Modifiability of Conduction Across Preganglionic Axonal Branch Points

跨节前轴突分支点传导的可修改性

• 批准号: 10196286
• 负责人: SHAWN HOCHMAN
• 金额: $ 42.04万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196286
• 关键词: Acute; Adult; Agonist; Autonomic Dysfunction; Axon; Behavioral; Blood; Blood Vessels; Body Temperature; Cavia; Chest; Chronic; Ensure; Failure; Frequencies; Functional disorder; Ganglia; Human; Hyperthermia; Impairment; Individual; Injury; Life; Lumbar spinal cord structure; Modification; Mus; Nervous System Trauma; Neurons; Nodal; Output; Pain; Pharmacology; Physiologic Thermoregulation; Physiological; Population; Property; Regulation; Role; Safety; Sensory; Signal Transduction; Site; Skin injury; Spinal Cord; Spinal cord injury; Splanchnic Nerves; Synapses; System; Temperature; Testing; Thoracic spinal cord structure; Time; Travel; Ventral Roots; Width; base; dermatome; experimental study; neuroregulation; neurosteroids; novel; optogenetics; presynaptic; prevent; receptor; receptor function; recruit; response; somatosensory

PROJECT SUMMARY Spinal cord sympathetic preganglionic neurons (SPNs) are found in the thoracic and lumbar spinal cord. They are the final arbiters of CNS sympathetic output. SPN axons branch to issue highly divergent multisegmental projections on paravertebral sympathetic chain ganglia postganglionic neurons (PNs). Divergence provides a mechanism for amplification of CNS sympathetic commands to the numerically much greater PNs. It is assumed that spike conduction is reliable across multisegmental branch points. This was based on ex vivo recordings from the sympathetic chain at room temperature (T°) where large increases in spike amplitude and width ensure a high safety factor for branch point conduction. As increasing T° promotes conduction failures, it is likely that SPN branch point conduction is also T°-sensitive. In somatosensory systems, branch points provide an important site for control of axonal conduction and extrasynaptic α5-containing GABAA receptors (GABAARs) are implicated. SPNs also express α5-GABAARs, and their expression at presynaptic axonal branch points may similarly control divergence and hence response amplification to PNs. We recorded from SPN axons diverging across ganglia in the adult mouse ex vivo thoracic paravertebral chain following stimulation of attached ventral roots. Initial experiments observed that conduction block was dependent on; number of traversed chain ganglia, T°, frequency, and GABAAR antagonists. Results support axonal divergence as a modifiable output stage in sympathetic gain control. [SA1] We hypothesize that preganglionic axonal conduction block across branch points is under neuromodulatory control by constitutively active, α5-containing GABAAR. We undertake experiments to aess axonal recruitment changes following application of GABAAR agonists, antagonists and endogenous neurosteroid allosteric modulators and tested across the physiological range of firing frequencies. [SA2] Many spinal cord injured (SCI) individuals have thermoregulatory dysfunction. As even small elevations in body T° can compromise spike conduction, SPN axonal function in the SCI population may be particularly vulnerable. We hypothesize that conduction across branch points is sensitive to the broader changes in T°core and will test the effect of T° on conduction block over a range of T° consistent with hypo- or hyperthermia. [SA3] We hypothesize that SCI leads to changes that promote conduction across branch points, including (a) increased GABAAR activity and (b) spike width broadening. Results above will be compared to those seen after T2 thoracic SCI at early (1-3 days) and chronic (4-6 weeks) time points. Exploring mechanisms that promote or prevent conduction across branch points is critical to understanding whether SPN signal amplification is hard-wired or physiologically modifiable (e.g. behavioral state dependent) and whether plasticity after SCI alters function at this important sympathetic output stage.

项目摘要 脊髓交感神经孕妇（SPN）在胸腔和腰椎中发现。他们 是中枢神经系统同情输出的最终仲裁者。 SPN轴突分支发出高度不同的多段 副脑交感神经神经节神经元（PNS）的预测。差异提供了 在数值上更大的PNS扩增CNS交感命令的机制。假设 在多段分支点之间，该尖峰传导是可靠的。这是基于离体录音 从室温（t°）的交感链中，尖峰放大器的大幅增加和宽度 分支点传导的高安全系数。随着T°的增加促进传导失败，很可能 SPN分支点传导也是T°敏感的。 在体感系统中，分支点为控制轴突传导和 暗示含有α5的GABAA受体（GABAAR）。 SPN还表达α5-gabaars，并且 它们在突触前的轴突分支点上的表达可能同样控制差异，因此反应 放大到PN。我们记录了成年小鼠外体内胸腔的SPN轴突横跨神经节的轴突 刺激附着的腹根刺激后的副链链。最初的实验观察到传导 块取决于;遍历的链神经节，T°，频率和Gabaar拮抗剂的数量。结果 支持轴突差异作为交感神经增益控制中的可修改输出阶段。 [SA1]我们假设跨分支点的怀孕的轴突传导块不在 由组成型活性，含α5的Gabaar进行神经调节控制。我们对AES进行实验 应用Gabaar激动剂，拮抗剂和内源性的轴突招募变化 神经固醇变构调节剂，并在发射频率的物理范围内进行了测试。 [SA2]许多脊髓受伤（SCI）个体患有热调节功能障碍。甚至很小的海拔 在身体T°可以损害尖峰传导中，SCI种群中的SPN轴突功能尤其是 易受伤害的。我们假设跨分支点的传导对T°核心的较大变化敏感 并将测试T°对与性降压或高温一致的T°范围内的传导块的影响。 [SA3]我们假设SCI导致变化，从而促进了分支点的传导，包括（a） 加巴活动增加和（b）尖峰宽度扩大。上面的结果将与之后看到的结果进行比较 早期（1-3天）和慢性（4-6周）时间点的T2胸科SCI。 探索促进或防止分支点传导的机制对于理解至关重要 SPN信号放大是硬连线还是物理修改（例如行为状态依赖性） 以及在这个重要的交感神经输出阶段，SCI后的可塑性是否会改变功能。