Correlates of motivation and reward

动机和奖励的相关性

• 批准号: 10699655
• 负责人: SATOSHI IKEMOTO
• 金额: $ 206.1万
• 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/10699655
• 关键词: Animals; Aversive Stimulus; Behavior; Behavioral; Brain region; Cell Nucleus; Compulsive Behavior; Cues; Desire for food; Dorsal; Electrophysiology (science); Fiber; Future; Glutamates; Hippocampus (Brain); Human; Hypothalamic structure; Implant; In Situ Hybridization; Lateral; Limb structure; Medial; Messenger RNA; Midbrain structure; Modeling; Motivation; Mus; National Institute of Drug Abuse; Neurons; Nose; Pathway interactions; Phase; Photometry; Play; Population; Preoptic Areas; Procedures; Process; Property; Punishment; Ramp; Research; Rewards; Role; Safety; Self Stimulation; Serotyping; Shock; Substantia Innominata; Sum; Synapses; System; Testing; Water; Work; classical conditioning; designer receptors exclusively activated by designer drugs; dopaminergic neuron; drug seeking behavior; drug withdrawal; foot; gamma-Aminobutyric Acid; motivated behavior; neural; neuromechanism; optogenetics; response

I discuss here two projects that have provided notable progress for the present fiscal year. Project 1 concerns paradoxical responses of medial septal GAD2 GABAergic neurons to rewarding and aversive stimuli. It is fundamental for humans and animals to seek rewards and safety from threats. To begin understanding neural mechanisms for such processes, we employed intracranial self-stimulation (ICSS), a model procedure for reward-seeking behavior, using optogenetic manipulations. In particular, we examined the roles of medial septal GABAergic (MS GABA) neurons using vGAT-Cre and GAD2-Cre mice. Mice quickly learned to stimulate MS GAD2 neurons (n=6), but not vGAT neurons (n=6). Next, we examined how these neuronal populations respond during appetitive and aversive contexts. AAV9-syn-FLEX-jGCaMP7f-WPRE was injected into the MS, and a probe was implanted in vGAT- and GAD2-Cre mice for fiber photometry. We then performed Pavlovian conditioning procedures with three different tones paired with a 100%, 50%, or 0% chance of a water reward or foot shock. MS vGAT neurons displayed heterogenous responses between mice (n= 6): vGAT neurons did not consistently respond to water rewards or cues predicting water rewards. By contrast, both certain and uncertain cues and water rewards decreased the activity of MS GAD2 neurons (n=4). During the shock procedure, MS vGAT neurons increased activity in response to foot shock, but not shock-paired tones, while MS GAD2 neurons displayed ramping activity during shock-paired tones and increased activity in response to shock. In sum, the results suggest that while vGAT is experessed in functionally heterogenous populations of MS GABA neurons, GAD2 is expressed in relatively homogenous MS GABA neurons. Concering MS GAD2 neurons, we obtained paradoxical results: First, we found that MS GAD2 neurons are involved in reward-seeking behavior as indicated by ICSS. Second, MS GAD2 neurons display decreased activity to rewards and cues predicting rewards. Third, MS GAD2 neurons increased activity in response to punishment and cues predicting punishment. We are currently examining our hypothesis that MS GAD2 neurons play a role in seeking for safety from threats, but not seeking for classical rewards. NIDA-IRP and the Center on Compulsive Behaviors supported this work. Project 2 concerns that supramammillary neurons projecting to the lateral preoptic area modulate reward-seeking behavior. Midbrain dopamine neurons are known to be critical in reward-seeking behavior. However, it is not well understood how other neural systems interact with dopamine neurons in reward-seeking behavior. Previous studies suggest that the supramammillary nucleus (SuM), particularly SuM glutamatergic neurons (GluN) projecting to the medial septum (MS), are important in reward-seeking behavior. In addition, SuM neurons appear to regulate reward-seeking behavior by coordinating the activities of multiple brain regions. To further understand such coordination role of the SuM and its mechanisms, first, we examined the hypothesis that SuM-MS neurons send collateral projections to multiple brain regions. We confirmed that about 95% of SuM-MS neurons were GluN using retrograde tracing and mRNA in situ hybridization procedures. Then, we examined collateral projections of SuM-MS GluN by injecting a retrograde AAV-Cre into the MS and an AAV-FLEX-mGFP-2A-SYP-mRuby. We found that SuM-MS neurons densely project to the dorsal tenia tecta, vertical and horizontal limb of the diagonal band, MS, substantia innominata, lateral preoptic area (LPO), lateral hypothalamus, and hippocampal CA1/CA2. Because the LPO is known to modulate reward-seeking behavior, we focused on the SuM-LPO pathway. Using the anterograde transsynaptic property of AAV serotype 1, we injected an AAV1-Cre into the SuM and found LPO neurons expressed Cre, confirming that SuM neurons have synaptic contacts with LPO neurons. We then examined whether optogenetic stimulation of SuM-LPO GluN instigates motivated behavior using an intracranial optogenetic self-stimulation test. We expressed channelrhodopsin-2 in SuM GluN-LPO of Vglut2-Cre mice. Mice quickly learned to press the lever that activated SuM GluN-LPO, suggesting that the stimulation of SuM-LPO GluN instigates and reinforces reward-seeking behavior. Finally, we tested SuM-LPO neuronal activity during reward-seeking behavior using a water-seeking test with GCaMP7s recording. We found that when mice nose-poked into water reward-port to drink water, SuM-LPO neuronal activity decreased, suggesting that SuM-LPO neurons are active during the reward-seeking phase, but not consummatory phase. In summary, our research suggests that SuM-MS GluN have collateral projections to multiple regions, including the LPO, and that SuM-LPO GluN instigate and reinforce reward-seeking behavior. Future studies will examine how SuM-LPO GluN interact with midbrain dopamine neurons in reward-seeking behavior.

