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Visualizing Presynaptic Active Zones and Synaptic Vesicles. 突触前活动区和突触小泡的可视化
IF 2.8 4区 医学 Q2 NEUROSCIENCES Pub Date : 2022-05-18 eCollection Date: 2022-01-01 DOI: 10.3389/fnsyn.2022.901341
Manfred Heckmann, Martin Pauli

The presynaptic active zone (AZ) of chemical synapses is a highly dynamic compartment where synaptic vesicle fusion and neurotransmitter release take place. During evolution the AZ was optimized for speed, accuracy, and reliability of chemical synaptic transmission in combination with miniaturization and plasticity. Single-molecule localization microscopy (SMLM) offers nanometer spatial resolution as well as information about copy number, localization, and orientation of proteins of interest in AZs. This type of imaging allows quantifications of activity dependent AZ reorganizations, e.g., in the context of presynaptic homeostatic potentiation. In combination with high-pressure freezing and optogenetic or electrical stimulation AZs can be imaged with millisecond temporal resolution during synaptic activity. Therefore SMLM allows the determination of key parameters in the complex spatial environment of AZs, necessary for next generation simulations of chemical synapses with realistic protein arrangements.

化学突触的突触前活性区(AZ)是一个高度动态的隔室,在这里发生突触囊泡融合和神经递质释放。在进化过程中,AZ在化学突触传递的速度、准确性和可靠性方面进行了优化,并结合了小型化和可塑性。单分子定位显微镜(SMLM)提供纳米空间分辨率以及AZ中感兴趣蛋白质的拷贝数、定位和取向信息。这种类型的成像可以量化活动依赖性AZ重组,例如,在突触前稳态增强的背景下。结合高压冷冻和光遗传学或电刺激,可以在突触活动期间以毫秒时间分辨率对AZ进行成像。因此,SMLM允许在AZ的复杂空间环境中确定关键参数,这对于下一代模拟具有真实蛋白质排列的化学突触是必要的。
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引用次数: 0
Chemical Imaging and Analysis of Single Nerve Cells by Secondary Ion Mass Spectrometry Imaging and Cellular Electrochemistry. 利用二次离子质谱成像和细胞电化学技术对单个神经细胞进行化学成像和分析
IF 2.8 4区 医学 Q2 NEUROSCIENCES Pub Date : 2022-05-16 eCollection Date: 2022-01-01 DOI: 10.3389/fnsyn.2022.854957
Alicia A Lork, Kim L L Vo, Nhu T N Phan

A nerve cell is a unit of neuronal communication in the nervous system and is a heterogeneous molecular structure, which is highly mediated to accommodate cellular functions. Understanding the complex regulatory mechanisms of neural communication at the single cell level requires analytical techniques with high sensitivity, specificity, and spatial resolution. Challenging technologies for chemical imaging and analysis of nerve cells will be described in this review. Secondary ion mass spectrometry (SIMS) allows for non-targeted and targeted molecular imaging of nerve cells and synapses at subcellular resolution. Cellular electrochemistry is well-suited for quantifying the amount of reactive chemicals released from living nerve cells. These techniques will also be discussed regarding multimodal imaging approaches that have recently been shown to be advantageous for the understanding of structural and functional relationships in the nervous system. This review aims to provide an insight into the strengths, limitations, and potentials of these technologies for synaptic and neuronal analyses.

