Correlates of motivation and reward

动机和奖励的相关性

• 批准号: 10931290
• 负责人: SATOSHI IKEMOTO
• 金额: $ 243.11万
• 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/10931290
• 关键词: Amygdaloid structure; Area; Attention; Behavior; Behavioral; Brain region; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Calcium; Cell Nucleus; Consumption; Cues; Electrophysiology (science); Emotions; Environment; FOS gene; Fiber; Future; Genetic; Glutamates; Habenular Nucleus; Lateral; Learning; Light; Loudness; Medial; Messenger RNA; Morphine; Motivation; Mus; Naloxone; Neurons; Noise; Pain; Photometry; Pontine structure; Population; Positive Reinforcements; Prefrontal Cortex; Preoptic Areas; Procedures; Process; Rewards; Role; Self Stimulation; Stimulus; Structure; Subgroup; System; Testing; Water; Withdrawal; Withdrawal Symptom; approach behavior; comparison control; designer receptors exclusively activated by designer drugs; drug seeking behavior; drug withdrawal; emotional symptom; fear memory; motivated behavior; mu opioid receptors; neural; neuromechanism; opioid withdrawal; optogenetics; parabrachial nucleus; response; sensory stimulus; septohippocampal

I am summarizing the findings of two ongoing projects: Project 1: Role of Parabrachial Nucleus in Opioid Withdrawal Opioid withdrawal leads to negative emotional symptoms, but the underlying neural mechanisms are not well understood. Previous studies show that during opioid withdrawal, the central nucleus of the amygdala (CEA), particularly its capsular part (CeC), becomes highly active. This raises questions about the brain regions that might activate CeC during opioid withdrawal. One candidate is the parabrachial nucleus (PBN), which has glutamatergic neurons, including calcitonin gene-related peptide (CGRP) neurons in the external lateral PBN (elPBN). These CGRP-expressing neurons project to the CeC and are implicated in pain-related negative emotions and fear memory. Additionally, PBN has a high expression of mu opioid receptors (MOR). The hypothesis is that during opioid withdrawal, a subgroup of PBN neurons becomes active, and the CeC-projecting elPBN CGRP-expressing neurons contribute to CeC activation. To study PBN neuron activity during opioid withdrawal, c-Fos, a marker of cellular activation, was examined in the PBN after inducing opioid withdrawal in mice using morphine and naloxone. The elPBN area showed significantly increased c-Fos expression compared to controls, and many activated elPBN neurons co-expressed MOR and CGRP mRNA. Moreover, differences in c-Fos-expressing neurons were observed in the lateral superior subdivisions of the PBN in naloxone-treated mice. Silencing glutamatergic PBN neurons using chemogenetic procedures reduced CeC activation and withdrawal symptoms including aversive effects in mice, indicating the role of PBN in opioid withdrawal. These findings suggest that PBN afferents are critical for CeC activation during withdrawal and contribute to aversive effects. Future studies will explore more specific neural populations in the PBN, including MOR- and CGRP-expressing neurons. Project 2: Functions of Supramammillary Neurons Projecting to the Lateral Preoptic Area The lateral preoptic area (LPO) projects strongly to the lateral habenular nucleus (LHb), associated with negative reward prediction errors and aversive effects. LPO receives inputs from the septohippocampal system, medial prefrontal cortex (MPFC), and the supramammillary region (SuM). This suggests that LPO conveys environment-dependent approach and avoidance responses to LHb. The influence of SuM inputs on LPO processes was studied. SuM sends efferents to LPO and other regions, receiving inputs from pontine structures, septohippocampal structures, and MPFC, among others. Notably, SuM transfers information from pontine structures to LPO. Optogenetic stimulation of SuM-LPO glutamatergic neurons was found to produce positive reinforcement. With an intracranial self-stimulation test, mice learned to activate SuM-LPO neurons, promoting operant approach behavior. Calcium fiber-photometry test showed that these neurons responded to positive and negative stimuli. Water and its cue decreased their activity, while footshock and its cue increased it. Salient sensory stimuli like bright light and loud noise also increased their activity. SuM-LPO GluN likely respond to uncertain and attention-demanding stimuli, facilitating investigatory behavior under stressful or uncertain conditions. Water and its cue might decrease activity because their activation promotes investigatory behavior rather than consumption. Further studies will validate these hypotheses.

