Neuroimaging of preclinical models of substance use disorders

物质使用障碍临床前模型的神经影像学

• 批准号: 10699669
• 负责人: Yihong Yang
• 金额: $ 259.81万
• 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/10699669
• 关键词: Abstinence; Adopted; Adverse effects; Agonist; Animal Experiments; Animal Testing; Area; Arousal; Baclofen; Behavior; Behavioral; Brain; Brain region; Cerebral hemisphere; Chemicals; Clinical; Clip; Consumption; Dopamine; Dorsal; Electrodes; Environment; Feedback; Functional Magnetic Resonance Imaging; Glutamates; Goals; Head; Hippocampus (Brain); Human; Hypothalamic structure; Implant; Incubated; Individual; Limb structure; Long-Term Potentiation; Medial; Mediating; Mental disorders; Methods; Midbrain structure; Modeling; Motivation; Motor Cortex; Motor Evoked Potentials; Mus; Muscimol; Muscle; Names; Nature; Neurons; Opiate Addiction; Opioid; Oxycodone; Participant; Pathway interactions; Performance; Pharmaceutical Preparations; Physiologic pulse; Physiological; Pre-Clinical Model; Prefrontal Cortex; Presynaptic Terminals; Psychological reinforcement; Radial; Rattus; Regulation; Relapse; Reporting; Rodent; Role; Signal Transduction; Structure; Substance Use Disorder; Substance of Abuse; Sucrose; Sum; Surface; System; Testing; Thalamic Nuclei; Thalamic structure; Time; Transcranial magnetic stimulation; Treatment outcome; Ventral Tegmental Area; Work; Yang; activity marker; adverse outcome; approach behavior; awake; craving; density; design; dopaminergic neuron; electric field; experimental study; improved; in vivo; manufacturing process; nervous system disorder; neural; neuroadaptation; neuroimaging; neuromechanism; neuroregulation; novel; optogenetics; receptor; reinforced behavior; repetitive transcranial magnetic stimulation; response; tool; translational potential

1. High-Density Theta Burst Paradigm Enhances the Aftereffects of Transcranial Magnetic Stimulation: Evidence from Focal Stimulation of Rat Motor Cortex Theta burst stimulation (TBS) is an efficient noninvasive neuromodulation paradigm that has been widely adopted clinically. However, the efficacy of TBS treatment remains similarly modest as conventional 10 Hz repetitive transcranial magnetic stimulation (TMS). We describe here a new TMS paradigm, named High-Density Theta Burst Stimulation (hdTBS). This paradigm delivers up to 6 pulses per burst, as opposed to only 3 in conventional TBS, while maintaining the inter-burst interval of 200 ms (or 5 Hz) --- a critical parameter in inducing long-term potentiation. This paradigm was implemented on a TMS stimulator developed in-house; its physiological effects were assessed in the motor cortex of awake rats using a rodent specific focal TMS coil. Microwire electrodes were implanted in rat limb muscles to longitudinally record motor-evoked potential (MEP). Four different TBS paradigms (3, 4, 5 or 6 pulses per burst, 200 sec per session) were tested; MEP signals were recorded immediately before (baseline) and up to 35 min post each TBS sessions. Animal experiments (n=15) revealed significant differences