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Schizophrenia related variants in CACNA1C also confer risk of autism

Schizophrenia related variants in CACNA1C also confer risk o...

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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： Jun Li Linnan Zhao Yang You Tianlan Lu Meixiang Jia Hao Yu Yanyan Ruan Weihua Yue Jing Liu Lin Lu Dai Zhang Lifang Wang Key Laboratory of Mental Health Ministry of Health (Peking University) Institute of Mental Health Peking University Peking University Sixth Hospital Peking-Tsinghua Center for Life Sciences Peking University PKU-IDG/McGovern Institute for Brain Research Peking University

Autism spectrum disorder(ASD) is a group of neurodevelopmental disorders with a strong genetic component. Many lines of evidence indicated that ASD shares common genetic variants with other psychiatric disorders(for example, schizophrenia). Previous studies identified that calcium channels are involved in the etiology of many psychiatric disorders including schizophrenia and autism. Significant association between CACNA1C(calcium channel, voltage-dependent, L type, alpha 1C subunit) and schizophrenia was reported. However, the genetic relationship between autism and CACNA1 C is not clear. To investigate the association between single nucleotide polymorphisms(SNPs) in CACNA1 C and autism, we first performed a family-based association test between eighteen SNPs in CACNA1 C and autism in 239 trios. All SNPs were genotyped using the Sequenom platform. Two SNPs(rs1006737 and rs4765905) have a trend of association with autism. To further confirm the association between these two SNPs with autism, we expanded the sample size to 553 trios by adding 314 trios. The results demonstrated that allele G of rs1006737 and allele G of rs4765905 showed a preferential transmission to affected offspring in 553 trios(p=0.035). Haplotype analyses showed that two haplotypes constructed by rs1006737-rs4765905 were significantly associated with autism(p=0.030, 0.023, respectively. Global p=0.046). These results were still significant after permutation correction(n=10,000, p=0.027). Our research suggests that CACNA1 C might play a role in the genetic etiology of autism in Chinese Han population.

关键词： autism CACNA1C family-based association study calcium channel

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The peripheral and spinal mechanisms of bone cancer pain

The peripheral and spinal mechanisms of bone cancer pain

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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： Zhang Yu-Qiu Institute of Neurobiology Institutes of Brain Science and State Key Laboratory of Medical NeurobiologyCollaborative Innovation Center for Brain ScienceFudan University

Bone cancer-induced pain is one of the most severe types of chronic pain. Approximately 90% of advanced bone cancer patients must cope with chronic pain syndromes related to tumor progression and failed treatment. Transforming growth factor-β(TGF-β), a major bone-derived growth factor, is largely released by osteoclast bone resorption during the progression of bone cancer, which contributes to proliferation, angiogenesis, immunosuppression, invasion and metastasis. Here, we further pointed to that TGF-β1 is critical for the bone cancer-induced pain sensitization. We found that following the progression of bone cancer TGF-β1 was highly expressed in tumor-bearing bone, and its receptors, TGFβRI and TGFβRII, significantly increased in the dorsal root ganglia(DRG) in a rat model of bone cancer pain by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. Blockade of TGFβ receptors by TGFβRI antagonist SD-208 robustly suppressed bone cancer-induced thermal hyperalgesia on post-tumor day 14(PTD 14). Peripheral injection of TGF-β1 directly induced thermal hyperalgesia in intact rats and wide-type mice, but not in TRPV1-/- mice. Whole-cell patch-clamp recordings from DRG neurons showed that transient receptor potential vanilloid(TRPV1) sensitivity was significantly heightened on PTD14. Extracellular application of TGF-β1 significantly potentiated TRPV1 currents and increase of [Ca2+]i in DRG neurons. These findings suggest that TGF-β1 signaling contributes to bone cancer pain via the upregulation and sensitization of TRPV1 in primary sensory neurons, and therapeutic targeting of TGF-β1 may ease the bone cancer pain in advanced cancer. Accumulating evidence suggests that activation of spinal microglia contributes to the development of inflammatory and neuropathic pain. However, the role of spinal microglia in the maintenance of chronic pain remains controversial. In the present study, we demonstrated an unconventional role of spinal microglia in the maintenanc

关键词： TGF The peripheral and spinal mechanisms of bone cancer pain

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LTP of EPSP evoked by ipsilateral pericentral canal stimulation in neonatal rat spinal cord motoneurons in vitro

LTP of EPSP evoked by ipsilateral pericentral canal stimulat...

