Reexamining the Role of Dendrites in Neuronal Function

重新审视树突在神经元功能中的作用

• 批准号: 10721626
• 负责人: Jayeeta Basu
• 金额: $ 268.12万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721626
• 关键词: 3-Dimensional; Action Potentials; Affect; Anatomy; Axon; Biophysical Process; Brain; Calibration; Cells; Communities; Computer Models; Computing Methodologies; Data; Data Set; Dendrites; Dendritic Spines; Development; Dimensions; Disease; Elements; Engineering; Excitatory Postsynaptic Potentials; Future; Generations; Goals; Holography; Image; In Vitro; Inhibitory Synapse; Laboratories; Logic; Maps; Measurement; Measures; Mediating; Mental disorders; Methods; Microscopy; Modeling; Molecular; Morphology; Mus; Neurons; Neurosciences; Outcome; Output; Pathologic; Play; Pyramidal Cells; Research; Research Personnel; Resolution; Role; Sensory; Series; Site; Structure; Synapses; Synaptic Potentials; Testing; Textbooks; Tissues; Trees; Vertebral column; Visual Cortex; WFS1 gene; Work; analog; area striata; biophysical analysis; cell type; design; experimental study; hippocampal pyramidal neuron; improved; in vivo; knowledge graph; nervous system disorder; network models; neuronal cell body; novel; optogenetics; patch clamp; phenomenological models; public database; reconstruction; response; screening; synergism; two-photon; ultra high resolution; voltage

The textbook model of a neuron is one where dendrites merely serve as recipients of excitatory or inhibitory synaptic inputs, integrated at the soma to generate action potentials. However, dendrites generate local spikes that could be critical nonlinear decision points, and recent data suggest that excitatory inputs may only have an effect in the neuronal output if they are activated together in clusters, triggering dendritic spikes. We want to re-examine the role of dendrites in neuronal function in vivo and help usher in, a new “dendrocentric” paradigm of how neurons work, as opposed to the current “somacentric” one. To bring this change, we will assemble a “Dendrite Consortium” of complementary laboratories, expert in genetically-encoded voltage indicators, volumetric two-photon imaging, holographic optogenetics and optochemistry, dendritic patching, EM connectomics, superresolution synaptic mapping and computational models. Wwe will use holographic optogenetics to activate dendritic spines in arbitrary patters (as if one were “playing the piano”), while imaging voltage in 3D with new GEVIs in dendrites from a subtype of L2/3 pyramidal neuron from mouse visual cortex in vivo during sensory stimulation and spontaneous activity, combining this with direct patch recordings from dendrites. These experiments will characterize the functional regimes that generate dendritic spikes in vivo and elucidate their biophysical mechanisms and overall impact on somatic spiking. We will then use connectomics and expansion microscopy to reconstruct complete morphologies and synapse compositions of these dendrites, including imaged ones. These combined functional and structural data will be used to build a rigorous computational model of the neurons, where the functional and computational roles of dendritic spikes will be explored numerically and systematically. Through a collective, integrated effort, we will elucidate the computational logic and functional roles of dendrites and help usher in a new working model of a neuron. We will also generate for the field open-access morphological, functional and computational datasets of complete dendritic trees from one pyramidal neuron subtype, activated by sensory stimulation or intracortical activity. These datasets, including “Rosetta” ones of the same exact neuron, could enable answers to outstanding basic questions on dendritic function in normal and pathological states, as dendrites are central functional elements in all brain circuits and are affected in many neurological and mental disorders.

在神经元的教科书模型中，树突仅充当神经元的接受者 兴奋性或抑制性突触输入，在体细胞中整合以产生作用 潜力。然而，树突会产生局部尖峰，这可能是严重的非线性 决策点，最近的数据表明，兴奋性输入可能只对 如果神经元在簇中一起激活，触发树突尖峰，则会产生神经元输出。 我们希望重新审视树突在体内神经元功能中的作用，并帮助迎来 一种关于神经元如何工作的新“树中心”范式，而不是当前的 “以身体为中心”的一个。为了实现这一改变，我们将组建一个“Dendrite Consortium” 互补实验室，基因编码电压指标专家，体积测量 双光子成像、全息光遗传学和光化学、树突修补、 EM 连接组学、超分辨率突触映射和计算模型。美国职业摔跤 将使用全息光遗传学以任意模式激活树突棘（就好像 其中一个在“弹钢琴”），同时使用树突中的新 GEVI 对电压进行 3D 成像 来自体内小鼠视觉皮层 L2/3 锥体神经元的亚型 感觉刺激和自发活动，将其与直接补丁录音相结合 来自树突。这些实验将表征产生的功能机制 体内树突尖峰并阐明其生物物理机制和总体影响 关于体细胞尖峰。然后我们将使用连接组学和扩展显微镜 重建这些树突的完整形态和突触组成， 包括有图像的。这些组合的功能和结构数据将用于 建立严格的神经元计算模型，其中功能和 树突尖峰的计算作用将以数值和系统方式进行探索。 通过集体、综合的努力，我们将阐明计算逻辑和 树突的功能作用并有助于开创神经元的新工作模型。我们将 还为现场生成开放获取的形态、功能和计算 来自一种锥体神经元亚型的完整树突树的数据集，由 感觉刺激或皮质内活动。这些数据集，包括“Rosetta”数据集 同样的神经元，可以回答有关的突出基本问题 正常和病理状态下的树突功能，因为树突是中心功能 所有大脑回路中的元素都受到许多神经和精神疾病的影响。