in the aftereffects induced by the four TBS paradigms: 3-, 4-, 5- and 6-pulse TBS (Friedman test, p=0.018). Post hoc analysis further revealed that, in comparison to conventional 3-pulse TBS, 5- and 6-pulse TBS enhanced the aftereffects of MEP signals by 56% and 92%, respectively, while maintaining identical time efficiency. In summary, A new stimulation paradigm is proposed, implemented and tested in the motor cortex of awake rats using a focal TMS coil developed in the lab. We observed enhanced aftereffects as assessed by MEP, with no obvious adverse effects, suggesting the translational potentials of this paradigm. (Meng et al., Brain Stimulation, 2022) 2. Angle-tuned coils: attractive building blocks for TMS with improved depth-spread performance A novel angle-tuned ring coil is proposed to improve the depth-spread performance of TMS coils and serve as the building blocks for high-performance composite coils and multisite TMS systems. Improving depth-spread performance was achieved by reducing field divergence through creating a more elliptical emitted field distribution from the coil. To accomplish that, instead of enriching the Fourier components along the planarized (x-y) directions, which requires different arrays to occupy large brain surface areas, we worked along the radial (z) direction by using tilted coil angles and stacking coil numbers to reduce the divergence of the emitted near field without occupying large head surface areas. The emitted electric field distributions were theoretically simulated in spherical and real human head models to analyze the depth-spread performance of proposed coils and compare with existing figure-8 coils. The results were then experimentally validated with field probes and in-vivo animal tests. The proposed 'angle-tuning' concept improves the depth-spread performance of individual coils with a significantly smaller footprint than existing and proposed coils. For composite structures, using the proposed coils as basic building blocks simplifies the design and manufacturing process and helps accomplish a leading depth-spread performance. In addition, the footprint of the proposed system is intrinsically small, making them suitable for multisite stimulations of inter and intra-hemispheric brain regions with an improved spread and less electric field divergence. The proposed AT coil goes beyond the traditional depth-spread tradeoff rule of TMS coils, which provides the possibility of building new composite structures and new multisite TMS tools. (Bagherzadeh et a., J neural Eng., 2022) 3. Role of ventral subiculum in incubation of oxycodone craving after electric barrier-induced voluntary abstinence High relapse rate is a key feature of opioid addiction. In humans, abstinence is often voluntary due to negative consequences of opioid seeking. To mimic this human condition, a rat model of incubation of oxycodone craving after electric barrier-induced voluntary abstinence was recently introduced. Here, we used the activity marker Fos, muscimol-baclofen (GABAa+GABAb