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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： Lei ZHANG Huan SONG Wen QIN Yu-Han SHI Meng-Ya WANG Cell Electrophysiology Laboratory Wannan Medical College

Objective To explore the possible synaptic plasticity of excitatory synaptic transmission from ipsilateral pericentral canal(iP CC), a presumed site of "central pattern generator" of motor control, to motoneurons(MNs) in spinal cord. Methods The intracellular recordings were performed in MNs of spinal cord slices isolated from neonatal rats(8-14 days old) and the excitatory postsynaptic potentials(EPSPs) were mainly evoked by electrical stimulation of i PCC, iP CC-EPSPs. Long-term potentiation(LTP) was induced by the tetanic electrical stimulation(100 Hz, 50 pulses/train, duration 0.3～1.0 ms, 6 trains, main interval 10 seconds, 20～100 V) on i PCC. The analysis method of apparent receptor kinetics of EPSP(Acta Physiol Sin 2014, 66: 129) was used to monitor the apparent receptor kinetic properties of i PCC-EPSPs. Results In 27 MNs with i PCC-EPSPs, the tetanic electrical stimulation of i PCC enhanced the amplitude of i PCC-EPSPs to more than 120% of the baseline and the enlargement lasted longer than 30 min in 9 cells, which could be referred to as LTP(iP CC-LTP). During i PCC-LTP, apparent association rate constant(K1) increased, apparent dissociation rate constant(K2) and apparent equilibrium dissociation constant(KT) decreased only in 4 MNs. It was also observed that the induction of i PCC-LTP was facilitated by pretreatment of bicuculline(30 μM) and strychnine(1 μM), but the maintenance of i PCC-LTP was nullified by APV(30 μM and DNQX(1 μM). Conclusion These preliminary data show that the possible long-term synaptic plasticity is induced in i PCC intraspinal pathways onto MNs, which may be considered as a candidate of neural basis underlying the "central pattern generator" of motor control.

关键词： motoneuron excitatory postsynaptic potential long-term potentiation

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Dioxygenases Ten-eleven translocation 1(TET1) regulates oligodendrocyte differentiation

Dioxygenases Ten-eleven translocation 1(TET1) regulates olig...

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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： Jian Wang Kaixiang Zhang Ke Fang Bo Zhao Wenting Wang Shengxi Wu Xianghui Zhao Department of Neuroscience The Fourth Military Medical University

The ten-eleven translocation(TET) family of methylcytosine dioxygenases catalyze oxidation of 5-methylcytosine(5m C) to 5-hydroxymethylcytosine(5hm C) and promote DNA demethylation. Despite the abundance of 5hm C and TET proteins in the brain, little is known about their role in oligodendrocytes(OLs). We have previously shown that three TET family members possess unique subcellular and temporal expression patterns during OL differentiation;the level of 5hm C exhibits dynamic changes. Furthermore, RNAi mediated silencing of TET family proteins in OLs demonstrated that each of the TET proteins is required for OL differentiation(Glia 2014;62:914-926). Among these members, TET1 is highly expressed in oligodendrocyte precursor cells(OPCs) and early differentiated immature OL. To understand the function of TET1 in OL development, we deleted TET1 in OL lineage cells, by crossing TET1loxp/loxp with Olig1Cre+/- mice, and observed significant deficits in OL lineage formation and differentiation. In vitro cell culture indicated that loss of TET1 in OLs represses the differentiation process. In vivo myelination deficits were confirmed by electron microscopy in the optic nerve of young TET1 mutants;and the stimulated compound action potentials recorded from optic nerve were attenuated in TET1 mutants. By m RNA profiling, we observed a cohort of reduced mR NAs in the mutants. Among them, several known regulators for OL development or myelination genes were identified, such as Notch1, Opalin, Nkx2.2, Olig1, Nkx6.2, Omgp, and Tcf7l2, et al. Our study provides new insight into the regulation of OL differentiation by dioxygenases and further suggests that activation of OL differentiation regulators by TET1 is a novel mechanism for the generation of OL lineage.

