Parvalbumin interneurons regulate nucleus accumbens synapses and behavior

小白蛋白中间神经元调节伏隔核突触和行为

• 批准号: 9698739
• 负责人: Brad Alan Grueter
• 金额: $ 6.2万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9698739
• 关键词: Acute; Address; Affective; Animal Model; Animals; Behavior; Behavioral; Brain; Brain region; CNR1 gene; Cannabinoids; Characteristics; Cocaine; Cognitive; Communication; Complex; Data; Depressed mood; Development; Disease; Dopamine D2 Receptor; Drug Addiction; Drug Exposure; Drug abuse; Electrophysiology (science); Emotional; Endocannabinoids; Equilibrium; Exposure to; Feedback; Frequencies; Gene Transfer; Glutamates; Goals; Grant; Hippocampus (Brain); Human; Illicit Drugs; Inhibitory Synapse; Interneurons; Knowledge; Learning; Mediating; Mediator of activation protein; Medical; Membrane; Mental Depression; Mission; Modification; Molecular; Motivation; Mus; National Institute of Drug Abuse; Negative Reinforcements; Neuromodulator; Neurons; Nucleus Accumbens; Output; Parvalbumins; Pattern; Pharmaceutical Preparations; Pharmacology; Play; Positive Reinforcements; Pre-Clinical Model; Predisposition; Preparation; Prevention; Process; Production; Property; Protocols documentation; Publishing; Receptor Signaling; Regulation; Research; Rewards; Role; Self Stimulation; Sensory; Shapes; Signal Transduction; Slice; Synapses; Synaptic Membranes; Synaptic Transmission; System; Techniques; Testing; Therapeutic; Time; Transgenic Mice; United States National Institutes of Health; Vanilloid; Viral; Work; addiction; awake; behavioral outcome; design; drug of abuse; endocannabinoid signaling; endogenous cannabinoid system; experience; improved; in vivo; insight; learned behavior; motivated behavior; neural circuit; neuronal excitability; novel strategies; optogenetics; prevent; receptor; recruit; synaptic function; therapeutic target; tool; translational impact

PROJECT SUMMARY Drug abuse and addiction remain a medical and societal burden with a relative paucity of prevention and treatment options. The nucleus accumbens (NAc) is an essential hub integrating cognitive, contextual, sensory and affective information into behavioral outcomes. Changes in excitatory synaptic function in the NAc is a leading molecular mechanism by which illicit drug exposure leads to the behavioral manifestations represented by addiction. While excitatory synaptic connections drive NAc neuronal firing, inhibitory synaptic transmission is important for coordinating and constraining neuronal excitability. Our work focuses on mechanisms of communication between NAc parvalbumin expressing fast-spiking interneurons (PV-FSIs) and specific medium spiny neuron subtypes (MSNs; D1 or D2 dopamine receptor expressing) in the NAc core. PV-FSIs, although limited in number, make vast inhibitory connections to MSNs thereby greatly influencing NAc output. Thus, PV- FSI synaptic activity is a putative mediator of NAc circuit adaptations. Changes in NAc excitatory and inhibitory circuit dynamics or the balance between excitation and inhibition, likely underlie addiction behaviors. Indeed, we find that manipulation of these PV-FSIs in the NAc modulate drug-related behaviors. Our data suggests that the strength of PV-FSI to MSN inhibitory synapses can be suppressed by endocannabinoid (eCB) signaling through cannabinoid receptor 1 (CB1R) and transient receptor potential vanillod 1 (TRPV1). We hypothesize that NAc PV-FSIs and MSNs communicate bi-directionally via the eCB system to regulate inhibitory synaptic function on MSNs underlying NAc-related behaviors and exposure to drugs of abuse leads to dysregulation of this process. In this grant, we will characterize the precise mechanisms by which PV-FSIs and eCB signaling at PV-FSI to MSN synapses mediate these actions. We will identify signaling mechanisms that alter synaptic strength at synapses onto NAc D1 or D2 MSNs using rigorous electrophysiological, optogenetic, and behavioral approaches in combinations of transgenic mouse lines. In turn, we will apply these protocols used to identify mechanisms of plasticity ex vivo to awake/behaving animals to determine behavioral responding. Furthermore, we will determine if manipulation of this signaling can regulate behavioral responding to drugs of abuse. The contribution of the proposed research is expected to be advancement in our knowledge of mechanisms by which PV-FSIs and more specifically, eCB signaling at PV-FSIs to MSN synapses, remodel NAc excitatory and inhibitory synaptic activity patterns and membrane firing properties, and the contribution this process likely plays in addiction-related disorders. These studies will identify mechanisms which can be exploited for the development of improved therapeutic tools for treating addiction.

项目摘要 药物滥用和成瘾仍然是一个医疗和社会负担，预防措施相对不足， 治疗方案。丘脑核（nucleus reverbens，NAc）是整合认知、语境、感觉和认知功能的重要中枢 和情感信息转化为行为结果。NAc兴奋性突触功能的变化是一个重要因素。 非法药物暴露导致所代表的行为表现的主要分子机制 上瘾。兴奋性突触连接驱动NAc神经元放电，抑制性突触传递 对于协调和限制神经元的兴奋性很重要。我们的工作重点是 表达NAc小清蛋白的快速尖峰中间神经元（PV-FSI）与特定培养基之间的通讯 NAc核心中的棘状神经元亚型（MSN;表达D1或D2多巴胺受体）。PV-FSI虽然 数量有限，使巨大的抑制连接到MSN，从而大大影响NAc输出。因此，PV- FSI突触活动是NAc回路适应的假定介质。NAc兴奋性和抑制性变化 回路动力学或兴奋和抑制之间的平衡，可能是成瘾行为的基础。的确， 我们发现在NAc中操纵这些PV-FSI调节药物相关行为。我们的数据表明 PV-FSI对MSN抑制性突触的强度可被内源性大麻素（eCB）抑制 通过大麻素受体1（CB 1 R）和瞬时受体电位香草醛1（TRPV 1）进行信号传导。我们 假设NAc PV-FSI和MSN经由eCB系统双向通信以调节 MSNs抑制性突触功能与NAC相关行为和药物暴露有关 这一过程的失调。在这项资助中，我们将描述PV-FSI的精确机制， 并且PV-FSI至MSN突触处的eCB信号传导介导这些作用。我们将识别信号机制 其使用严格的电生理学改变NAc D1或D2 MSN上的突触处的突触强度， 光遗传学和行为学方法在转基因小鼠系的组合中。反过来，我们将应用这些 用于鉴定离体可塑性机制以唤醒/表现动物以确定行为的方案 响应.此外，我们将确定是否操纵这种信号可以调节行为反应 滥用药物。本研究的贡献在于增进我们的知识 PV-FSI，更具体地说，PV-FSI到MSN突触的eCB信号转导， NAc兴奋性和抑制性突触活动模式和膜放电特性及其贡献 这一过程可能在成瘾相关的疾病中起作用。这些研究将确定可以 开发用于治疗成瘾的改进治疗工具。