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Collaborative Research: Glial regulation of extracellular potassium as an underlying developmental mechanism for the male-female difference in pacemaker neuron firing frequency

合作研究：细胞外钾的神经胶质调节作为起搏器神经元放电频率男女差异的潜在发育机制

基本信息

批准号：
1946910
负责人：
Gunther Zupanc
金额：
$ 86.24万
依托单位：
Northeastern University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1946910&HistoricalAwards=false
关键词：
Collaborative Research Glial regulation extracellular

项目摘要

Differences in body form and behavior between males and females are well established in numerous species, but little is known about how they are organized during development. Electric communication by the brown ghost knifefish provides a unique opportunity for elucidating the cellular mechanisms mediating one such difference. In this weakly electric fish, males produce electric organ discharges that contain higher frequencies than those of females. The difference in discharge frequencies is controlled by the pacemaker nucleus, a neural circuit in the brainstem. Using an interdisciplinary strategy, a novel mechanistic hypothesis will be tested: astrocytes (a glial cell type) regulate (buffer) extracellular potassium ions differently in males and females, and this is responsible for the difference in their electric organ discharges. Besides providing new insights into the molecular and cellular mechanisms that underlie one specific behavior that is dimorphic between males and females, this research will also advance knowledge about the role of astrocytes in potassium buffering in the nervous system, and about the regulation of neural networks by these ions. The latter two topics play an important role in the etiology of pathological conditions involving pattern-generating neural circuits (for example, high-frequency epileptic seizures are thought to result from an impairment in potassium buffering that enhances the susceptibility for such seizures). Because of the interdisciplinary nature of this research, multiple opportunities are also provided for training students in diverse disciplines, and for curriculum development at the interface between biology and other STEM disciplines. Undergraduates will be involved in carrying out this research project via directed study courses being offered at both Northeastern University and the University of Virginia; 6-month internships will also be offered for students from Northeastern University to participate in the parts of the project conducted and at the University of Virginia. The PI and co-PI will also use parts of this research in laboratory-based upper-level undergraduate courses that they teach at their respective institutions, as well as engaging in outreach activities at local high schools and a series of STEM events for the general public. The electric organ discharge of the weakly electric fish Apteronotus leptorhynchus is a robust and well-characterized behavioral system. The frequency of these discharges is reliably different in males and females, and controlled by the neural activity of the pacemaker nucleus, an endogenous oscillator in the medulla oblongata. The neurons critically involved in the generation of these oscillations are the pacemaker and relay cells, which are enveloped by astrocytic syncytia. Significant male-female differences exist in the morphology of these astrocytes, their expression of glia-specific proteins, and the gap-junction coupling of individuals cells within the syncytium. The study will test the hypothesis that the development of the male-female difference in the frequency of the electric organ discharge is regulated through modulation by the astrocytic buffering capacity of extracellular potassium ions in the pacemaker nucleus, thereby resulting in changes in the extracellular potassium concentration and ultimately in the oscillation frequency of the neural network composed of pacemaker and relay cells. To achieve this objective, a multi- and interdisciplinary approach will be employed, including morphological and molecular analysis of the association of the astrocytic syncytium with the pacemaker and relay cells; pharmacological manipulation of glial function and examination of its behavioral effect; electrophysiological characterization of the ionic mechanisms of astrocytes that control the firing frequency of the pacemaker nucleus; and computational modeling of (i) the uptake and redistribution of potassium ions by the astrocytic syncytium, (ii) the effect of this action on the frequency of the neural oscillations of the pacemaker nucleus.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在许多物种中，雄性和雌性之间的身体形态和行为差异已经得到了很好的证实，但人们对它们在发育过程中是如何组织的知之甚少。电通信的棕色鬼刀鱼提供了一个独特的机会，阐明介导这样的差异的细胞机制。在这种弱电鱼类中，雄性产生的电器官放电频率高于雌性。放电频率的差异是由起搏核控制的，起搏核是脑干中的神经回路。使用跨学科的策略，一个新的机制假设将被测试：星形胶质细胞（神经胶质细胞类型）调节（缓冲）细胞外钾离子在男性和女性不同，这是负责他们的电器官放电的差异。除了提供新的见解的分子和细胞机制，是一个特定的行为，是两性之间的二态性，这项研究也将推进知识星形胶质细胞在钾缓冲在神经系统中的作用，以及关于神经网络的调节这些离子。后两个主题在涉及模式生成神经回路的病理条件的病因学中起着重要作用（例如，高频率癫痫发作被认为是由于钾缓冲受损而导致的，这增强了对此类发作的易感性）。由于这项研究的跨学科性质，也提供了多种机会，培养学生在不同的学科，并在生物学和其他STEM学科之间的接口课程开发。本科生将通过东北大学和弗吉尼亚大学提供的定向学习课程参与开展这一研究项目;东北大学的学生也将参加该项目的部分工作，并在弗吉尼亚大学进行为期6个月的实习。PI和co-PI还将在他们各自机构教授的基于实验室的高级本科课程中使用部分研究，以及在当地高中开展外联活动和一系列STEM活动。弱电鱼Apteronotusleptorhynchus的电器官放电是一个具有丰富特征的行为系统。这些放电的频率在男性和女性中确实不同，并且由延髓中的内源性振荡器起搏核的神经活动控制。关键参与产生这些振荡的神经元是起搏细胞和中继细胞，它们被星形细胞合胞体包裹。这些星形胶质细胞的形态、胶质细胞特异性蛋白的表达以及合胞体内单个细胞的间隙连接偶联存在显著的男女差异。该研究将检验以下假设：电器官放电频率的男女差异的发展是通过起搏核中细胞外钾离子的星形胶质细胞缓冲能力的调节来调节的，从而导致细胞外钾浓度的变化，并最终导致由起搏细胞和中继细胞组成的神经网络的振荡频率的变化。为了实现这一目标，将采用多学科和跨学科的方法，包括星形胶质细胞合胞体与起搏细胞和中继细胞之间联系的形态学和分子学分析;胶质细胞功能的药理学操纵及其行为效应的检查;控制起搏核放电频率的星形胶质细胞离子机制的电生理学特征;以及（i）星形细胞合胞体对钾离子的摄取和再分布，（二）该奖项反映了NSF的法定使命，并已被认为值得通过使用基金会的智力价值和更广泛的影响审查评估的支持的搜索.

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The effect of urethane and MS-222 anesthesia on the electric organ discharge of the weakly electric fish Apteronotus leptorhynchus

DOI：
10.1007/s00359-022-01606-6
发表时间：
2023-02-17
期刊：
JOURNAL OF COMPARATIVE PHYSIOLOGY A-NEUROETHOLOGY SENSORY NEURAL AND BEHAVIORAL PHYSIOLOGY
影响因子：
2.1
作者：
Eske，Annika I.;Lehotzky，David;Zupanc，Guenther K. H.
通讯作者：
Zupanc，Guenther K. H.

Computational modeling predicts regulation of central pattern generator oscillations by size and density of the underlying heterogenous network