Adolescence, motivation and the maturation of the prefrontal cortex.

青春期、动机和前额皮质的成熟。

基本信息

批准号：
10558708
负责人：
Eduardo David Leonardo
金额：
$ 50.72万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10558708
关键词：
Address Adolescence Adolescent Adult Affect Agonist Animal Model Animals Anxiety Behavior Behavioral Brain Cells Child Childhood Costs and Benefits Data Dependence Desire for food Development Disease Drug Modulation Fiber Future Goals Human Intervention Life Link Literature Medial Mediating Mental Depression Mental disorders Moods Motivation Mus Nature Neurons Outcome Pathway interactions Pharmaceutical Preparations Photometry Physiological Physiology Population Prefrontal Cortex Property Psychological reinforcement Rewards Schizophrenia Serotonergic System Serotonin Serotonin Receptor 5-HT1A Signal Transduction Slice Stimulus Syndrome System Taxes Testing Time Work designer receptors exclusively activated by designer drugs dorsal raphe nucleus experimental study gain of function hedonic hippocampal pyramidal neuron in vivo loss of function mature animal motivated behavior mouse model neuronal excitability neuroregulation postnatal development receptor receptor function response stressor willingness

项目摘要

The aim of the current proposal is to test the hypothesis that signaling through 5-HT1A receptors in the medial prefrontal cortex during adolescence is important for establishing lifelong motivation. Prior work suggests that disruption of the serotonin system during early post-natal development in animal models results in altered anxiety and mood related behaviors in the full-grown adult animal. One receptor that is particularly relevant in this regard is the 5-HT1A receptor. Recent data from our lab suggests that loss of serotonin signaling through 5-HT1A receptors in the medial prefrontal cortex during adolescence but not during adulthood, results in decreased motivation related behavioral setpoints. We hypothesize that this is true for both appetitive and avoidance motivation. The current proposal both examines mechanisms through which altered serotonin signaling through 5-HT1A receptors in adolescence leads to changes in motivation and further elucidates the specific nature of the reinforcement related behavior that is affected. In addition to a loss of function, we will use a biased 5-HT1A agonist as a gain of function approach bi-directionally modulate 5-HT1A signaling Using slice physiology, we will assess whether 5-HT1A expressing neurons alter their intrinsic properties as a result of the disrupted 5-HT1A mediated signaling, or whether there are compensatory changes in circuit properties resulting from the disruption. Using fiber photometry, we will determine how the medial prefrontal cortex engages with other circuit nodes like the dorsal raphe nucleus in tasks that tax motivational systems, with the goal of understanding the circuit basis for the disrupted behavior. Finally, we will directly assess whether the sensitivity of mPFC pyramidal neurons to inputs during adolescence is the critical factor in establishing later motivation. We will do this by manipulating mPFC principal neuron activity during the sensitive period in adolescence using DREADDS. Understanding how mPFC plasticity in adolescence can be harnessed to modulate motivation is a potentially promising strategy for addressing disorder that emerge in adolescence and often include a prominent motivational component. !

当前提案的目的是测试通过 5-HT1A 发出信号的假设青春期内侧前额叶皮层的受体对于建立终生的动力。先前的研究表明，血清素系统的破坏动物模型的产后早期发育导致焦虑和情绪改变成年动物的相关行为。一种特别相关的受体在这方面是5-HT1A受体。我们实验室的最新数据表明， 5-羟色胺信号传导通过内侧前额叶皮质中的 5-HT1A 受体青春期但不是成年期，会导致与行为相关的动机下降设定点。我们假设这对于食欲动机和回避动机都是成立的。目前的提案都研究了改变血清素的机制青春期通过 5-HT1A 受体发出的信号会导致动机和行为发生变化进一步阐明了强化相关行为的具体性质做作的。除了功能丧失之外，我们还将使用偏向的 5-HT1A 激动剂作为增益使用切片生理学功能方法双向调节 5-HT1A 信号传导，我们将评估表达 5-HT1A 的神经元是否会改变其作为 5-HT1A 介导的信号传导被破坏的结果，或者是否存在补偿中断导致电路特性发生变化。使用光纤光度测定法，我们将决定内侧前额叶皮层如何与其他电路节点（例如中缝背核负责激励系统的任务，其目标是了解中断行为的电路基础。最后我们直接评估青春期 mPFC 锥体神经元对输入的敏感性是建立后来动机的关键因素。我们将通过操纵来做到这一点 mPFC 在青春期敏感期的主要神经元活动恐惧。了解如何利用青春期的 mPFC 可塑性调节动机是解决疾病的一种潜在有前途的策略出现在青春期，并且通常包含突出的动机成分。！