关键词： Oligodendrocyte,Differentiation,Dioxygenases,TET1,Epigenetic regulation

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Persistent hyperactivity of hippocampal dentate interneurons after a silent period in the rat pilocarpine model of epilepsy

Persistent hyperactivity of hippocampal dentate interneurons...

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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： Xiaochen Wang Dandan Guo Lin Wu Ren-Zhi Zhan Department of Physiology Shandong University School of Medicine

Purpose: To profile activity of GABAergic interneurons in the hippocampal dentate gyrus after the silent period following pilocarpine-induced status epilepticus(SE) in the rat. Methods: SE for more than 2 hours was induced in male Sprague-Dawley rats by intraperitoneal injection of pilocarpine. Animals were sacrificed at 1 hour, 1 week, 2 weeks or more than 10 weeks after SE to determine activity of GABAergic interneurons in the hippocampal dentate gyrus by observing immediate early gene expression and spontaneous firing at near resting membrane potential. For animals to be examined at 1 hour after SE, SE lasted for 2 hours was terminated by an intraperitoneal injection of diazepam. Key findings: c-fos and activity-regulated cytoskeletal associated protein(Arc) in hilar GABAergic interneurons were up-regulated after SE in a biphasic manner;they were increased at 1 hour and more than 10 weeks, but not 1 week after SE. Ten weeks after SE, more than 65% of hilar GABAergic cells expressed c-fos or Arc;most of them expressed c-fos and Arc more intensely than the neighboring granule cells. The percentages of calretinin(CR)-, neuronal nitric oxide synthase(n NOS)-, parvalbumin(PV)-, neuropeptide Y(NPY), and somatostatin(SOM)-positive cells expressed c-fos(compared to the control) were 19%, 27%, 28%, 49%, 51% respectively. Without the resting membrane potential to be more depolarizing in SE-induced rats, cell-attached recording mode revealed that more than 80% of hilar interneurons fired spontaneously at near resting membrane potentials(while less than 20% of the same cell population did so in controls). Significances: Pilocarpine-induced status epilepticus eventually leads to a state in whichsurviving dentate GABAergic interneurons become hyperactive with a subtype-dependent manner;this implicates a fragile balance between excitation and inhibition in the dentate gyrus and the need to strengthen GABAergic inhibition to prevent spontaneous seizures to occur. Also, for treat

关键词： GABAergic immediate early genes neuronal nitric oxide synthase neuropeptides parvalbumin spontaneous firing

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Neuronal representations in the dorsolateral prefrontal cortex and the medial temporal lobe during a temporal-order-memory task

Neuronal representations in the dorsolateral prefrontal cort...

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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： Yuji Naya Cen Yang He Chen Wendy A Suzuki Department of Psychology and Beijing Key Laboratory of Behavior and Mental Health Peking University Center for life sciences Peking University IDG/McGovern Institute for Brain Research Peking University Center for neural science New York University

Episodic memory, the ability to remember our autobiographical events, contains temporal context in which the events took place. Neuropsychological studies have shown that the memory for the temporal-order of events or items is impaired in patients with lesions of either medial temporal lobe(MTL)(Mayes et al., 2001) or frontal lobe(Shimamura, 1990). In the present study, we recorded single-unit activities from both MTL and dl-PFC of non-human primates during a temporal-order memory task that requires the subjects to encode two visual objects and their temporal order(Naya and Suzuki, 2011), and compared the activity between the two brain regions directly. We found two types of task related neurons that may be involved in encoding the sequence of two objects in both regions. One group of neurons showed stimulus-selective responses for either the first cue or the second cue stimulus and are referred to as item cells. We found that dl-PFC, particularly its ventral part contained substantial number of item cells. However, their representation manner for integrating an item and its presented temporal order was different from those in MTL. Onset of stimulus-selective responses in dl-PFC was significantly later than the perirhinal cortex of MTL and visual area TE, but not the entorhinal cortex. In addition, only dl-PFC but not MTL carried item information of the first cue presentation until the next cue presentation. Another group of neurons showed different amplitudes of responses between two cue presentations and are referred to as order-selective neurons. We found that the dorsal part of dl-PFC provided an incremental timing signal representing the passage of time between the two cue presentations similar to hippocampus. These results indicate dl-PFC and MTL may work in the service of temporal order memory in a complementary manner.

