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θ波爆发模式增强经颅磁刺激的后效：来自大鼠运动皮质局灶性刺激的证据