Deciphering neural origins of interhemispheric striatal resting-state functional connectivity using simultaneous chemogenetic fMRI and triple-spectral fiber photometry

使用同步化学遗传学功能磁共振成像和三光谱光纤光度测定破译半球间纹状体静息态功能连接的神经起源

• 批准号: 10727994
• 负责人: Yen-Yu Ian Shih
• 金额: $ 42.76万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727994
• 关键词: Address; Agonist; Anatomy; Anesthesia procedures; Animals; Architecture; Behavior; Bilateral; Brain; Brain region; Calcium; Cerebral hemisphere; Cognition; Color; Complex; Corpus striatum structure; Data; Dopamine; Dorsal; Event; Fiber; Functional Magnetic Resonance Imaging; Genetic; Glutamates; Hemoglobin; Huntington Disease; Interruption; Investigation; Ipsilateral; Knowledge; Lasers; Link; Literature; Measures; Mediating; Morphologic artifacts; Motivation; Motor; Mus; Nerve Degeneration; Network-based; Neurologic; Neurons; Parkinson Disease; Pattern; Photometry; Research; Research Personnel; Rest; Rewards; Scanning; Signal Transduction; Source; Stroke; Techniques; Time; Treatment Protocols; Viral; Work; absorption; analytical method; awake; behavior prediction; causal model; cellular imaging; cohort; design; designer receptors exclusively activated by designer drugs; dopaminergic neuron; driving force; evidence base; experimental study; genetic approach; hemodynamics; imaging modality; innovation; interest; member; motor control; nervous system disorder; neural; neural correlate; neuron component; neuropsychiatric disorder; nodal myocyte; novel; postsynaptic; presynaptic; sensor; tool

PROJECT SUMMARY The brain is a complex patchwork of interconnected regions, and network approaches have become increasingly useful for understanding its functional architecture. Resting-state fMRI (rs-fMRI) has emerged as the prominent tool for non-invasive investigation of large-scale functional networks at rest. However, little is known about the neuronal mechanisms responsible for the formation of rs-fMRI functional connectivity. This knowledge is critical to interpret rs-fMRI data, causally model brain states, predict behavior, and design network- based treatment regimens for neuropsychiatric and neurological disorders. Among all brain regions, striatum may represent a unique example to study the neural origins of rs-fMRI. Findings in literature have repeatedly shown that rs-fMRI signals in the striatum of both hemispheres are highly synchronized, yet viral tracing studies showed no direct anatomical connections between bilateral striatum. This raises an intriguing question – how is bilateral striatal rs-fMRI connectivity formed without any direct anatomical connection? Addressing this question could have major implications in understanding what rs-fMRI signals in striatum represent. Three possible scenarios may explain the existence of interhemispheric striatal rs-fMRI connectivity: (1) synchronous firing of striatal GABAergic MSNs, (2) synchronous release of glutamate from cortico-striatal or thalamo-striatal projections, and (3) synchronous release of dopamine from nigro-striatal projections. Here, we hypothesize that (2) and (3) are the origins, with (3) being the most prominent source. We formed such a hypothesis because (1) rigorous prior study from our team members suggested that MSN firing between two hemispheres is asynchronous, and (2) dopamine neurons are well known pacemaker cells. Our team recently pioneered a multi- channel, spectrally resolved, MR-compatible fiber photometry technique that is ideal to decipher the neural origins of rs-fMRI. Rigorous prior research has demonstrated our unique ability to simultaneously measure multiple fluorescent sensor activities across multiple brain regions during fMRI. In Aim 1, we will measure three major neuronal components with simultaneous fiber-photometry and fMRI in bilateral striatum. Those components are: (1) presynaptic glutamatergic releases; (2) presynaptic dopaminergic releases; and (3) postsynaptic calcium-weighted neuronal activities. We hypothesized that interhemispheric striatal fMRI connectivity might be related to presynaptic dopamine releases in the striatum. In Aim 2, we will interrogate the causal influence of glutaminergic and dopaminergic projections on interhemispheric striatal rs-fMRI connectivity using chemogenetics. We hypothesized that silencing unilateral dopamine activity in the SNc may interrupt interhemispheric striatal rs-fMRI connectivity. We will unilaterally express inhibitory DREADD in striatum- projecting cortical neurons, in MSNs, and in nigral dopamine neurons, and repeat the same experiments as in Aim 1 before and after the administration of DREADD agonist deschloroclozapine (DCZ). In summary, this project aims to address significant missing knowledge about the neural correlates of interhemispheric striatal fMRI connectivity. The investigators have a strong track record in this line of research and will bring Innovation to the field by bridging local cellular imaging and analytical methods to address novel hypotheses well supported by rigorous prior research.

