Correlates of motivation and reward

我现在总结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 阿片类药物的戒断会导致消极的情绪症状，但其潜在的神经机制尚不清楚。以前的研究表明，在阿片类药物戒断过程中，杏仁核中央核(CEA)，特别是其包膜部分(CEC)变得高度活跃。这引发了人们对在阿片类药物戒断过程中可能激活CEC的大脑区域的质疑。臂旁核(PBN)是一种候选核团，它在外侧臂旁核(PBN)内有谷氨酸能神经元，包括降钙素基因相关肽(CGRP)神经元。这些表达CGRP的神经元投射到CEC，与疼痛相关的负面情绪和恐惧记忆有关。此外，PBN高表达Mu阿片受体(MOR)。假设在阿片类药物戒断过程中，PBN神经元的一个亚群变得活跃，表达CEC的elPBN CGRP神经元参与了CEC的激活。 用吗啡和纳洛酮诱导小鼠戒断阿片后，观察外周核神经元在阿片戒断过程中的活性变化。与对照组相比，elPBN区c-Fos表达显著增加，许多被激活的elPBN神经元同时表达MOR和CGRP mRNA。此外，在纳洛酮处理的小鼠的PBN外侧上亚区，c-Fos表达的神经元也有差异。使用化学发生程序沉默谷氨酸能PBN神经元可以减少CEC的激活和小鼠的戒断症状，包括厌恶效应，表明PBN在阿片类药物戒断中的作用。这些发现表明，在戒断过程中，PBN传入对CEC的激活起关键作用，并有助于产生厌恶效应。未来的研究将探索PBN中更特定的神经群，包括表达MOR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)，与负奖赏预测误差和厌恶效应有关。LPO从隔-海马区、内侧前额叶皮质(MPFC)和乳房上区(SUM)接受输入。这表明LPO向LHb传递环境依赖的方法和回避反应。研究了和输入对LPO过程的影响。SUM将传出信号发送到LPO和其他区域，接受来自桥脑结构、隔-海马结构和MPFC等的输入。值得注意的是，SUM将信息从桥结构传递到LPO。 对Sum-LPO谷氨酸能神经元的光遗传刺激可产生阳性强化。通过颅内自我刺激测试，小鼠学会了激活SUM-LPO神经元，促进可操作的接近行为。钙纤维光度法检测结果显示，这些神经元对正负向刺激均有反应。水和它的提示降低了它们的活动，而脚电击和它的提示增加了它的活性。强烈的感官刺激，如明亮的光线和巨大的噪音，也会增加它们的活动。Sum-LPO Glun可能对不确定和要求注意的刺激做出反应，促进在压力或不确定条件下的调查行为。水和它的线索可能会减少活动，因为它们的激活促进了研究行为，而不是消费。进一步的研究将验证这些假说。

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.