神经细胞是神经系统中神经元交流的单位,是一种异质性的分子结构,它是高度介导的,以适应细胞功能。在单细胞水平上理解神经通讯的复杂调控机制需要具有高灵敏度、特异性和空间分辨率的分析技术。本文将介绍神经细胞化学成像和分析的挑战性技术。次级离子质谱(SIMS)允许在亚细胞分辨率下对神经细胞和突触进行非靶向和靶向分子成像。细胞电化学非常适合于定量从活的神经细胞释放的活性化学物质的量。这些技术也将讨论最近被证明有利于理解神经系统结构和功能关系的多模态成像方法。本文综述了这些技术在突触和神经元分析中的优势、局限性和潜力。
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引用次数: 0
Dexmedetomidine and Ketamine Attenuated Neuropathic Pain Related Behaviors via STING Pathway to Induce ER-Phagy 右美托咪定和氯胺酮通过STING途径诱导er吞噬减轻神经性疼痛相关行为
IF 3.7 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-05-13 DOI: 10.3389/fnsyn.2022.891803
Yongda Liu, Shihui Kuai, M. Ding, Zhibin Wang, Limei Zhao, P. Zhao
Our previous work indicated that ER-phagy level had altered in spinal nerve ligation (SNL) rats. In this study, we investigated whether dexmedetomidine or ketamine exhibits anti-anxiety or anti-nociceptive effects via modulation of the spinal STING/TBK pathway to alter ER-phagy in SNL rats. We evaluated the analgesic and anti-anxiety effects of ketamine and dexmedetomidine in SNL rats. 2’3’-cGAMP (a STING pathway agonist) was administrated to investigate whether enhanced spinal STING pathway activation could inhibit dexmedetomidine or ketamine treatment effects in SNL rats. Analgesic effects were assessed with the mechanical withdrawal threshold (MWT) and anti-anxiety effects were measured via an open field test (OFT). Protein expression levels were evaluated by immunoblotting. Distribution and cellular localization of Grp78 (ER stress marker) were evaluated by confocal immunofluorescence. SNL induced mechanical hypersensitivity and anxiety in rats; dexmedetomidine and ketamine both provided analgesia and anti-anxiety effects in SNL rats. Furthermore, the STING pathway was involved in the modulation of ER stress and ER-phagy in SNL rats and dexmedetomidine and ketamine alleviated ER stress by inhibiting STING pathway to enhance ER-phagy. Thus, both ketamine and dexmedetomidine provided anti-anxiety and anti-nociceptive effects by alleviating ER stress through the inhibition of the STING/TBK pathway to modulate spinal ER-phagy in SNL rats.
我们之前的研究表明,脊髓神经结扎(SNL)大鼠er吞噬水平发生了改变。在这项研究中,我们研究了右美托咪定或氯胺酮是否通过调节脊髓STING/TBK通路来改变SNL大鼠的er吞噬而表现出抗焦虑或抗伤害作用。我们评价氯胺酮和右美托咪定对SNL大鼠的镇痛和抗焦虑作用。我们给药2’3’-cGAMP(一种STING通路激动剂)来研究增强脊髓STING通路激活是否能抑制右美托咪定或氯胺酮对SNL大鼠的治疗效果。采用机械戒断阈值(MWT)评估镇痛作用,通过开放场试验(OFT)测量抗焦虑作用。免疫印迹法检测蛋白表达水平。共聚焦免疫荧光法检测内质网应激标志物Grp78的分布和细胞定位。SNL诱导大鼠机械超敏反应和焦虑;右美托咪定和氯胺酮对SNL大鼠均有镇痛和抗焦虑作用。此外,STING通路参与了SNL大鼠内质网应激和ER吞噬的调节,右美托咪定和氯胺酮通过抑制STING通路增强ER吞噬来减轻内质网应激。因此,氯胺酮和右美托咪定均通过抑制STING/TBK通路调节SNL大鼠脊髓ER吞噬,减轻内质网应激,具有抗焦虑和抗伤害作用。
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引用次数: 5
Presynaptic Mitochondria Communicate With Release Sites for Spatio-Temporal Regulation of Exocytosis at the Motor Nerve Terminal 突触前线粒体与释放位点通讯,以调控运动神经末梢的胞吐
IF 3.7 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-05-12 DOI: 10.3389/fnsyn.2022.858340
Mario López-Manzaneda, Andrea Fuentes-Moliz, L. Tabares
Presynaptic Ca2+ regulation is critical for accurate neurotransmitter release, vesicle reloading of release sites, and plastic changes in response to electrical activity. One of the main players in the regulation of cytosolic Ca2+ in nerve terminals is mitochondria, which control the size and spread of the Ca2+ wave during sustained electrical activity. However, the role of mitochondria in Ca2+ signaling during high-frequency short bursts of action potentials (APs) is not well known. Here, we studied spatial and temporal relationships between mitochondrial Ca2+ (mCa2+) and exocytosis by live imaging and electrophysiology in adult motor nerve terminals of transgenic mice expressing synaptophysin-pHluorin (SypHy). Our results show that hot spots of exocytosis and mitochondria are organized in subsynaptic functional regions and that mitochondria start to uptake Ca2+ after a few APs. We also show that mitochondria contribute to the regulation of the mode of fusion (synchronous and asynchronous) and the kinetics of release and replenishment of the readily releasable pool (RRP) of vesicles. We propose that mitochondria modulate the timing and reliability of neurotransmission in motor nerve terminals during brief AP trains.
