeningeal lesions. For cross-validation, neuritic plaques were examined and documented as a reference system when appropriate. Primary cell cultures were also used to verify the existence of the amyloidogenic machinery in vascular and meningeal cells. Immunoreactivity(IR) for BACE1 was essentially not visible at vasculature in cases without cerebral amyloidosis(control group, n=15, age=86.1±10.3 year). In cases with brain amyloid pathology(n=15, age=78.7±12.7 year), increased BACE1 IR was identified locally at capillaries, arterioles and along the pia, localizing to endothelia, perivascular dystrophic neurites and meningeal cells, and often coexisting with vascular iron deposition. Double immunofluorescence with densitometric analysis confirmed a site-specific BACE1 elevation at cerebral arterioles in the development o

关键词： Amyloidosis Brain aging Blood brain barrier Dementia Neurodegeneration

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Visualization of neuronal assembly in hippocampal CA1 during spatial memory task

Visualization of neuronal assembly in hippocampal CA1 during...

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第六届亚太神经科学联合会学术会议暨中国神经科学学会第十一届全国学术会议

作者： Yasunori Hayashi RIKEN Brain Science Institute Saitama University Brain and Body System Science Institute School of Life Science South China Normal University

Hippocampus plays an important role in the formation of memories for space and events. However, it is not fully understood how neuronal circuits are reorganized during the formation of memory for a particular place with value for the animal(such as reward). We hypothesize that the neuronal assembly- a group of neurons firing together- is formed and reorganized within hippocampal network during memory formation. To visualize hippocampal network activity during learning, we established a new virtual spatial memory task for head-fixed mice combined with two-photon calcium imaging. In this task, the mice run on a virtual linear track where three target zones are defined by a different pattern on the wall. Mice begin to run from one end of the virtual linear track to seek for rewards delivered at one of the three zones. The training protocol consists of three phases.(1) Non-delayed task: mice are rewarded immediately whenever they enter and pass through the target zone.(2) Delayed task: mice have to visually navigate to the same target and stay there for 1-2 sec of delay to receive rewards.(3) Target shift task: the reward location is shifted to one of the other zones and mice are trained to locate the new zone. We trained transgenic mice that express the G-Ca MP7 fluorescent calcium sensor proteins in hippocampal CA1 pyramidal neurons and imaged neuronal activities during the behavior by two-photon microscopy. Our analysis revealed that a population of neurons exhibited virtual place-specific activity. In addition, another group of neurons demonstrated time-locked activity to the entry of the mice into the target zone. These preliminary results raise an intriguing possibility that time and space are coded by different subpopulations of pyramidal neurons in the dorsal CA1 hippocampus.

关键词： Visualization of neuronal assembly in hippocampal CA1 during spatial memory task

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