receptor agonists) global inactivation, and Daun02 selective inactivation of putative relapse-associated neuronal ensembles to demonstrate a key role of ventral subiculum (vSub) neuronal ensembles in incubation of oxycodone craving after voluntary abstinence but not homecage forced abstinence. We also used a longitudinal functional MRI method and showed that functional connectivity changes in vSub-related circuits can predict opioid relapse after abstinence induced by adverse consequences of opioid seeking. We showed that vSub neuronal ensembles contribute to incubation of opioid craving after abstinence induced by negative consequences of drug seeking. We also showed that vSub activity did not contribute to incubation of opioid craving after forced abstinence, suggesting distinct mechanisms of incubation after forced versus voluntary abstinence. Finally, longitudinal functional connectivity changes between vSub and retrosplenial cortex (RSC) and dorsal hippocampus (dHipp), and dHipp with medial orbitofrontal cortex (OFC) and other areas predicted incubated opioid seeking. (Under review) 4. Medial prefrontal cortex and anteromedial thalamus interaction regulates goal-directed behavior and dopaminergic neuron activity The prefrontal cortex is involved in goal-directed behavior. Here, we investigate circuits of the PFC regulating motivation, reinforcement, and its relationship to dopamine neuron activity. Stimulation of medial PFC (mPFC) neurons in mice activated many downstream regions, as shown by fMRI. Axonal terminal stimulation of mPFC neurons in downstream regions, including the anteromedial thalamic nucleus (AM), reinforced behavior and activated midbrain dopaminergic neurons. The stimulation of AM neurons projecting to the mPFC also reinforced behavior and activated dopamine neurons, and mPFC and AM showed a positive-feedback loop organization. We also found using fMRI in human participants watching reinforcing video clips that there is reciprocal excitatory functional connectivity, as well as co-activation of the two regions. Our results suggest that this cortico-thalamic loop regulates motivation, reinforcement, and dopaminergic neuron activity. (Yang et al., Nature Commun., 2022) 5. Supramammillary neurons projecting to the septum regulate dopamine and motivation for environmental interaction in mice The supramammillary region (SuM) is a posterior hypothalamic structure, known to regulate hippocampal theta oscillations and arousal. However, recent studies reported that the stimulation of SuM neurons with neuroactive chemicals, including substances of abuse, is reinforcing. We conducted experiments to elucidate how SuM neurons mediate such effects. Using optogenetics, we found that the excitation of SuM glutamatergic (GLU) neurons was reinforcing in mice; this effect was relayed by their projections to septal GLU neurons. SuM neurons were active during exploration and approach behavior and diminished activity during sucrose consumption. Consistently, inhibition of SuM neurons disrupted approach responses, but not sucrose consumption. Such functions are similar to those of mesolimbic dopamine neurons. Indeed, the stimulation of SuM-to-septum GLU neurons and septum-to-ventral tegmental area (VTA) GLU neurons activated mesolimbic dopamine neurons. We propose that the supramammillo-septo-VTA pathway regulates arousal that reinforces and energizes behavioral interaction with the environment. (Kesner et al., Nature Commun., 2022)