突触前Ca2+调节对于准确的神经递质释放,释放位点的囊泡重新加载以及响应电活动的塑性变化至关重要。神经末梢胞质Ca2+调节的主要参与者之一是线粒体,它在持续电活动期间控制Ca2+波的大小和传播。然而,线粒体在高频短脉冲动作电位(APs)中Ca2+信号传导中的作用尚不清楚。在这里,我们通过实时成像和电生理研究了表达synaptophysin-pHluorin (SypHy)的转基因小鼠成年运动神经末梢线粒体Ca2+ (mCa2+)与胞外分泌的时空关系。我们的研究结果表明,胞吐和线粒体的热点是在亚突触功能区组织的,线粒体在几次ap后开始摄取Ca2+。我们还表明,线粒体有助于调节融合模式(同步和异步)以及囊泡易释放池(RRP)的释放和补充动力学。我们认为线粒体在短暂的AP训练中调节运动神经末梢神经传递的时间和可靠性。
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引用次数: 4
Different Synaptic Plasticity After Physiological and Psychological Stress in the Anterior Insular Cortex in an Observational Fear Mouse Model 观察性恐惧小鼠模型中前岛皮质生理和心理应激后突触可塑性的差异
IF 3.7 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-05-11 DOI: 10.3389/fnsyn.2022.851015
Wenlong Shi, Yuan Fu, Tian-yao Shi, Wenxia Zhou
Post-traumatic stress disorder (PTSD) can be triggered not only in people who have personally experienced traumatic events but also in those who witness them. Physiological and psychological stress can have different effects on neural activity, but little is known about the underlying mechanisms. There is ample evidence that the insular cortex, especially the anterior insular cortex (aIC), is critical to both the sensory and emotional experience of pain. It is therefore worthwhile to explore the effects of direct and indirect stress on the synaptic plasticity of the aIC. Here, we used a mouse model of observational fear to mimic direct suffering (Demonstrator, DM) and witnessing (Observer, OB) of traumatic events. After observational fear training, using a 64-channel recording system, we showed that both DM and OB mice exhibited a decreased ratio of paired-pulse with intervals of 50 ms in the superficial layers of the aIC but not in the deep layers. We found that theta-burst stimulation (TBS)–induced long-term potentiation (LTP) in OB mice was significantly higher than in DM mice, and the recruitment of synaptic responses occurred only in OB mice. Compared with naive mice, OB mice showed stronger recruitment and higher amplitude in the superficial layers of the aIC. We also used low-frequency stimulation (LFS) to induce long-term depression (LTD). OB mice showed greater LTD in both the superficial and deep layers of the aIC than naive mice, but no significant difference was found between OB and DM mice. These results provide insights into the changes in synaptic plasticity in the aIC after physiological and psychological stress, and suggest that different types of stress may have different mechanisms. Furthermore, identification of the possible causes of the differences in stress could help treat stress-related disorders.
