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

• 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

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，男性和女性之间的身体形态和行为差异已经很好地确立，但是关于它们在发育过程中的组织方式知之甚少。 Brown Ghost Knife鱼通过电动通信提供了一个独特的机会，可以阐明介导一种这种差异的细胞机制。在这种弱的电鱼中，雄性产生的电气器官排放量比女性的频率更高。出院频率的差异由起搏器核（Pacemaker Nucleus）（脑干中的神经回路）控制。使用跨学科策略，将测试一种新型的机理假设：男性和女性的星形胶质细胞（神经胶质细胞类型）调节（缓冲液）细胞外钾离子不同，这是其电动器官放电的差异。除了提供有关男性和女性之间具有二态性能的分子和细胞机制的新见解外，这项研究还将提高人们对星形胶质细胞在神经系统中缓冲钾的作用以及这些离子对神经网络的调节的知识。后两个主题在涉及模式生成神经回路的病理疾病的病因中起着重要作用（例如，高频癫痫发作被认为是由于钾缓冲的损害而导致的，从而增强了这种癫痫发作的易感性）。由于这项研究的跨学科性质，还为培训不同学科的学生以及生物学与其他STEM学科之间界面的课程发展提供了多种机会。本科生将通过在东北大学和弗吉尼亚大学提供的指示学习课程来参与该研究项目；还将为来自东北大学的学生提供6个月的实习，以参加所进行的项目的部分和弗吉尼亚大学。 PI和Co-Pi还将在他们在各自机构中教授的基于实验室的高级本科课程中使用这项研究的一部分，并在当地高中进行外展活动，并为公众开展一系列STEM活动。弱电鱼垂体的电气器官排放是一种健壮且表征良好的行为系统。这些放电的频率在男性和女性中有可靠的不同，并且受到起搏器核的神经活性的控制，而起搏器核的神经活性是髓质的内源性振荡器。这些振荡产生的神经元是起搏器和继电器细胞，这些神经元被星形胶质细胞合成细胞包裹。这些星形胶质细胞的形态存在显着的男女差异，它们的神经胶质特异性蛋白的表达以及合成剂中个体细胞的间隙结耦合。该研究将检验以下假设：电机排放频率的男性女性差异的发展受到调节的调节，该假设是通过调节的调节，通过调节起搏器核中细胞外钾离子的星形缓冲能力，从而导致细胞外钾的浓度变化，并最终在Pacemaker和Pacemaker和相关的Neural网络频率中最终。为了实现这一目标，将采用多学科和跨学科的方法，包括对星形胶质细胞合成与起搏器和继电器细胞关联的形态和分子分析；对神经胶质功能的药理操纵及其行为效应的检查；控制起搏器核的发射频率的星形胶质细胞离子机制的电生理表征； （i）通过星形胶质细胞合成剂对钾离子的摄取和重新分布的计算模型，（ii）这种动作对PAPEMAKER核神经振荡频率的影响。该奖项反映了NSF的法定任务，并通过使用基金会的智力效果和宽阔的影响来评估NSF的法定任务，并具有评估的支持。

项目成果

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

• DOI: 10.1007/s10827-022-00835-7
• 发表时间: 2022-10-06
• 期刊: JOURNAL OF COMPUTATIONAL NEUROSCIENCE
• 影响因子: 1.2
• 作者: Ilies, Iulian;Zupanc, Gunther K. H.
• 通讯作者: Zupanc, Gunther K. H.

Modeling of sustained spontaneous network oscillations of a sexually dimorphic brainstem nucleus: the role of potassium equilibrium potential

• DOI: 10.1007/s10827-021-00789-2
• 发表时间: 2021-05-25
• 期刊: JOURNAL OF COMPUTATIONAL NEUROSCIENCE
• 影响因子: 1.2
• 作者: Hartman, Daniel;Lehotzky, David;Zupanc, Gunther K. H.
• 通讯作者: Zupanc, Gunther K. H.

Suggested reviewers: friends or foes?

• DOI: 10.1007/s00359-022-01553-2
• 发表时间: 2022-05-07
• 期刊: JOURNAL OF COMPARATIVE PHYSIOLOGY A-NEUROETHOLOGY SENSORY NEURAL AND BEHAVIORAL PHYSIOLOGY
• 影响因子: 2.1
• 作者: Zupanc, Gunther K. H.