关键词： time cell declarative memory

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Chinese Speech Decoding Using Intracranial EEG

Chinese Speech Decoding Using Intracranial EEG

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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： Bo Hong Department of Biomedical Engineering School of MedicineTsinghua University

A finite set of phonetic units is used in human speech, but how our brain recognizes these units from speech stream is still largely unknown. The revealing of this neural mechanism may lead to the development of new types of speech brain computer interfaces and computer speech recognition systems. In this study, we used intracranial EEG(iE EG) signal from human cortex to decode Chinese phonetic units during the perception of continuous speech. By exploring the time-frequency features, we identified i EEG electrodes that have selective response to specific Chinese phonemes. High-gamma power of these electrodes was further combined to separate sets of phonemes into clusters. The clustered organization largely coincided with phonological categories defined by discriminative features, similar as that has been found in English(Mesgarani et al, 2014). These findings were incorporated into a decoding framework of Chinese phonemes clusters and achieved consistent accuracies higher than chance level. Additionally, in tonal languages, like Chinese, lexical tone also serves as a key feature to provide contrast in word meaning. Behavior studies suggest that Mandarin Chinese tone is categorically perceived(Wang 1976;Xu et al. 2006). However, the neural mechanism underlying Mandarin tone perception is still poorly understood. In this study, an Oddball paradigm was designed by selecting two standard-deviant stimulus pairs with same physical distance but different category labels, among the synthesized tones with continuously varying pitch contours. Using i EEG recording over human auditory cortex, high temporal and spatial resolution cortical neural signals were used for the first time to investigate the cortical processing of lexical tone. We found distinct neural responses to the two standard-deviant tone pairs, and the difference increased from low to high-level electrodes along the hierarchy of auditory processing. In the two dimensional neural space, cross-category neural dis

关键词： Chinese Speech Decoding Using Intracranial EEG

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AT1 receptor blockade in the central nucleus of amygdala attenuates the effects of muscimol on sodium intake

AT1 receptor blockade in the central nucleus of amygdala att...

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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： Bo Hu Hu Qiao Bo Sun Ru Jia Yuanyuan Fan Nan Wang Bo Lu Jianqun Yan Department of Physiology and Pathophysiology Xi'an Jiaotong University Health Science Center Department of Prosthodontics Xi'an Jiaotong University College of stomatology

Evidence based on experimental animal studies indicates that the blockade of the GABAA receptors(GABAARs) in central nucleus of the amygdala(Ce A) with muscimol reduces hypertonic NaC l and water intake by sodium-deplete rats. Since angiotensin IItype-1 receptors(AT1Rs) have been reported to have important roles in modulation of GABAergic synaptic transmission and produce opposite effects, depending on whether preor post-synaptic AT1 Rs are activated, angiotensin II type-1 receptor is a candidate molecule that may influence the inhibitory effects of muscimol in Ce A on sodium and water ingestion. To evaluate the effects of pre-injection of AT1 Rs antagonist, losartan, into CeA on hypertonic Na Cl and water intake inhibited by muscimol injected bilaterally in the same area, hypertonic Na Cl and water consumption was assessed using a two-bottle test(0.3 M Na Cl vs. water) in rats submitted to water deprivation-partial rehydration protocol and in diuretic furosemide treated rats. Immunocytochemistry labeling revealed that the immunoreactivity of AT1 Rs was colocalized with GABAARs in the CeA. Bilateral injections of muscimol(0.2 nmol/0.5μl, n=8/group) into the CeA in WD-PR-treated rats reduced 0.3 M Na Cl intake and water intake, and pre-treatment of the CeA with losartan(50μg/0.5μl) reversed this inhibitory effect of *** negative effect of muscimol on the sodium and water intake could also be blocked by pretreatment with losartan intra-Ce A microinjection in rats submitted to FURO(n=8/group). These results suggest that endogenous angiotensin II acting on AT1 Rs is essential for complete activation of GABAergic mechanisms by muscimol injections into the CeA, which prevents rats to ingest hypertonic NaCl.

关键词： Sodium appetite GABAA receptor Angiotensin type 1 receptor Central nucleus of the amygdala

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The role of a novel P300 cofactor JMY during neuronal radial migration and morphogenesis in the developing neocortex

The role of a novel P300 cofactor JMY during neuronal radial...

