Neurotrophic and ontogenic factors in medial orbitofrontal cortical function

摘要 在日常生活中，我们经常必须通过想象我们行为的可能结果来选择行动，然后我们进行调整 当预期结果变得或多或少有价值时，我们的行为。这种前瞻性决策的能力 制造可能会受到成瘾药物的危害，因此患有药物使用障碍的人可能 不顾对社会关系、就业等的威胁，寻求上瘾的药物。 选择将导致有价值的奖励的动作的能力需要内侧眶额叶皮质(MO)， 特别是当这些回报没有立即交付(看不到)，而且必须预料到的时候。 像可卡因这样的上瘾药物会导致MO萎缩，并阻碍啮齿动物和人类的MO功能， 强调需要充分了解气象组织协调未来行动选择的方式。 神经营养因子、脑源性神经营养因子及其高亲和力受体 原肌球蛋白受体激酶B(TrkB)控制MO功能。BDNF在MO中的存在是必要和充分的 使小鼠适当地引导行为倾向于相对于低价值选项更高价值的奖励。此外， 局部过度表达TrkB的截短亚型(TrkB.t1)，其充当显性否定，或局部过度表达 消融TrkB阻碍了基于价值的行动，特别是在潜在回报看不到的情况下。我们 假设神经营养因子信号稳定对适应性选择至关重要的神经连接。 选择行为需要哪些神经连接？我们最近发现腹侧 海马区(VHC)对MO的输入是价值记忆更新所必需的--尤其是整合 将新的价值信息纳入工具性应对战略。同时，从MO到MO的预测 杏仁基底外侧核(BLA)是价值记忆提取(而不是更新)所必需的。因此，VHC输入到 MO似乎更新值记忆，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VHC到MO和MO到BLA的功能连接 需要TrkB介导的信号在兴奋性MO神经元上的传播。 (2)接下来，我们将确定MO神经元是否形成适应所需的稳定值记忆痕迹 选择，以及痕迹形成是否需要i。)VHC输入，i.)TrkB和III。)局部树突棘的可塑性。 (3)预期目标导向行动的能力在整个青春期都有所提高。正因为如此， 通过研究青少年的发展，可以获得机械性的见解。我们将描绘出青少年 VHC-MO投射的发展，投射定义的第V层MO神经元的形态成熟， 以及在小鼠决策任务中对TrkB+MO神经元的刺激。我们将检验假设 TrkB控制着典型的发育，并且TrkB+MO神经元在测试 随着老鼠的成熟，行为的灵活性最终会形成稳定的记忆痕迹，以适应有价值的信息。

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.