Role of astrocyte-based cholinergic neuromodulation in cognition and in the treatment of cognitive disorders

基于星形胶质细胞的胆碱能神经调节在认知和认知障碍治疗中的作用

• 批准号: 10280174
• 负责人: Thomas Papouin
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10280174
• 关键词: Adult; Agonist; Astrocytes; Behavior; Behavioral; Benchmarking; Binding; Biology; Brain; Brain Diseases; Cells; Characteristics; Clinical; Clinical Treatment; Clinical Trials; Code; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Coupling; Crystallization; Cues; Data; Dose; Electron Microscopy; Environment; FDA approved; Failure; Fluorescence; Genetic; Human; Impaired cognition; Intervention; Knockout Mice; Ligands; Light; Link; Maps; Measures; Mediating; Mental Health; Mental disorders; Modality; Molecular; Morphology; Mus; National Institute of Mental Health; Neurobehavioral Manifestations; Neuroglia; Neurons; Neurophysiology - biologic function; Nootropic Agents; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase III Clinical Trials; Pilot Projects; Positioning Attribute; Process; Quantum Dots; Research; Role; Route; Schizophrenia; Seminal; Serine; Shapes; Signal Transduction; Surface; Synapses; Testing; Therapeutic; Work; alpha-bungarotoxin receptor; base; behavioral outcome; cell type; cholinergic; cognitive disability; cognitive enhancement; cognitive function; drinking water; drug development; excitatory neuron; imaging study; in vivo; inhibitory neuron; nanoscale; nervous system disorder; neural circuit; neuroregulation; particle; programs; receptor; response; stimulant use; success; therapeutic evaluation

ABSTRACT Neurons are viewed as the cellular correlate of cognition and only target of clinical therapeutics, in part because manipulating neurons rapidly and directly alters behavior. Yet, the human brain is also made of glial cells, which morphological and genetic complexification is a striking feature of the human brain. Astrocytes, in particular, are now known to orchestrate many neural functions, crystalizing the possibility of a direct astrocyte contribution to cognitive functions and mental health. However, a lack of understanding of the rules that govern astrocytes activity and their involvement in neural circuits has limited our ability to test this idea. Collective work recently showed that astrocytes transduce neuromodulatory information onto synaptic circuits. Specifically, we found that α7 nicotinic acetylcholine receptors (α7nAChRs) on astrocytes regulate the release of the astrocyte transmitter D-serine onto synapses. Neuromodulation, in particular cholinergic signaling, permits behavioral adaptations to changes in the environment, and its alteration is linked to cognitive deficits in schizophrenia. Coincidently, the α7nAChR has focalized major drug development efforts in the past decade to restore the cognitive symptoms of patients with schizophrenia. Here, we will take advantage of this new astrocyte-based α7nAChR pathway to test the role of astrocytes in cognitive functions and pro-cognitive interventions, and elucidate the mechanisms through which neuromodulation is sensed and transduced by astrocytes at the cellular and molecular levels. In doing so, we will test a set of general principles which we hypothesize govern input output fidelity in astrocytes (positional coupling). In Aim 1, we will test the hypothesis that α7nAChRs are located in the immediate vicinity of D-serine pools, directly linking Ca2+ influx through α7nAChR channel activity to the Ca2+-dependent D-serine release machinery. We will conduct fluorescence Ca2+ imaging studies to understand the spatial, temporal and molecular rules of α7nAChR-mediated Ca2+ signals and their relation to D-serine release. We will then map the physical association of α7nAChR and D-serine pools in perisynaptic astrocytic processes, using electron microscopy. In addition, we will conduct single-particle tracking studies to understand how the dynamic distribution of α7nAChR at the surface of astrocytes, with respect to D-serine pools, is influenced by the binding of endogenous and exogenous ligands. In Aim 2, we will generate cell-specific knockout mouse lines to selectively ablate α7nAChR from astrocytes, excitatory neurons or inhibitory neurons in the brain, and canvas the contribution of each cell-types to characteristic behaviors supported by α7nAChRs. We recently showed that an α7nAChR partial agonist tested in Phase-III clinical trials for the treatment of cognitive deficits in patients with schizophrenia, elevates D-serine levels in the mouse brain. Based on our observations that inactivating astrocyte-based α7nAChR signaling leads to specific alterations in D-serine levels and cognitive behavior, we will then test the hypothesis that astrocytes, but not neurons, enable the behavioral efficacy of cognitive enhancers tested in clinical trials, and that D-serine signaling is the circuit actuator of these effects.

抽象的 神经元被视为认知的细胞相关物，也是临床治疗的唯一目标，部分原因是 然而，人类大脑也是由神经胶质细胞组成的，快速并直接地改变神经元的行为。 形态和遗传的复杂性是人脑的一个显着特征，尤其是星形胶质细胞。 现在已知可以协调许多神经功能，具体化了星形胶质细胞直接贡献的可能性 然而，缺乏对星形胶质细胞控制规则的了解。 活动及其对神经回路的参与限制了我们最近测试这一想法的能力。 研究表明星形胶质细胞将神经调节信息转导到突触回路上。 星形胶质细胞上的 α7 烟碱乙酰胆碱受体 (α7nAChR) 调节星形胶质细胞递质的释放 D-丝氨酸作用于突触，特别是胆碱能信号传导，允许行为适应。 巧合的是，环境的变化与精神分裂症的认知缺陷有关。 α7nAChR 在过去十年中集中于主要药物开发工作，以恢复认知症状 在这里，我们将利用这种新的基于星形胶质细胞的α7nAChR通路进行测试。 星形胶质细胞在认知功能和促认知干预中的作用，并阐明其机制 星形胶质细胞通过它在细胞和分子水平上感知和转导神经调节。 这样做，我们将测试一组主要控制星形胶质细胞输入输出保真度的一般原则 （位置耦合）在目标 1 中，我们将检验 α7nAChR 位于附近的假设。 D-丝氨酸库，通过 α7nAChR 通道活性直接将 Ca2+ 流入与 Ca2+ 依赖性 D-丝氨酸联系起来 我们将进行荧光 Ca2+ 成像研究，以了解空间、时间和释放机制。 然后我们将绘制 α7nAChR 介导的 Ca2+ 信号的分子规则及其与 D-丝氨酸释放的关系。 α7nAChR 和 D-丝氨酸池在突触周围星形胶质细胞过程中的物理关联，使用电子 此外，我们还将进行单粒子跟踪研究，以了解动态如何。 α7nAChR 在星形胶质细胞表面的分布，相对于 D-丝氨酸库，受到结合的影响 在目标 2 中，我们将生成细胞特异性敲除小鼠系。 选择性地消除大脑中星形胶质细胞、兴奋性神经元或抑制性神经元的 α7nAChR，以及画布 我们最近表明，每种细胞类型对 α7nAChR 支持的特征行为的贡献。 α7nAChR 部分激动剂在 III 期临床试验中进行了测试，用于治疗患有认知障碍的患者 根据我们的观察，精神分裂症会提高小鼠大脑中的 D-丝氨酸水平。 基于星形胶质细胞的 α7nAChR 信号传导导致 D-丝氨酸水平和认知行为的特定改变，我们 然后将检验星形胶质细胞而非神经元能够实现认知行为功效的假设 临床试验中测试了增强剂，D-丝氨酸信号传导是这些效应的电路执行器。