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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： Yuan-Yuan Liu Guo-He Tan Lan-Bo-Ling Guo Ze-Qiang Zhang Lu Wang Ren-Chao Chen Zhi-Qi Xiong Institute of Neuroscience and State Key Laboratory of Neuroscience Chinese Academy of Sciences

Neuronal radial migration is essential for cortical development and its defect is largely implicated in many brain disorders. However, the molecular mechanism underlying this process is still obscure. We show here that junction-mediating and regulatory protein(JMY) is required for the radial migration of newborn cortical neurons. JMY is a P300 cofactor that can augment the transcriptional activity of P53, and was found recently to act as an actin nucleator, implying a role of it in central nervous system. However, the expression and function of JMY in mammalian brain remain largely unclear so far. We found that JMY is selectively enriched in developing central nervous system and its expression peaks at perinatal stages. Combining In Utero electroporation with RNAi technique, we then found that down-regulation of JMY expression impaired neuronal migration. The defect of neuronal migration can be rescued by over-expression of JMY. We then generated Jmy-floxed mice and observed consistent results by transfecting CAG-Cre or DCX-Cre vectors with Loxp-Stop-Loxp-e GFP plasmids into Jmy-floxed mouse brains. Moreover, in vitro and in vivo data show that downregulation of JMY impairs neuritogenesis of neurons, while overexpression of JMY promote it. JMY-/-;Nestin-Cre mice were used to confirmed the defect in neuronal morphology caused by ablation of JMY. Thus, the above findings indicate a regulatory role of JMY in neuronal migration and morphogenesis during cortical development. Taken together, this work underscored the importance of JMY in brain development, providing new insights into the regulatory molecular mechanisms underlying cortical development and the pathogenesis of possible relevant disorders.

关键词： JMY neuronal migration cortical development In Utero electroporation

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Fear memory-associated pre-and postsynaptic rewiring of amygdalocortical connections

Fear memory-associated pre-and postsynaptic rewiring of amyg...

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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： Yang Yang Dan-Qian Liu Wei Huang Fu-Qiang Xu Yi Zuo Mu-Ming Poo Institute of Neuroscience State Key Laboratory of NeuroscienceCAS Center for Excellence in Brain ScienceShanghai Institutes for Biological SciencesChinese Academy of Sciences Graduate School University of Chinese Academy of Sciences Institute of Mathematics and Physics CAS Center for Excellence in Brain ScienceChinese Academy of Sciences Department of Molecular Cell and Developmental BiologyUniversity of California Santa Cruz

Experience-induced synaptic modification is believed to be the cellular basis of learning and memory. Previous studies on neural circuits underlying associative fear learning have extensively characterized feed-forward projections from sensory thalamus and cortices to the amygdala, and learning-induced synaptic plasticity in these areas. Here we report a previously unknown feedback pathway from the lateral amygdala(LA) to the auditory cortex(ACx) in mice that was selectively modified after auditory fear conditioning, through increases in newly formed pre- and postsynaptic structures. Monosynaptic projections from LA excitatory neurons to ACx were identified by antero- and retrograde tracing. Dual-colour in vivo two-photon imaging over a period of days showed a gradual increase in putative synaptic pairs formed by LA axon boutons and apical dendritic spines of ACx layer 5(L5) neurons after auditory fear conditioning. This increase in synaptic structures was pathway-specific, as no increase was observed in new boutons on axonal projections from the prefrontal cortex or new dendritic spines on L2/3 neurons in ACx. Furthermore, long-term concurrent imaging of pre- and postsynaptic elements showed that essentially all new putative synaptic contacts were made by newly formed boutons on existing spines ornew spines on existing boutons, suggesting that new synapses in the adult cortex are made by adding new partners to existing synaptic elements. Finally, conditioning-induced synaptic remodelling strongly correlated with the magnitude of the freezing response, consistent with its involvement in fear memory. Together, these findings unravel a novel feedback projection associated with fear learning, and delineate a pathway-specific synaptic structural remodelling that may serve as a substrate for long-term fear memory.

关键词： fear conditioning synaptic plasticity structural dynamics in vivo two-photon imaging synapse formation

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