创伤后应激障碍(PTSD)不仅会发生在亲身经历过创伤事件的人身上,也会发生在亲眼目睹这些事件的人身上。生理和心理压力对神经活动有不同的影响,但对其潜在机制知之甚少。有充分的证据表明,岛叶皮质,尤其是前岛叶皮质(aIC),对疼痛的感觉和情感体验都至关重要。因此,直接应激和间接应激对aIC突触可塑性的影响值得进一步探讨。在这里,我们使用观察性恐惧的小鼠模型来模拟创伤事件的直接痛苦(演示者,DM)和目击(观察者,OB)。在观察恐惧训练后,采用64通道记录系统,我们发现DM和OB小鼠在aIC的浅层中出现间隔50 ms的成对脉冲比率下降,而在深层中则没有。我们发现β -爆发刺激(TBS)诱导的长期增强(LTP)在OB小鼠中显著高于DM小鼠,并且突触反应的募集仅发生在OB小鼠中。与幼稚小鼠相比,OB小鼠在aIC浅层表现出更强的招募和更高的振幅。我们还使用低频刺激(LFS)诱导长期抑郁(LTD)。OB小鼠aIC浅层和深层的LTD均高于幼稚小鼠,但OB与DM小鼠之间无显著差异。这些结果揭示了生理和心理应激后aIC突触可塑性的变化,并提示不同类型的应激可能有不同的机制。此外,确定压力差异的可能原因有助于治疗压力相关疾病。
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引用次数: 2
Resilient Hippocampal Gamma Rhythmogenesis and Parvalbumin-Expressing Interneuron Function Before and After Plaque Burden in 5xFAD Alzheimer's Disease Model. 5xFAD阿尔茨海默病模型斑块负荷前后海马伽马节律发生和小蛋白表达的中间神经元功能
IF 3.7 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-05-11 eCollection Date: 2022-01-01 DOI: 10.3389/fnsyn.2022.857608
Connie A Mackenzie-Gray Scott, Kenneth A Pelkey, Adam P Caccavano, Daniel Abebe, Mandy Lai, Khayla N Black, Nicolette D Brown, Andrew J Trevelyan, Chris J McBain

Recent studies have implicated impaired Parvalbumin Fast-Spiking Interneuron (PVIN) function as a precipitating factor underlying abnormalities in network synchrony, oscillatory rhythms, and cognition associated with Alzheimer's disease (AD). However, a complete developmental investigation of potential gamma deficits, induced by commonly used carbachol or kainate in ex vivo slice preparations, within AD model mice is lacking. We examined gamma oscillations using field recordings in acute hippocampal slices from 5xFAD and control mice, through the period of developing pathology, starting at 3 months of age, when there is minimal plaque presence in the hippocampus, through to 12+ months of age, when plaque burden is high. In addition, we examined PVIN participation in gamma rhythms using targeted cell-attached recordings of genetically-reported PVINs, in both wild type and mutant mice. In parallel, a developmental immunohistochemical characterisation probing the PVIN-associated expression of PV and perineuronal nets (PNNs) was compared between control and 5xFAD mice. Remarkably, this comprehensive longitudinal evaluation failed to reveal any obvious correlations between PVIN deficits (electrical and molecular), circuit rhythmogenesis (gamma frequency and power), and Aβ deposits/plaque formation. By 6-12 months, 5xFAD animals have extensive plaque formation throughout the hippocampus. However, a deficit in gamma oscillatory power was only evident in the oldest 5xFAD animals (12+ months), and only when using kainate, and not carbachol, to induce the oscillations. We found no difference in PV firing or phase preference during kainate-induced oscillations in younger or older 5xFAD mice compared to control, and a reduction of PV and PNNs only in the oldest 5xFAD mice. The lack of a clear relationship between PVIN function, network rhythmicity, and plaque formation in our study highlights an unexpected resilience in PVIN function in the face of extensive plaque pathology associated with this model, calling into question the presumptive link between PVIN pathology and Alzheimer's progression.