我在这里讨论两个项目，它们在本财政年度取得了显著进展。 项目1涉及内侧隔GAD 2 GABA能神经元对奖赏和厌恶刺激的矛盾反应。对于人类和动物来说，从威胁中寻求回报和安全是最基本的。为了开始理解这些过程的神经机制，我们采用了颅内自我刺激（ICSS），一种使用光遗传学操作的奖励寻求行为的模型程序。特别是，我们使用vGAT-Cre和GAD 2-Cre小鼠研究了内侧隔GABA能（MS GABA）神经元的作用。小鼠很快学会刺激MS GAD 2神经元（n=6），但不刺激vGAT神经元（n=6）。接下来，我们研究了这些神经元群体在食欲和厌恶背景下的反应。将AAV 9-syn-FLEX-jGCaMP 7 f-WPRE注射到MS中，并将探针植入vGAT-和GAD 2-Cre小鼠中用于纤维光度测定。然后，我们用三种不同的音调进行巴甫洛夫条件反射程序，分别有100%、50%或0%的机会得到水奖励或脚电击。MS vGAT神经元显示小鼠之间的异质性反应（n= 6）：vGAT神经元没有一贯响应水奖励或线索预测水奖励。与此相反，确定和不确定的线索和水奖励降低MS GAD 2神经元的活性（n=4）。在休克过程中，MS vGAT神经元增加活动，以响应脚休克，但不休克配对音，而MS GAD 2神经元显示斜坡活动在休克配对音和增加活动，以响应休克。总之，结果表明，虽然vGAT在MS GABA神经元的功能异质群体中表达，但GAD 2在相对同质的MS GABA神经元中表达。关于MS GAD 2神经元，我们得到了矛盾的结果：首先，我们发现MS GAD 2神经元参与ICSS所示的奖赏寻求行为。第二，MS GAD 2神经元对奖励和预测奖励的线索显示出降低的活性。第三，MS GAD 2神经元增加了对惩罚和预测惩罚的线索的反应。我们目前正在研究我们的假设，即MS GAD 2神经元在寻求安全威胁中发挥作用，但不寻求经典奖励。NIDA-IRP和强迫行为中心支持这项工作。 项目2关注投射到外侧视前区的乳头体上神经元调节奖赏寻求行为。众所周知，中脑多巴胺神经元在奖赏寻求行为中至关重要。然而，在奖赏寻求行为中，其他神经系统如何与多巴胺神经元相互作用还不清楚。以往的研究表明，乳头体上核（SuM），特别是向内侧隔（MS）投射的SuM谷氨酸能神经元（GluN），在奖赏寻求行为中起重要作用。此外，SuM神经元似乎通过协调多个大脑区域的活动来调节寻求奖励的行为。为了进一步了解这种协调作用的SuM及其机制，首先，我们研究了假设，SuM-MS神经元发送侧支投射到多个脑区。我们证实，约95%的SuM-MS神经元GluN逆行追踪和mRNA原位杂交程序。然后，我们通过将逆行AAV-Cre和AAV-FLEX-mGFP-2A-SYP-mRuby注射到MS中来检查SuM-MS GluN的侧支投射。我们发现SuM-MS神经元密集地投射到背侧顶盖、对角带垂直和水平肢体、MS、无名质、外侧视前区（LPO）、外侧下丘脑和海马CA 1/CA 2。因为已知LPO调节奖赏寻求行为，所以我们专注于SuM-LPO通路。利用AAV血清1型的顺行跨突触特性，我们将AAV 1-Cre注射到SuM中，发现LPO神经元表达Cre，证实SuM神经元与LPO神经元具有突触接触。然后，我们使用颅内光遗传学自我刺激测试来检查SuM-LPO GluN的光遗传学刺激是否引发动机行为。我们在VEGF 2-Cre小鼠的SuM GluN-LPO中表达了通道视紫红质-2。小鼠很快学会了按下激活SuM GluN-LPO的杠杆，这表明SuM-LPO GluN的刺激会激发并加强奖励寻求行为。最后，我们使用GCaMP 7s记录的找水测试来测试奖赏寻求行为期间SuM-LPO神经元的活动。我们发现当小鼠将鼻子戳入水奖赏口饮水时，SuM-LPO神经元的活性降低，这表明SuM-LPO神经元在奖赏寻求阶段是活跃的，而不是完成阶段。总之，我们的研究表明，SuM-MS GluN对多个区域有间接投射，包括LPO，并且SuM-LPO GluN煽动和加强奖励寻求行为。未来的研究将探讨SuM-LPO GluN如何与中脑多巴胺神经元在奖励寻求行为中相互作用。