Neurotrophic and ontogenic factors in medial orbitofrontal cortical function

总结 在日常生活中，我们经常必须通过设想我们行为的可能结果来选择行动，我们调整 我们的行为，如果预期的结果变得更有价值或更少。这种前瞻性决策的能力 成瘾性药物可能危及制造，使得患有物质使用障碍的个体可能 不顾对社会关系、就业等的威胁而寻求成瘾药物。 选择能够带来有价值奖励的行为的能力需要内侧眶额皮层（MO）， 特别是当这些奖励没有立即交付（不可观察）并且必须预期时。 可卡因等成瘾药物会导致啮齿动物和人类的MO萎缩并阻碍MO功能， 强调需要充分理解MO协调预期行动选择的方式。 神经营养因子，脑源性神经营养因子（BDNF）及其高亲和力受体 原肌球蛋白受体激酶B（Trk B）控制MO功能。BDNF在MO中的存在是必要和充分的 对于小鼠来说，相对于低价值的选择，适当地将行为导向更高价值的奖励。此外，本发明还 局部过表达TrkB的截短同种型（TrkB.t1），其作为显性阴性，或局部 消除TrkB会阻碍基于价值的行动，特别是当潜在回报不可观察时。我们 假设神经营养因子信号稳定神经连接必不可少的适应性选择。 选择行为需要哪些神经连接？我们最近发现腹侧 海马（vHC）输入到MO是必要的价值记忆更新-特别是，整合 将新的价值信息转化为工具性应对策略。与此同时，从MO到 基底外侧杏仁核（BLA）是价值记忆提取（而不是更新）所必需的。因此，vHC输入到 MO表现为更新值存储器，而输出检索新存储器以执行自适应动作。 本提案的目标是：（1）确定功能性vHC至MO和MO至BLA连接是否 需要TrkB介导的兴奋性MO神经元上的信号传播。 (2)接下来，我们将确定MO神经元是否形成自适应所需的稳定值记忆轨迹。 选择，以及迹线形成是否需要i.）vHC输入，ii.）TrkB，和iii.）局部树突棘可塑性。 (3)在整个青春期，前瞻性目标导向行动的能力得到提高。正因为如此， 通过研究青少年的发展可以获得机械的见解。我们将描述青少年 vHC到MO投射的发展，投射定义层VMO神经元的形态成熟， 以及在小鼠的决策任务期间刺激TrkB+ MO神经元。我们将测试假设， TrkB控制典型的发育，并且TrkB+ MO神经元在测试期间受到越来越多的刺激。 行为灵活性随着老鼠的成熟，最终形成稳定的记忆痕迹调谐到价值信息。

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.