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.

项目摘要 大脑是互连区域的复杂拼布，网络方法已成为 对于理解其功能架构的越来越有用。静止状态fMRI（RS-FMRI）已出现为 在静止状态下对大规模功能网络进行非侵入性研究的突出工具。但是，几乎没有 关于负责RS-FMRI功能连通性形成的神经元机制已知。这 知识对于解释RS-FMRI数据，因果关系对大脑状态进行建模，预测行为和设计网络至关重要 - 基于神经精神和神经系统疾病的基于治疗方案。在所有大脑区域中，纹状体 可能是研究RS-FMRI的神经起源的独特例子。文学中的发现反复 表明两个半球的纹状体中的RS-FMRI信号是高度同步的，但病毒式追踪研究 在双侧纹状体之间没有直接解剖连接。这就提出了一个有趣的问题 - 如何 双侧纹状体RS-FMRI连接形成没有任何直接解剖连接？解决这个问题 可能在理解纹状体中的RS-FMRI信号方面具有重大影响。三个可能 方案可能解释了异形纹状体RS-FMRI连接的存在：（1）同步触发 纹状体GABA能MSN，（2）从皮质 - 纹状体或丘脑纹状体中同步谷氨酸同步释放 预测，（3）从黑人 - 纹状体预测中同步释放多巴胺。在这里，我们假设 （2）和（3）是起源，（3）是最突出的来源。我们形成了这样的假设，因为（1） 我们团队成员的严格研究表明，两个半球之间的MSN射击是 异步和（2）多巴胺神经元是众所周知的起搏器细胞。我们的团队最近开创了一个多人 通道，频谱解决，兼容MR兼容的纤维光度法技术，非常适合破译神经 RS-FMRI的起源。严格的先前研究表明了我们同时测量的独特能力 fMRI期间，多个大脑区域的多个荧光传感器活动。在AIM 1中，我们将测量三个 双侧纹状体中具有简单纤维光度法和fMRI的主要神经元成分。那些 组件是：（1）突触前谷氨酸能释放； （2）突触前多巴胺能释放； （3） 突触后钙加权神经元活性。我们假设半球间纹状体fMRI 连通性可能与纹状体中突触前多巴胺释放有关。在AIM 2中，我们将审问 谷氨酰胺能和多巴胺能项目对纹状体间RS-FMRI连通性的因果影响 使用化学遗传学。我们假设在SNC中沉默的单侧多巴胺活性可能会中断 半球间纹状体RS-FMRI连接性。我们将在纹状体中单方面表达抑制性恐惧 在MSN和nigral多巴胺神经元中投射皮质神经元，并重复与中的相同的实验 AIM 1前后，Dreadd激动剂脱氯唑（DCZ）。总而言之，这 项目旨在解决有关纹状体间纹状体的神经相关性的重要缺失知识 fMRI连接。调查人员在这一研究中有很强的记录，并将带来创新 通过桥接局部细胞成像和分析方法来探讨良好支持的新假设 通过严格的先前研究。