项目概要 大脑是由相互关联的区域组成的复杂拼凑而成，网络方法已成为 静息态功能磁共振成像（rs-fMRI）对于理解其功能结构越来越有用。 对大规模静态功能网络进行非侵入性研究的重要工具然而，却很少。 了解负责形成 rs-fMRI 功能连接的神经机制。 知识对于解释 rs-fMRI 数据、因果模型大脑状态、预测行为和设计网络至关重要。 在所有大脑区域中，纹状体是基于神经精神和神经系统疾病的治疗方案。 可能代表了研究 rs-fMRI 神经起源的独特例子，文献中的发现已多次出现。 研究表明，两个半球纹状体中的 rs-fMRI 信号高度同步，但病毒追踪研究 显示双侧纹状体之间没有直接的解剖学联系，这提出了一个有趣的问题——这是如何的。 双侧纹状体 rs-fMRI 连接的形成没有任何直接的解剖学连接？ 可能对理解纹状体中的 rs-fMRI 信号代表什么具有重大意义。 场景可以解释半球间纹状体 rs-fMRI 连接的存在：（1）同步发射 纹状体 GABA 能 MSN，(2) 从皮质纹状体或丘脑纹状体同步释放谷氨酸 投射，以及（3）从黑质纹状体投射同步释放多巴胺。 (2) 和 (3) 是起源，其中 (3) 是最突出的来源，我们形成这样的假设是因为 (1)。 我们团队成员之前进行的严格研究表明，MSN 在两个半球之间发射 异步和（2）多巴胺神经元是众所周知的起搏细胞，我们的团队最近开创了一种多巴胺神经元。 通道、光谱解析、MR 兼容的光纤光度测量技术，是破译神经网络的理想选择 rs-fMRI 的起源 严格的先前研究已经证明了我们同时测量的独特能力。 在功能磁共振成像期间，多个大脑区域的多个荧光传感器活动在目标 1 中，我们将测量三个。 双侧纹状体的主要神经元成分同时进行纤维光度测定和功能磁共振成像。 成分是：（1）突触前谷氨酸释放；（2）突触前多巴胺能释放；以及（3） 我们研究了半球间纹状体功能磁共振成像。 连接性可能与纹状体中突触前多巴胺的释放有关。在目标 2 中，我们将探究纹状体中的突触前多巴胺释放。 谷氨酰胺能和多巴胺能预测对半球间纹状体 rs-fMRI 连接的因果影响 我们利用化学遗传学探索了沉默 SNc 中的单侧多巴胺活性可能会中断。 我们将在纹状体中单方面表达抑制性 DREADD。 投射皮质神经元、MSN 和黑质多巴胺神经元，并重复与 目标 1 在施用 DREADD 激动剂去氯氯氮平 (DCZ) 之前和之后 总而言之，这。 该项目旨在解决有关半球间纹状体神经相关性的重大缺失知识 功能磁共振成像连接性研究人员在这一领域拥有良好的记录，并将带来创新。 通过连接局部细胞成像和分析方法来解决得到充分支持的新假设 通过严格的先前研究。