Neuroimaging of animal models of neurologic and psychiatric disorders

神经和精神疾病动物模型的神经影像学

• 批准号: 10267546
• 负责人: Yihong Yang
• 金额: $ 103.66万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10267546
• 关键词: Acute; Aging; Animal Model; Anterior; Base of the Brain; Behavior; Bilateral; Biological Markers; Brain; Brain region; Cells; Cerebral cortex; Chronic; Clinical Research; Cognitive; Corpus striatum structure; Data; Dependence; Development; Dorsal; Drug usage; Event; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Hippocampus (Brain); Human; Impairment; Individual Differences; Insula of Reil; Learning; Left; Link; Measurement; Medial; Mediating; Memory; Memory Loss; Memory impairment; Mental disorders; Methamphetamine; Modeling; Motivation; Neurocognitive; Neurodegenerative Disorders; Nicotine; Nicotine Dependence; Outcome; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Pre-Clinical Model; Predisposition; Prefrontal Cortex; Procedures; Process; Punishment; Rattus; Resistance; Rest; Role; Seeds; Self Administration; Severities; Shock; System; Testing; Treatment Efficacy; Treatment outcome; Ventral Striatum; Withdrawal; addiction; age effect; age group; age related; aged; base; behavior test; cingulate cortex; effective therapy; experimental study; foot; improved; indexing; motivated behavior; nervous system disorder; neuroadaptation; neuroimaging; neuropsychopharmacology; novel; preclinical study; trait

1. Pharmacological Manipulations of Brain Regions in a Model of Compulsive Drug Taking Addiction is characterized by compulsive drug use despite negative consequences. Preclinical and clinical studies suggest that impaired frontal system, especially the prelimbic cortex (PrL) and orbitofrontal cortex (OFC) regions, could be crucial in promoting compulsive drug use. However, the PrL and OFC are necessary for both expression and suppression of different drug-related behaviors, and each region may contribute to different functions depend on specifics of the behavior tested. To better understand the roles of PrL and OFC during compulsive drug use, we used a rat model of methamphetamine self-administration (SA) in the presence of concomitant foot shocks, thought to parallel compulsive drug taking by humans, and pharmacologically inactivated each region during this process. In addition, we examined the effects of inactivation during seeking test and progressive ratio (PR) procedure to detect the roles of PrL and OFC in drug-seeking and motivation, respectively. Bilateral inactivation of PrL, but not OFC, repressed the compulsive drug use in the shock resistant rats during punishment SA phase and decreased motivation for drug during PR. No effect of inactivation was found during seeking test. Our data indicate that the PrL regulates both compulsive drug use and motivated behavior, while the role of OFC is not observed in the current experiments. These results provide a basis for further exploration of the circuit mechanism of prefrontal system on compulsive drug use. 2. Intrinsic Differences in Insular Circuits Moderate the Negative Association between Nicotine Dependence and Cingulate-striatal Connectivity Strength The development of brain-based biomarkers to assess nicotine dependence severity and treatment efficacy are essential to improve the current marginally effective treatment outcomes. Cross-sectional resting state functional connectivity (rsFC) studies in humans identified a circuit between the dorsal anterior cingulate cortex and the ventral striatum that negatively correlated with increased nicotine dependence severity but was unaffected by acute nicotine administration, suggesting a trait marker of addiction. However, whether this trait circuit dysregulation is predispositional to or resultant from nicotine dependence is unclear. Using a rat model of nicotine dependence with longitudinal fMRI measurements, we assessed the relationship between ACC-striatal rsFC and nicotine dependence severity. Data-driven modularity-based parcellation of the rat medial prefrontal cortex (mPFC) combined with seed-based connectivity analysis with the striatum recapitulated the cingulate-striatum relationship observed in humans. Furthermore, the relationship between cingulate-striatal brain circuits and nicotine dependence severity as indexed by the intensity of precipitated withdrawal, was fully statistically moderated by a predispositional insular-frontal cortical functional circuit. These data suggest that the identified trans-species ACC-striatal circuit relationship with nicotine dependence severity is dysregulated following chronic nicotine administration-induced dependence and may be biased by individual differences in predispositional insula-based striatal-frontal circuits, highlighting the circuit's potential as a biomarker of dependence severity. (Keeley et al., Neuropsychopharmacology, 2020) 3. Functional Connectivity of Hippocampal CA3 Predicts Neurocognitive Aging via CA1-Frontal Circuit The CA3 and CA1 principal cell fields of the hippocampus are vulnerable to aging, and age-related dysfunction in CA3 may be an early seed event closely linked to individual differences in memory decline. However, whether the differential vulnerability of CA3 and CA1 is associated with broader disruption in network-level functional interactions in relation to age-related memory impairment, and more specifically, whether CA3 dysconnectivity contributes to the effects of aging via CA1 network connectivity, has been difficult to test. Here, using resting-state fMRI in a group of aged rats uncontaminated by neurodegenerative disease, aged rats displayed widespread reductions in functional connectivity of CA3 and CA1 fields. Age-related memory deficits were predicted by connectivity between left CA3 and hippocampal circuitry along with connectivity between left CA1 and infralimbic prefrontal cortex. Notably, the effects of CA3 connectivity on memory performance were mediated by CA1 connectivity with prefrontal cortex. We additionally found that spatial learning and memory were associated with functional connectivity changes lateralized to the left CA3 and CA1 divisions. These results provide novel evidence that network-level dysfunction involving interactions of CA3 with CA1 is an early marker of poor cognitive outcome in aging. (Liang et al., Cerebral Cortex, 2020)

