Neurotrophic and ontogenic factors in medial orbitofrontal cortical function

内侧眶额皮质功能中的神经营养和个体发育因素

• 批准号: 10652720
• 负责人: Shannon Leigh Gourley
• 金额: $ 42.47万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652720
• 关键词: Ablation; Adolescence; Adolescent; Adolescent Development; Adult; Affinity; Amygdaloid structure; Award; Behavior; Behavior Control; Biological Factors; Brain-Derived Neurotrophic Factor; Cells; Choice Behavior; Cocaine; Cognitive; Contracts; Decision Making; Dendritic Spines; Development; Dominant-Negative Mutation; Employment; Enterobacteria phage P1 Cre recombinase; FOS gene; Failure; Food Poisoning; Funding; Genetic; Goals; Growth; Health; Hippocampus; Human; Individual; Infusion procedures; Knowledge; Lead; Life; Link; Maps; Medial; Mediating; Memory; Mental Health; Morphology; Mus; National Institute of Drug Abuse; Neuromodulator; Neurons; Organism; Outcome; Output; Pattern; Pharmaceutical Preparations; Phosphotransferases; Population; Process; Protein Isoforms; Psychopathology; Psychoses; Reporting; Research; Restaurants; Retrieval; Rewards; Rodent; Role; Signal Transduction; Structure; Substance Use Disorder; Supporting Cell; System; Tamoxifen; Testing; Time; Transgenic Mice; Tropomyosin; Update; Viral Vector; behavior test; cerebral atrophy; combat; combinatorial; compulsion; design; drug misuse; flexibility; genetic approach; high reward; improved; insight; interest; memory retrieval; neural; neurodevelopment; neuroregulation; neurotrophic factor; novel; overexpression; prospective; receptor; response; reward processing; social; stressor

SUMMARY In day-to-day life, we often must select actions by envisioning the likely outcomes of our behaviors, and we adjust our behavior if prospective outcomes become more or less valuable. This capacity for prospective decision making can be imperiled by addictive drugs, such that individuals suffering from substance use disorders may seek addictive drugs despite threats to social ties, employment, etc. The ability to select actions that will result in valued rewards requires the medial orbitofrontal cortex (MO), particularly when those rewards are not immediately delivered (are unobservable) and must be anticipated. Addictive drugs like cocaine cause MO atrophy and impede MO function in both rodents and humans, emphasizing the need to fully understand the manner by which the MO coordinates prospective action selection. The neurotrophic factor, Brain-Derived Neurotrophic Factor (BDNF), and its high-affinity receptor tropomyosin receptor kinase B (TrkB) control MO function. BDNF presence in the MO is necessary and sufficient for mice to appropriately direct behaviors towards rewards of higher value relative to low-value options. Further, locally overexpressing a truncated isoform of TrkB (TrkB.t1), which acts as a dominant negative, or locally ablating TrkB occludes value-based action, particularly when potential rewards are unobservable. We hypothesize that neurotrophin signaling stabilizes neural connections essential to adaptive choice. Which neural connections are necessary for choice behavior? We recently discovered that ventral hippocampal (vHC) inputs to the MO are necessary for value memory updating – and particularly, the integration of new value information into instrumental response strategies. Meanwhile, projections from the MO to the basolateral amygdala (BLA) are necessary for value memory retrieval (and not updating). Thus, vHC inputs to the MO appear to update value memory, while outputs retrieve new memories to execute adaptive action. The goals of this proposal are to: (1) determine whether functional vHC-to-MO and MO-to-BLA connections require TrkB-mediated signal propagation on excitatory MO neurons. (2) We will next determine whether MO neurons form stable value memory traces necessary for adaptive choice, and whether trace formation requires i.) vHC inputs, ii.) TrkB, and iii.) local dendritic spine plasticity. (3) The capacity for prospective goal-directed action improves throughout adolescence. Because of this, mechanistic insights can be gained by studying adolescent development. We will delineate the adolescent development of vHC-to-MO projections, the morphological maturation of projection-defined layer V MO neurons, and the stimulation of TrkB+ MO neurons during decision-making tasks in mice. We will test the hypotheses that TrkB controls typical development, and that TrkB+ MO neurons are increasingly stimulated during tests of behavioral flexibility as mice mature, ultimately forming stable memory traces attuned to value information.

概括 在日常生活中，我们经常必须通过设想行为的可能结果来选择行动，并调整 如果潜在的结果变得或多或少有价值，我们的行为。潜在决定的能力 加性药物可能会损害，使患有药物使用障碍的人可能 寻求其他毒品目的地威胁社会关系，就业等。 选择将带来有价值奖励的动作的能力需要介质轨道额皮层（MO）， 特别是当这些奖励未立即交付时（无法观察），必须预料到。 可卡因等上瘾的药物会导致萎缩并阻碍啮齿动物和人类的功能， 强调需要充分理解MO协调前瞻性行动选择的方式。 神经营养因子，脑衍生的神经营养因子（BDNF）及其高亲和力受体 肌球蛋白受体激酶B（TRKB）控制MO功能。在MO中存在BDNF是必要且足够的 使小鼠适当地将行为定向到相对于低价值选项的较高价值的奖励。更远， 局部过表达TRKB的截短同工型（TRKB.T1），它充当主要的负面或局部 消融TRKB会阻止基于价值的动作，尤其是当潜在的奖励无法观察到时。我们 假设神经营养蛋白信号传导稳定自适应选择必不可少的神经元连接。 选择行为需要哪些神经连接？我们最近发现腹侧 MO的海马（VHC）输入是值的价值内存更新所必需的，尤其是集成 新价值信息中的仪器响应策略。意思是从MO到MO的项目 Bosolatoral Amygdala（BLA）对于价值内存检索（而不是更新）是必需的。那就是VHC输入到 MO外观更新值内存，而输出检索新记忆以执行自适应动作。 该建议的目标是：（1）确定功能性VHC-to-Mo和Mo-to-Bla连接是否存在 需要在兴奋性MO神经元上进行TRKB介导的信号传播。 （2）接下来，我们将确定MO神经元是否形成自适应的稳定值存储器迹线 选择，以及痕量形成是否需要i。）VHC输入，ii。）trkb和iii。）局部树突状脊柱可塑性。 （3）在整个青少年中，前瞻性目标行动的能力提高了。因为这， 可以通过研究青少年发展来获得机械洞察力。我们将描绘青少年 VHC到MO预测的发展，投影定义的层Vo神经元的形态成熟， 以及小鼠决策任务中TRKB+ MO神经元的刺激。我们将测试假设 TRKB控制了典型的发展，并且在测试期间越来越刺激了TRKB+ MO神经元 作为小鼠成熟的行为灵活性，最终形成了稳定的记忆痕迹，以使其重视信息。