1。高密度theta爆发范式增强了经颅磁刺激的后遗症：大鼠运动皮层局灶性刺激的证据 theta爆发刺激（TBS）是一种有效的非侵入性神经调节范式，已在临床上广泛采用。然而，TBS处理的功效仍然与常规10 Hz重复的经颅磁刺激（TMS）相似。我们在这里描述了一种新的TMS范式，称为高密度theta爆发刺激（HDTBS）。该范式每爆发最多可提供6个脉冲，而传统TB中仅提供3个脉冲，同时保持200 ms（或5 Hz）的爆发间隔间隔 - 诱导长期增强的关键参数。该范式是在内部开发的TMS刺激器上实施的。使用啮齿动物特异性局灶性TMS线圈在清醒大鼠的运动皮层中评估其生理作用。将微线电极植入大鼠肢体肌肉中，以纵向记录运动诱发电位（MEP）。测试了四个不同的TBS范式（每次爆发的3、4、5或6个脉冲，每节200秒）； MEP信号在（基线）之前立即记录，每个TBS会话结束后最多35分钟。动物实验（n = 15）表明，四个TBS范式引起的后遗症存在显着差异：3-，4-，5和6-Pulse TBS（Friedman Test，P = 0.018）。事后分析进一步表明，与传统的3脉冲TBS相比，5和6-Pulse TBS分别提高了MEP信号的后效率，分别提高了56％和92％，同时保持了相同的时间效率。总而言之，使用实验室中开发的焦点TMS线圈提出了一种新的刺激范式，在清醒大鼠的运动皮层中进行了新的刺激范式。我们观察到了MEP评估的增强的后效应，没有明显的不利影响，这表明该范式的翻译潜力。 （Meng等人，脑刺激，2022年） 2。角度调整线圈：具有改进深度性能的TMS的吸引人的构件 提出了一种新型的角度调节环线圈，以改善TMS线圈的深度性能，并充当高性能复合线圈和多站点TMS系统的构件。通过从线圈中创建更椭圆形的发射场分布来减少场差异，可以提高深度扩展性能。为此，我们没有使用倾斜的线圈角和堆叠线圈数来沿着径向（z）方向占据大脑表面积，而不是沿平面（X-Y）方向富含傅立叶组件（X-Y）方向，而不是沿着径向（Z）方向进行工作，以减少靠近现场的差异而无需占用大型较大的头表面区域。理论上在球形和真实的人头模型中对发射的电场分布进行了模拟，以分析拟议的线圈的深度性能，并与现有的图8线圈进行比较。然后通过实验探针和体内动物测试对结果进行实验验证。提出的“角度调节”概念可改善与现有和拟议的线圈相比，其占地面积明显小得多的单个线圈的深度性能。对于复合结构，使用拟议的线圈作为基本构建块简化了设计和制造过程，并有助于实现领先的深度性能。此外，所提出的系统的足迹本质上很小，使其适用于对跨膜间和半球内大脑区域的多站点刺激，并具有改善的扩散和较小的电场差异。提议的线圈超出了TMS线圈的传统深度折衷规则，该规则提供了建立新的复合结构和新的多站点TMS工具的可能性。 （Bagherzadeh等，J Neural Eng。，2022年） 3。腹侧下调在电屏障引起的自愿节制后渴望孵化中的作用 高复发率是阿片类药物成瘾的关键特征。在人类中，由于阿片类药物的负面影响，禁欲通常是自愿的。为了模仿这种人类的状况，最近引入了电屏障引起的自愿节制后的羟考酮渴望的大鼠模型。 Here, we used the activity marker Fos, muscimol-baclofen (GABAa+GABAb receptor agonists) global inactivation, and Daun02 selective inactivation of putative relapse-associated neuronal ensembles to demonstrate a key role of ventral subiculum (vSub) neuronal ensembles in incubation of oxycodone craving after voluntary abstinence but not归乡强迫禁欲。我们还使用了纵向功能MRI方法，并表明与VSUB相关电路中的功能连通性变化可以预测阿片类药物的不良后果引起的禁欲后阿片类药物复发。我们表明，VSUB神经元集合有助于在寻求药物的负面后果引起的禁欲后孵化阿片类药物的渴望。我们还表明，VSUB活性在强迫节制后没有促进阿片类药物的渴望，这表明强迫与自愿戒酒后的孵化机制不同。最后，纵向功能连通性在VSUB和肾后皮层（RSC）和背侧海马（Dhipp）和带有内侧轨道额右皮层（OFC）和其他预测的孵育阿片类药物寻求的区域之间发生变化。 （审查） 4。内侧前额叶皮层和前丘脑相互作用调节目标指导的行为和多巴胺能神经元活性 前额叶皮层参与目标定向行为。在这里，我们研究了PFC调节动机，增强及其与多巴胺神经元活性的关系。如fMRI所示，小鼠中内侧PFC（MPFC）神经元的刺激激活了许多下游区域。在下游区域中MPFC神经元的轴突末端刺激，包括前丘脑前核（AM），增强行为和激活的中脑多巴胺能神经元。投射到MPFC的AM神经元的刺激也增强了行为和激活的多巴胺神经元，MPFC和AM显示了一个阳性的反馈回路组织。我们还发现，在观看加强视频片段的人类参与者中使用fMRI，存在相互兴奋的功能连接性以及两个区域的共激活。我们的结果表明，这种皮质 - 丘脑环路可以调节动机，增强和多巴胺能神经元活性。 （Yang等人，自然界，2022年） 5。投射到隔膜调节多巴胺的超肌神经元和小鼠环境相互作用的动机 超木甲状腺（SUM）是下丘脑后结构，已知可以调节海马theta振荡和唤醒。但是，最近的研究报告说，用神经活性化学物质（包括滥用物质）刺激总和神经元正在加强。我们进行了实验，以阐明总和神经元如何介导此类作用。使用光遗传学，我们发现谷氨酸能（GLU）神经元的激发在小鼠中加强了。它们的预测转换给了GLU神经元。总和神经元在探索和进近行为过程中是活跃的，并且在蔗糖消耗期间的活性减少。一致地，对总和神经元的抑制会破坏方法反应，但不会消耗蔗糖。这样的功能与中唇多巴胺神经元的功能相似。实际上，刺激GLU神经元和隔离间隔段区域（VTA）GLU神经元的刺激激活了中羟基多巴胺神经元。我们提出，超米乳 - 塞普托-VTA途径调节唤醒，从而增强和为环境的行为相互作用提供了能量。 （Kesner等人，自然界，2022年）