我总结了两个正在进行的项目的结果： 项目1：臂旁核在阿片类药物戒断中的作用 阿片类药物戒断会导致负面情绪症状，但其潜在的神经机制尚不清楚。先前的研究表明，在阿片类药物戒断期间，杏仁核中央核（CEA），特别是其囊状部分（CeC）变得高度活跃。这引发了关于阿片类药物戒断期间可能激活CeC的大脑区域的问题。一个候选者是臂旁核（PBN），其具有降钙素能神经元，包括外外侧PBN（elPBN）中的降钙素基因相关肽（CGRP）神经元。这些表达CGRP的神经元投射到CeC，并与疼痛相关的负面情绪和恐惧记忆有关。此外，PBN具有μ阿片受体（莫尔）的高表达。假设是在阿片类药物戒断期间，PBN神经元的亚组变得活跃，并且CeC投射eIPBN CGRP表达神经元有助于CeC激活。 为了研究阿片类药物戒断过程中PBN神经元的活性，在使用吗啡和纳洛酮诱导小鼠阿片类药物戒断后，在PBN中检测c-Fos，细胞活化的标志物。与对照组相比，elPBN区域显示出显著增加的c-Fos表达，并且许多活化的elPBN神经元共表达莫尔和CGRP mRNA。此外，在纳洛酮处理的小鼠中，在PBN的外侧上级亚部中观察到c-Fos表达神经元的差异。使用化学发生程序沉默阿片能PBN神经元减少了CeC激活和戒断症状，包括小鼠的厌恶效应，表明PBN在阿片戒断中的作用。这些发现表明，PBN传入是至关重要的CeC激活在撤退，并有助于厌恶的影响。未来的研究将探索PBN中更特异的神经群，包括表达莫尔和CGRP的神经元。 项目2：投射到外侧视前区的乳头上神经元的功能 外侧视前区（LPO）强烈投射到外侧缰核（LHb），与负奖励预测错误和厌恶效应相关。LPO接收来自隔海马系统、内侧前额叶皮质（MPFC）和乳头上区（SuM）的输入。这表明，LPO传达环境依赖的方法和回避LHb的反应。研究了SuM输入对LPO过程的影响。SuM向LPO和其他区域发送传出神经，接收来自脑桥结构、隔海马结构和MPFC等的输入。值得注意的是，SuM将信息从脑桥结构传递到LPO。 发现光发生刺激SuM-LPO能神经元产生正强化。通过颅内自我刺激试验，小鼠学会了激活SuM-LPO神经元，促进操作性接近行为。钙纤维光度测定显示这些神经元对正性和负性刺激均有反应。水和水的刺激降低了它们的活动性，而电击和电击的刺激则增加了它们的活动性。SuM-LPO GluN可能会对不确定和需要注意力的刺激做出反应，促进压力或不确定条件下的行为。水和它的线索可能会减少活动，因为它们的激活促进了行为，而不是消费。进一步的研究将验证这些假设。

项目成果

Mesopontine median raphe regulates hippocampal ripple oscillation and memory consolidation.

中桥中缝调节海马波纹振荡和记忆巩固。

• DOI: 10.1038/nn.3998
• 发表时间: 2015-05
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Wang, Dong V.;Yau, Hau-Jie;Broker, Carl J.;Tsou, Jen-Hui;Bonci, Antonello;Ikemoto, Satoshi
• 通讯作者: Ikemoto, Satoshi

Whole brain dynamics during optogenetic self-stimulation of the medial prefrontal cortex in mice.

• DOI: 10.1038/s42003-020-01612-x
• 发表时间: 2021-01-14
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Cover CG;Kesner AJ;Ukani S;Stein EA;Ikemoto S;Yang Y;Lu H
• 通讯作者: Lu H

Seeking motivation and reward: Roles of dopamine, hippocampus, and supramammillo-septal pathway.

• DOI: 10.1016/j.pneurobio.2022.102252
• 发表时间: 2022-05
• 期刊: Progress in neurobiology
• 影响因子: 6.7
• 作者: Kesner AJ;Calva CB;Ikemoto S
• 通讯作者: Ikemoto S

Medial prefrontal cortex and anteromedial thalamus interaction regulates goal-directed behavior and dopaminergic neuron activity.

• DOI: 10.1038/s41467-022-28892-7
• 发表时间: 2022-03-16
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Yang C;Hu Y;Talishinsky AD;Potter CT;Calva CB;Ramsey LA;Kesner AJ;Don RF;Junn S;Tan A;Pierce AF;Nicolas C;Arima Y;Lee SC;Su C;Coudriet JM;Mejia-Aponte CA;Wang DV;Lu H;Yang Y;Ikemoto S
• 通讯作者: Ikemoto S