1.强迫吸毒模型中脑区的药物调控 上瘾的特征是尽管有负面后果，但仍强制使用药物。临床前和临床研究表明，额叶系统受损，特别是前额叶皮质(PRL)和眶前叶皮质(OFC)区域，可能在促进强迫药物使用方面起关键作用。然而，PRL和OFC是表达和抑制不同药物相关行为所必需的，每个区域可能根据所测试行为的具体情况而发挥不同的功能。为了更好地了解PRL和OFC在强迫性药物使用中的作用，我们使用了一种甲基苯丙胺自我给药(SA)的大鼠模型，在存在伴随的足部电击的情况下，被认为是平行的人类强迫性服药，并在这一过程中对每个区域进行药物灭活。此外，我们还考察了寻求测试和累进比(PR)过程中的失活效应，以分别检测PRL和OFC在药物寻找和动机中的作用。双侧PRL的失活抑制了抗休克大鼠在惩罚SA时的强迫用药，降低了PR时的用药动机，但不影响OFC。在寻道试验中未发现灭活效果。我们的数据表明，PRL既调节强迫药物的使用，也调节动机行为，而OFC的作用在目前的实验中没有观察到。这些结果为进一步探讨强迫性药物使用前额叶系统的回路机制提供了依据。 2.岛叶环路的内在差异调节尼古丁依赖与扣带回-纹状体连接强度之间的负关联 开发基于大脑的生物标记物来评估尼古丁依赖的严重程度和治疗效果，对于改善目前略微有效的治疗结果至关重要。人类的横断面静息状态功能连接性(RsFC)研究发现，背侧前扣带回皮质和腹侧纹状体之间存在一个回路，该回路与尼古丁依赖程度的增加呈负相关，但不受急性尼古丁给药的影响，表明这是成瘾的特征标志。然而，这种特征回路失调是尼古丁依赖的前置因素还是结果尚不清楚。使用尼古丁依赖的大鼠模型和纵向fMRI测量，我们评估了ACC-纹状体rsFC与尼古丁依赖严重程度的关系。基于数据驱动、模块化的大鼠内侧前额叶皮质(MPFC)的分割，结合基于种子的纹状体连接性分析，概括了在人类中观察到的扣带回-纹状体关系。此外，扣带回-纹状体脑回路与尼古丁依赖严重程度之间的关系(以催促戒断的强度为指标)在统计学上完全受前倾向性岛叶-额叶皮质功能回路的调节。这些数据表明，在尼古丁慢性给药诱导的依赖后，已发现的跨物种ACC-纹状体回路与尼古丁依赖严重程度的关系是失调的，并且可能受到基于配置前脑岛的纹状体-额叶回路的个体差异的偏见，突显了该回路作为依赖严重程度的生物标志物的潜力。(Keeley等人，《神经精神药理学》，2020) 3.海马区CA3的功能连接通过CA1-额叶回路预测神经认知老化 海马区的CA3和CA1主细胞场容易受到衰老的影响，CA3的年龄相关功能障碍可能是一种早期种子事件，与记忆衰退的个体差异密切相关。然而，CA3和CA1的不同脆弱性是否与与年龄相关的记忆损伤相关的网络水平功能相互作用的更广泛的干扰有关，更具体地说，CA3连接障碍是否通过CA1网络连接而导致衰老的影响，一直难以测试。在这里，在一组没有受到神经退行性疾病污染的老年大鼠中，使用静息状态的fMRI，老年大鼠显示出CA3和CA1区功能连接的广泛减少。通过左侧CA3和海马神经元之间的连接以及左侧CA1和下缘前额叶皮质之间的连接来预测与年龄相关的记忆缺陷。值得注意的是，CA3连接对记忆成绩的影响是通过CA1与前额叶皮质的连接来调节的。我们还发现，空间学习和记忆与左侧CA3和CA1区的功能连通性改变有关。这些结果提供了新的证据，表明涉及CA3和CA1相互作用的网络水平功能障碍是衰老过程中认知结果较差的早期标志。(梁等人，大脑皮层，2020)

项目成果

Withdrawal from long-term methamphetamine self-administration 'normalizes' neurometabolites in rhesus monkeys: a (1) H MR spectroscopy study.

• DOI: 10.1111/adb.12078
• 发表时间: 2015-01
• 期刊: Addiction biology
• 影响因子: 3.4
• 作者: Yang S;Belcher AM;Chefer S;Vaupel DB;Schindler CW;Stein EA;Yang Y
• 通讯作者: Yang Y

Acute nicotine-induced tachyphylaxis is differentially manifest in the limbic system.

急性尼古丁引起的快速耐受在边缘系统中表现不同。

• DOI: 10.1038/npp.2011.139
• 发表时间: 2011
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Zuo,Yantao;Lu,Hanbing;Vaupel,DBruce;Zhang,Yi;Chefer,SvetlanaI;Rea,WilliamR;Moore,AnnaV;Yang,Yihong;Stein,ElliotA
• 通讯作者: Stein,ElliotA

Brain regional synchronous activity predicts tauopathy in 3×TgAD mice.

• DOI: 10.1016/j.neurobiolaging.2018.06.016
• 发表时间: 2018-10
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Liu D;Lu H;Stein E;Zhou Z;Yang Y;Mattson MP
• 通讯作者: Mattson MP