CRCNS: State dependent neural mechanisms for respiratory pattern generation

CRCNS：呼吸模式生成的状态依赖神经机制

• 批准号: 7898548
• 负责人: Ilya A Rybak
• 金额: $ 28.12万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-02 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898548
• 关键词: Abdomen; Brain Stem; Breathing; Collaborations; Complex; Computer Simulation; Data; Dependency; Generations; Goals; Hybrids; Investigation; Ion Channel; Laboratories; Methods; Modeling; Motor; Motor output; National Institute of Neurological Disorders and Stroke; Network-based; Neurons; Pacemakers; Pattern; Pontine structure; Preparation; Property; Respiration Disorders; Sleep Apnea Syndromes; Sodium; Spinal cord injury; Structure of phrenic nerve; Synaptic Transmission; System; Testing; United States National Institutes of Health; Universities; insight; multidisciplinary; neuromechanism; research study; respiratory; simulation

DESCRIPTION (provided by applicant): Generation of the respiratory motor pattern is performed in the lower brainstem and involves complex cross-level interactions of cellular, network, and systems-level mechanisms. Because of these complex interactions, the system can operate in different functional states and engage different rhythmogenic mechanisms in each state. We hypothesize that the rhythmogenic mechanism operating in the respiratory network (i.e., network-based, pacemaker-driven or hybrid) is defined by the state of the pre-Botzinger complex, which in turn operates under control of other medullary and pontine circuits. We also suggest that the pons controls the state of the pre-Botzinger complex (and hence the rhythmogenic mechanism) directly and/or through other medullary circuits, such as the Botzinger complex. The overall goal of this multidisciplinary collaborative project is to investigate and understand these complex interactions and the state-dependency of respiratory rhythm generation by using experimental studies combined with computational modeling. The experimental studies will be performed by Dr. Smith (NINDS, NIH) and Dr. Paton (University of Bristol). The applied experimental methods will include (1) reduction of the operating respiratory network by sequential and highly precise transections applied to the pons and medulla and (2) using specific blockers of intrinsic neuronal properties (e.g., persistent sodium and other ionic channels) and network interactions (e.g., inhibitory synaptic transmission) applied to intact and reduced preparations. The computational model of the ponto-medullary respiratory network will be further developed by the group of Dr. Rybak (Drexel University) in close interactive collaboration with Drs. Smith and Paton using data accumulated in their laboratories. In turn, complementary experimental studies in these laboratories will be driven by modeling predictions. The resultant comprehensive computational model will be developed, tested and elaborated to reproduce the experimentally observed state-dependent changes in the firing patterns of respiratory neurons and in the discharge patterns of output motor nerves (phrenic, hypoglossal, central vagal and abdominal) under different experimental conditions. The proposed collaborative study will provide important insights into the complex neural mechanisms for control of breathing Ultimately, the model that will be developed in this project may be used for simulation of multiple respiratory disorders and diseases (e.g., sleep apnea, brainstem/spinal cord injury, CCHS), and for developing and investigations new methods for their treatment.

描述（由申请人提供）：呼吸运动模式的产生在脑干下部进行，涉及复杂的细胞、网络和系统级机制的跨水平相互作用。由于这些复杂的相互作用，系统可以在不同的功能状态下运行，并在每种状态下参与不同的节律机制。我们假设在呼吸网络（即网络为基础，起搏器驱动或混合）中运行的节律机制是由前波青格复合体的状态定义的，而波青格复合体又在其他髓质和脑桥电路的控制下运行。我们还认为，脑桥直接或通过其他髓质回路，如波青格复合体，控制波青格前复合体的状态（从而控制心律机制）。这个多学科合作项目的总体目标是通过实验研究结合计算建模来调查和理解这些复杂的相互作用和呼吸节律产生的状态依赖性。实验研究将由Smith博士（NINDS， NIH）和Paton博士（布里斯托尔大学）进行。应用的实验方法将包括(1)通过应用于脑桥和髓质的顺序和高度精确的横切来减少操作的呼吸网络，(2)使用特定的神经元固有特性阻滞剂（例如，持久的钠和其他离子通道）和网络相互作用（例如，抑制性突触传递）应用于完整和减少的制剂。Rybak博士（Drexel大学）的研究小组将与dr。史密斯和佩顿使用了他们实验室积累的数据。反过来，这些实验室的补充实验研究将由建模预测驱动。由此产生的综合计算模型将被开发、测试和详细阐述，以重现实验观察到的呼吸神经元放电模式和输出运动神经（膈神经、舌下神经、中央迷走神经和腹部神经）在不同实验条件下放电模式的状态依赖变化。该合作研究将为呼吸控制的复杂神经机制提供重要的见解，最终，该项目将开发的模型可用于多种呼吸系统疾病和疾病的模拟（例如，睡眠呼吸暂停，脑干/脊髓损伤，CCHS），并用于开发和研究其治疗的新方法。

项目成果

Interacting oscillations in neural control of breathing: modeling and qualitative analysis.

• DOI: 10.1007/s10827-010-0281-0
• 发表时间: 2011-06
• 期刊: JOURNAL OF COMPUTATIONAL NEUROSCIENCE
• 影响因子: 1.2
• 作者: Rubin, Jonathan E.;Bacak, Bartholomew J.;Molkov, Yaroslav I.;Shevtsova, Natalia A.;Smith, Jeffrey C.;Rybak, Ilya A.
• 通讯作者: Rybak, Ilya A.

Location and properties of respiratory neurones with putative intrinsic bursting properties in the rat in situ.

大鼠原位具有假定内在爆发特性的呼吸神经元的位置和特性。

• DOI: 10.1113/jphysiol.2009.170308
• 发表时间: 2009
• 期刊: The Journal of physiology
• 作者: St-John,WalterM;Stornetta,RuthL;Guyenet,PatriceG;Paton,JulianFR
• 通讯作者: Paton,JulianFR

Physiological and pathophysiological interactions between the respiratory central pattern generator and the sympathetic nervous system.

• DOI: 10.1016/b978-0-444-63488-7.00001-x
• 发表时间: 2014
• 期刊: Progress in brain research
• 作者: Molkov YI;Zoccal DB;Baekey DM;Abdala AP;Machado BH;Dick TE;Paton JF;Rybak IA
• 通讯作者: Rybak IA

Structural-functional properties of identified excitatory and inhibitory interneurons within pre-Botzinger complex respiratory microcircuits.

• DOI: 10.1523/jneurosci.4427-12.2013
• 发表时间: 2013-02-13
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Koizumi H;Koshiya N;Chia JX;Cao F;Nugent J;Zhang R;Smith JC
• 通讯作者: Smith JC

Effects of glycinergic inhibition failure on respiratory rhythm and pattern generation.

• DOI: 10.1016/b978-0-444-63274-6.00002-3
• 发表时间: 2014
• 期刊: PROGRESS IN BRAIN RESEARCH
• 作者: Shevtsova, Natalia A.;Buesselberg, Dietrich;Molkov, Yaroslav I.;Bischoff, Anne M.;Smith, Jeffrey C.;Richter, Diethelm W.;Rybak, Ilya A.
• 通讯作者: Rybak, Ilya A.