最近的研究表明,小白蛋白快速脉冲中间神经元(PVIN)功能受损是阿尔茨海默病(AD)相关的网络同步、振荡节律和认知异常的诱发因素。然而,在AD模型小鼠中,缺乏对离体切片制剂中常用的氨基酚或海因酸盐诱导的潜在γ缺陷的完整发育研究。我们通过对5xFAD小鼠和对照小鼠急性海马切片的场记录来检测伽马振荡,从3个月大开始,海马中存在最小的斑块,到12个多月大,斑块负担高。此外,在野生型和突变型小鼠中,我们使用基因报道的PVINs的靶向细胞附着记录来检测PVIN在伽马节律中的参与。同时,比较了对照和5xFAD小鼠pvin相关的PV和神经元周围网(PNNs)表达的发育免疫组织化学特征。值得注意的是,这项全面的纵向评估未能揭示PVIN缺陷(电和分子)、电路节律发生(伽马频率和功率)和Aβ沉积/斑块形成之间的任何明显相关性。到6-12个月时,5xFAD动物在整个海马区形成广泛的斑块。然而,伽马振荡能力的缺陷仅在年龄最大的5xFAD动物(12个月以上)中表现明显,并且仅在使用海纳酸盐而不是氨基酚来诱导振荡时才会出现。我们发现,与对照组相比,年轻或年老的5xFAD小鼠在kainate诱导的振荡中PV放电或相偏好没有差异,并且仅在年老的5xFAD小鼠中PV和PNNs减少。在我们的研究中,PVIN功能、网络节律性和斑块形成之间缺乏明确的关系,这突出了PVIN功能在面对与该模型相关的广泛斑块病理时的意想不到的弹性,这对PVIN病理与阿尔茨海默病进展之间的假定联系提出了质疑。
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引用次数: 0
Selective Recruitment of Presynaptic and Postsynaptic Forms of mGluR-LTD 突触前和突触后mGluR-LTD的选择性募集
IF 3.7 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-05-09 DOI: 10.3389/fnsyn.2022.857675
Thomas M. Sanderson, Liam Ralph, M. Amici, Ai Na Ng, B. Kaang, M. Zhuo, S. Kim, J. Georgiou, G. Collingridge
In area CA1 of the hippocampus, long-term depression (LTD) can be induced by activating group I metabotropic glutamate receptors (mGluRs), with the selective agonist DHPG. There is evidence that mGluR-LTD can be expressed by either a decrease in the probability of neurotransmitter release [P(r)] or by a change in postsynaptic AMPA receptor number. However, what determines the locus of expression is unknown. We investigated the expression mechanisms of mGluR-LTD using either a low (30 μM) or a high (100 μM) concentration of (RS)-DHPG. We found that 30 μM DHPG generated presynaptic LTD that required the co-activation of NMDA receptors, whereas 100 μM DHPG resulted in postsynaptic LTD that was independent of the activation of NMDA receptors. We found that both forms of LTD occur at the same synapses and that these may constitute the population with the lowest basal P(r). Our results reveal an unexpected complexity to mGluR-mediated synaptic plasticity in the hippocampus.
在海马CA1区,在选择性激动剂DHPG的作用下,激活I组代谢性谷氨酸受体(mGluRs)可诱导长期抑郁(LTD)。有证据表明,mGluR-LTD可以通过神经递质释放概率的降低[P(r)]或突触后AMPA受体数量的变化来表达。然而,是什么决定了表达位点是未知的。我们使用低(30 μM)和高(100 μM)浓度的(RS)-DHPG来研究mGluR-LTD的表达机制。我们发现30 μM DHPG产生的突触前LTD需要NMDA受体的共同激活,而100 μM DHPG产生的突触后LTD不依赖于NMDA受体的激活。我们发现这两种形式的LTD发生在相同的突触上,这些可能构成了最低基础P(r)的群体。我们的研究结果揭示了mglur介导的海马突触可塑性的意想不到的复杂性。
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引用次数: 3
Editorial: The Emerging Role of Endocannabinoids in Synaptic Plasticity, Reward, and Addiction 社论:内源性大麻素在突触可塑性、奖赏和成瘾中的新作用
IF 3.7 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-05-09 DOI: 10.3389/fnsyn.2022.898090
J. G. Edwards, L. Cristino, Dan P Covey
Endocannabinoids (eCBs) are lipid-signaling molecules that often work in a retrograde fashion. Themost common eCBs are 2-arachidonoylglycerol (2-AG) and anandamide, which bind receptors such as cannabinoid receptor 1 (CB1) and CB2. Endocannabinoid signaling controls synaptic transmission throughout the central nervous system, and is important in modulating activity and behavior in the mesolimbic reward circuit, including the ventral tegmental area (VTA), nucleus accumbens (NAc), and lateral habenula (LHb). In these regions, the eCB system is essential for normal reward learning and for some maladaptive behaviors underlying drug abuse and addiction. Recently identified lipid-signaling eCB-like molecules are also now understood to shape mesolimbic system function and reward-related behaviors. Further elucidating how the eCB system contributes to reward and addiction is especially pertinent given the recent legalization ofmedicinal or recreationalmarijuana throughout the world. Themajor psychoactive component inmarijuana is1-9-tetrahydrocannabinol (THC), which binds CB1. Common effects of THC are short-termmemory loss, appetite stimulation, and reward. There is still much to investigate concerning THC use, particularly the impact of adolescent use, with a focus on long-term alterations in eCB system function and behavioral changes. Further research is required to clarify the role of the endogenous eCB system, and the effect of exogenous CB1 or CB2targeting drugs on mesolimbic function, including synaptic plasticity, to support reward behaviors and addiction. This Research Topic focuses on endogenous eCB system function in the mesolimbic circuit with an emphasis on synaptic plasticity, reward behavior, novel eCB-like molecules, and pain.
