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.强迫性吸毒模型中脑区的药理学操作 成瘾的特点是强迫性使用药物，尽管有负面后果。临床前和临床研究表明，受损的额叶系统，特别是前边缘皮质（PrL）和眶额皮质（OFC）区域，可能是促进强迫性药物使用的关键。然而，PrL和OFC对于不同药物相关行为的表达和抑制都是必需的，并且每个区域可能取决于所测试的行为的具体情况而贡献于不同的功能。为了更好地了解在强迫性药物使用过程中的作用，我们使用了大鼠模型的甲基苯丙胺自我管理（SA）的存在下，伴随足部电击，被认为是平行的强迫性药物服用的人类，并在此过程中，每个区域的cardiac失活。此外，我们研究了失活过程中寻求测试和累进比率（PR）程序的影响，以检测PrL和OFC的药物寻求和动机的作用，分别。双侧PrL的失活抑制了休克抵抗大鼠在惩罚SA期的强迫性药物使用，降低了PR期的药物动机，而OFC的失活则无影响。我们的数据表明，PrL调节强迫性药物使用和动机行为，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前额叶系统在强迫性药物使用中的回路机制提供了依据。 2.岛叶回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相关 开发基于大脑的生物标志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边际有效的治疗结果至关重要。在人类中进行的横截面静息状态功能连接（rsFC）研究确定了背侧前扣带皮层和腹侧纹状体之间的回路，该回路与尼古丁依赖严重程度增加呈负相关，但不受急性尼古丁给药的影响，这表明成瘾的特征标记。然而，这种特质回路失调是否是尼古丁依赖的易感因素或结果尚不清楚。使用尼古丁依赖的大鼠模型与纵向功能磁共振成像测量，我们评估ACC-纹状体rsFC和尼古丁依赖的严重程度之间的关系。大鼠内侧前额叶皮层（mPFC）的数据驱动的基于模块化的分组结合基于种子的连接分析与纹状体概括了在人类中观察到的扣带-纹状体关系。此外，扣带-纹状体脑回路与尼古丁依赖严重程度之间的关系，以沉淀戒断的强度为指标，完全由易感性岛叶-额叶皮质功能回路在统计学上调节。这些数据表明，确定的跨物种ACC-纹状体回路与尼古丁依赖严重程度的关系在慢性尼古丁给药诱导的依赖后失调，并且可能受到基于易感性岛叶的纹状体-额叶回路的个体差异的影响，突出了该回路作为依赖严重程度生物标志物的潜力。（Keeley等人，神经精神药理学，2020） 3.海马CA 3区的功能连接性通过CA 1-额叶回路预测神经认知老化 海马的CA 3和CA 1主细胞区易受衰老的影响，CA 3中与年龄相关的功能障碍可能是与记忆衰退的个体差异密切相关的早期种子事件。然而，CA 3和CA 1的差异脆弱性是否与与年龄相关的记忆障碍相关的网络级功能相互作用的更广泛破坏有关，更具体地说，CA 3连接障碍是否有助于通过CA 1网络连接老化的影响，一直难以测试。在这里，使用静息态功能磁共振成像在一组未受神经退行性疾病污染的老年大鼠中，老年大鼠显示CA 3和CA 1区域的功能连接广泛减少。通过左侧CA 3和海马回路之间的连接以及左侧CA 1和边缘下前额叶皮层之间的连接沿着预测与海马相关的记忆缺陷。值得注意的是，CA 3连接对记忆表现的影响是通过CA 1与前额叶皮层的连接介导的。我们还发现，空间学习和记忆与左侧CA 3和CA 1分区的功能连接变化有关。这些结果提供了新的证据表明，涉及CA 3与CA 1相互作用的网络水平功能障碍是衰老中认知结果不良的早期标志。（Liang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