Role of Lateral Hypothalmic Area Perineuronal Nets in the Reinstatement of Cocaine-Seeking Behavior

外侧下丘脑区神经周围网络在恢复可卡因寻求行为中的作用

• 批准号: 9598308
• 负责人: Jordan Michael Blacktop
• 金额: $ 10.56万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9598308
• 关键词: Address; Anterior; Applications Grants; Area; Behavior; Behavioral; Chondroitinases; Cocaine; Cocaine Dependence; Consultations; Cues; Dopamine; Dorsal; Drug Addiction; Drug Use Disorder; Drug abuse; Electrophysiology (science); Enzymes; Excision; Extracellular Matrix; FDA approved; Faculty; Future; Glutamates; Goals; Health Sciences; Hypothalamic structure; Lateral; Lateral Hypothalamic Area; Light; Mentors; Modeling; Motivation; Neurobiology; Neuronal Plasticity; Neurons; Optics; Oregon; Pharmaceutical Preparations; Pharmacotherapy; Phase; Positioning Attribute; Postdoctoral Fellow; Prefrontal Cortex; Rattus; Regulation; Relapse; Research; Rodent Model; Role; Slice; Structure; Substance Use Disorder; Synapses; Synaptic Transmission; Testing; Training; Transgenes; Universities; Viral; Viral Vector; career; cocaine prevention; cocaine relapse prevention; disorder later incidence prevention; dopaminergic neuron; drug abuse prevention; drug of abuse; drug relapse; effective therapy; experience; gamma-Aminobutyric Acid; in vivo; interdisciplinary approach; motivated behavior; neuromechanism; novel; optogenetics; presynaptic; prevent; receptor; tenure track

Abstract Substance use disorders and subsequent relapse occurs as a result of long-term or permanent changes in the neurocircuitry of motivated behavior (drug-induced neuroplasticity). My recent studies have uncovered a discrete region of the lateral hypothalamus (LHA) that critically contributes to cocaine-induced behaviors, but its role in drug addiction was unknown until now. This region is striking in that it is heavily wrapped in a specialized extracellular matrix structures called perineuronal nets (PNNs). PNNs are an emerging and promising target for preventing drug-induced neuroplasticity because their removal profoundly alters neuroplasticity by cocaine. My recent studies have found and defined a discrete region of the dorsal and intermediate zones of the anterior LHA (LHAad/i) with remarkably robust expression of PNNs around GABAergic neurons that I have discovered to be critical for cocaine- but not sucrose-induced behaviors. The LHAad/i receives input from the prelimbic prefrontal cortex (PL PFC) and sends projections to the VTA. PL PFC and the VTA are major components of the mesocorticolimbic circuitry of motivated behavior and intimately involved in relapse of drug seeking. The role of the LHAad/i within this circuitry has not been studied but is importantly involved in cocaine-seeking behavior. Notably, it is not a part of the more heavily studied regions of the lateral hypothalamic area. I have established that these PNNs are critical for the acquisition of cocaine- but not sucrose-induced behaviors and for cue-induced reinstatement of cocaine seeking. Here I propose to test three hypotheses in three Specific aims that focus on the mechanism and circuitry underlying the prevention of cocaine-induced behavior by LHAad/i PNN removal. Specific Aim 1 (K99 period) will test the hypothesis that LHAad/i PNN removal will increase presynaptic GABA input on VTA DA neurons. I will be formally trained in ex vivo electrophysiology and optically stimulate LHAad/i terminals within the VTA to define the impact of LHAad/i PNN removal on synaptic transmission of VTA neurons. I will begin Specific Aim 2 during the last part of the K99 phase. Specific Aim 2 (K99 and R00 period) will test the hypothesis that chemogenetic activation of LHAad/i neurons that project to the VTA will block cue-induced reinstatement of cocaine seeking. I will continue my training in the use of advanced viral vectors to chemogenetically activate LHAad/i neurons that project to the VTA. Specific Aim 3 (R00 period) will test the hypothesis that LHAad/i PNN removal will reduce PL PFC glutamate input onto LHAad/i neurons. PL PFC projections to the LHAad/i will be optogenetically stimulated. This Aim will be conducted independently during years 4 and 5 of the R00 period to apply the training I received during the K99 period. Central to successful long-term relapse prevention is the need to modify new targets that underlie cocaine-induced plasticity within the circuitry of motivated behavior. The proposed training is fundamental for the PI’s successful transition from postdoctoral fellow to an independent tenure-track faculty position.

抽象的 由于长期或永久性变化的结果，物质使用障碍和随后的缓解发生了 动机行为的神经记录（药物诱导的神经可塑性）。我最近的研究发现了 下丘脑（LHA）的离散区域有助于可卡因诱导的行为，但 到目前为止，它在吸毒成瘾中的作用尚不清楚。这个区域令人惊讶，因为它被大量包裹在 专门的细胞外基质结构称为会内神经元网（PNNS）。 PNN是一个新兴的人， 预防药物引起的神经可塑性的有希望的靶标，因为它们的去除深刻改变了 可卡因神经塑性。我最近的研究发现并定义了背侧的离散区域 前LHA（LHAAD/i）的中间区域，围绕PNN的表达非常强大 我发现的GABA能神经元对于可卡因而言至关重要，但不是蔗糖诱导的行为。这 LHAAD/I收到前额叶皮层（PL PFC）的输入，并将项目发送到VTA。 pl PFC和VTA是融合行为的中皮质降压电路的主要组成部分， 参与救济毒品。 Lhaad/i在此电路中的作用尚未研究，但 重要的是参与寻求可卡因的行为。值得注意的是，这不是研究更严重的地区的一部分 下丘脑区域。我已经确定这些PNN对于获取可卡因至关重要 - 但是 不是蔗糖引起的行为，也不是针对可卡因寻求可卡因的恢复。我在这里建议测试 三个特定目标中的三个假设，侧重于预防的机制和电路 可卡因诱导的LHAAD/I PNN去除行为。具体目标1（K99时期）将检验以下假设。 LHAAD/I PNN去除将增加VTA DA神经元的突触前GABA输入。我将在Ex Vivo中进行正式培训 电生理学和光学刺激VTA内的LHAAD/I端子，以定义LHAAD/I PNN的影响 VTA神经元的突触传递去除。我将在K99阶段的最后一部分开始特定目标2。 具体目标2（K99和R00时期）将检验以下假设，即LHAAD/I神经元的化学发生激活 VTA的项目将阻止提示引起的可卡因寻求恢复。我将继续我的使用培训 高级病毒载体的化学源会激活向VTA投射的LHAAD/I神经元。特定目标3（R00 时期）将检验以下假设：LHAAD/I PNN去除将减少PL PFC谷氨酸输入到LHAAD/I 神经元。 PL PFC向LHAAD/I项目将被刺激。这个目标将进行 在R00期间的第4年和第5年独立应用我在K99期间接受的培训。中心 成功的长期救济预防是需要修改可卡因引起的基础的新目标 动机行为电路内的可塑性。拟议的培训对于PI的成功至关重要 从博士后研究员过渡到独立的终身教师职位。