内源性大麻素(eCBs)是脂质信号分子,通常以逆行方式工作。最常见的eCBs是2-花生酰甘油(2-AG)和阿那达明,它们结合受体,如大麻素受体1(CB1)和CB2。内源性大麻素信号控制整个中枢神经系统的突触传递,并在调节中边缘奖赏回路的活动和行为中发挥重要作用,包括腹侧被盖区(VTA)、伏隔核(NAc)和外侧缰核(LHb)。在这些地区,eCB系统对于正常的奖励学习以及药物滥用和成瘾背后的一些不适应行为至关重要。最近鉴定的脂质信号传导eCB样分子现在也被理解为塑造中边缘系统功能和奖励相关行为。鉴于最近世界各地的医用或娱乐大麻合法化,进一步阐明eCB系统如何促进奖励和成瘾尤其重要。大麻的主要精神活性成分是-9-四氢大麻酚(THC),它能结合CB1。四氢大麻酚的常见影响是短期记忆丧失、食欲刺激和奖励。关于四氢大麻酚的使用,特别是青少年使用的影响,还有很多需要研究,重点是eCB系统功能和行为变化的长期改变。需要进一步的研究来阐明内源性eCB系统的作用,以及外源性CB1或CB2靶向药物对中边缘功能的影响,包括突触可塑性,以支持奖励行为和成瘾。本研究主题关注中边缘回路中的内源性eCB系统功能,重点关注突触可塑性、奖励行为、新型eCB样分子和疼痛。
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引用次数: 0
Cellular Strategies for Frequency-Dependent Computation of Interaural Time Difference 基于频率相关的耳间时差计算的元策略
IF 3.7 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-05-06 DOI: 10.3389/fnsyn.2022.891740
Rei Yamada, H. Kuba
Binaural coincidence detection is the initial step in encoding interaural time differences (ITDs) for sound-source localization. In birds, neurons in the nucleus laminaris (NL) play a central role in this process. These neurons receive excitatory synaptic inputs on dendrites from both sides of the cochlear nucleus and compare their coincidences at the soma. The NL is tonotopically organized, and individual neurons receive a pattern of synaptic inputs that are specific to their tuning frequency. NL neurons differ in their dendritic morphology along the tonotopic axis; their length increases with lower tuning frequency. In addition, our series of studies have revealed several frequency-dependent refinements in the morphological and biophysical characteristics of NL neurons, such as the amount and subcellular distribution of ion channels and excitatory and inhibitory synapses, which enable the neurons to process the frequency-specific pattern of inputs appropriately and encode ITDs at each frequency band. In this review, we will summarize these refinements of NL neurons and their implications for the ITD coding. We will also discuss the similarities and differences between avian and mammalian coincidence detectors.
双耳一致性检测是对用于声源定位的耳间时间差(ITD)进行编码的初始步骤。在鸟类中,层核(NL)的神经元在这一过程中起着核心作用。这些神经元在耳蜗核两侧的树突上接收兴奋性突触输入,并比较它们在胞体处的一致性。NL是非局部组织的,单个神经元接收特定于其调谐频率的突触输入模式。NL神经元沿眼压轴的树突形态不同;它们的长度随着调谐频率的降低而增加。此外,我们的一系列研究揭示了NL神经元形态和生物物理特征的几个频率依赖性改进,如离子通道的数量和亚细胞分布以及兴奋性和抑制性突触,这使神经元能够适当地处理频率特异性输入模式,并在每个频带编码ITD。在这篇综述中,我们将总结NL神经元的这些改进及其对ITD编码的意义。我们还将讨论鸟类和哺乳动物重合探测器之间的异同。
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引用次数: 0
Mechanisms Underlying Mu Opioid Receptor Effects on Parallel Fiber-Purkinje Cell Synaptic Transmission in Mouse Cerebellar Cortex Mu阿片受体对小鼠小脑皮质平行纤维浦肯野细胞突触传递影响的机制
IF 3.7 4区 医学 Q3 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-04-25 DOI: 10.3389/fnsyn.2022.862704
Yi Yang, Jinliang Bai, Jianyuan Sun, Ting Ye, Lu Zhang, Fengfeng Wu, Jun Nan, Yan Lan
μ-opioid receptors (MOR) are widely expressed in the brain, varying in density in different areas. Activation of MORs underlies analgesia, euphoria, but may lead to tolerance, dependence, and ultimately opioid addiction. The Purkinje cell (PC) is the only efferent neuron in the cerebellar cortex and receives glutamatergic synaptic inputs from the parallel fibers formed by the axons of granule cells. Studies have shown that MORs are expressed during the development of cerebellar cells. However, the distribution of MOR and their effects on PF-PC synaptic transmission remain unclear. To examine these questions, we used whole-cell patch clamp recordings and pharmacological methods to determine the effects and mechanisms of MOR activation on synaptic transmission at PF-PC synapses. The MOR-selective agonist DAMGO significantly reduced the amplitude and area under the curve (AUC) of PF-PC evoked (e) EPSCs, and increased the paired-pulse ratio (PPR).DAMGO-induced inhibitory effects on PF-PC eEPSCs and PPR were abolished by MOR specific blocker CTOP. Further, DAMGO significantly reduced the frequency of PF-PC mEPSCs, but had no obvious effect on their amplitude, suggesting a presynaptic site of action. The DAMGO-induced reduction in the frequency of PF-PC mEPSCs also was blocked by CTOP. A protein kinase A (PKA) inhibitor PKI added in the pipette solution did not affect the inhibitory effects on PF-PC mEPSCs induced by DAMGO. Both the PKA inhibitor K5720 and MEK inhibitor U0126 in artificial cerebrospinal fluid (ACSF) prevented the inhibitory effects of DAMGO on PF-PC mEPSCs. These findings reveal that MORs are expressed in presynaptic PF axon terminals, where DAMGO can activate presynaptic MORs to inhibit PF-PC synaptic transmission by regulating the release of glutamate. G-protein-dependent cAMP-PKA signaling pathway may be involved in this process.
μ-阿片受体(μ-opioid receptor, MOR)在大脑中广泛表达,在不同区域密度不同。MORs的激活是镇痛、欣快的基础,但也可能导致耐受性、依赖性,最终导致阿片类药物成瘾。浦肯野细胞(PC)是小脑皮层中唯一的传出神经元,接受由颗粒细胞轴突形成的平行纤维的谷氨酸突触输入。研究表明MORs在小脑细胞发育过程中表达。然而,MOR的分布及其对PF-PC突触传递的影响尚不清楚。为了研究这些问题,我们使用全细胞膜片钳记录和药理学方法来确定MOR激活对PF-PC突触突触传递的影响和机制。mor选择性激动剂DAMGO显著降低了PF-PC诱发的(e) EPSCs的振幅和曲线下面积(AUC),增加了配对脉冲比(PPR)。damgo诱导的对PF-PC eEPSCs和PPR的抑制作用被MOR特异性阻断剂CTOP消除。此外,DAMGO显著降低了PF-PC mEPSCs的频率,但对其振幅没有明显影响,提示其作用于突触前部位。damgo诱导的PF-PC mEPSCs频率的降低也被CTOP阻断。在移液中加入蛋白激酶A (PKA)抑制剂PKI对DAMGO诱导的PF-PC mEPSCs的抑制作用不受影响。人工脑脊液(ACSF)中PKA抑制剂K5720和MEK抑制剂U0126均可阻止DAMGO对PF-PC mEPSCs的抑制作用。这些发现表明MORs在突触前PF轴突末端表达,DAMGO可以通过调节谷氨酸的释放激活突触前MORs抑制PF- pc突触传递。g蛋白依赖性cAMP-PKA信号通路可能参与了这一过程。
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引用次数: 2
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Frontiers in Synaptic Neuroscience
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