Understanding how social interactions influence reward-seeking behaviors: Developmental mechanisms

摘要 社交互动会影响日常决策，甚至是缺乏明确社交内容的决策。哺乳动物是如何 对过程社会信息进行了深入调查。尽管如此，先前的社会经历如何影响后来的决定 制造还没有被很好地理解，部分原因可能是缺乏用于可延展的模式生物的分析方法。 我的团队开发了一个被称为未来选择的社会激励(SIFC)的任务。老鼠是经过训练的 为了在操作条件反射室内对两种同样偏爱的食物做出反应，然后将其中一种食物与 与新奇的同种生物互动的机会。另一种食物与一种新奇的物体搭配在一起。我们发现老鼠 以后会对同种相关的食物做出更多反应，即使在没有同种的情况下也是如此。因此，之前 社会经验似乎赋予了熟悉的奖励以价值，并激励人们选择这种奖励而不是另一种奖励。 -类似于一个人反复偏爱一家特定的餐厅，因为这是他第一次约会的地方。 内侧眶前叶皮质(MO)是产生奖赏行为所必需的 可能的奖励功能不可用，必须预想--就像在SIFC中，当老鼠必须回忆社会 互动。脑源性神经营养因子(BDNF)是多发性硬化症发育过程中不可或缺的一部分，我们最近发现 生命早期MO中神经元BDNF的耗竭阻碍了SIFC的发展。许多悬而未决的问题仍然存在。我们会： 目标1：确定发展中的MO中的BDNF是否通过MO-BLA影响社会价值加工 关系。我们将测试这一假设，即MO-BLA连接需要神经元来源的BDNF 成熟，使发育中的MO神经元中的BDNF沉默，而不是其他类型的细胞，将：1)减少MO BLA的终末密度和2)兴奋性BLA上依赖学习的树突棘可塑性的闭塞 神经元。3)我们将检验BLA中树突棘可塑性是SIFC发生所必需的假说。 目的2：分离突触前TrkB和突触后TrkB在SIFC中的作用。BDNF易受顺势影响 运输；因此，BDNF必须与其普遍表达的高亲和力受体原肌球蛋白受体结合 控制SIFC的蛋白激酶B(TrkB)目前仍不清楚。我们将检验假设BDNF-TrkB在MO和 对于老鼠来说，将社会信息整合到决策行为中是必要的，而不是BLA。然后我们将更换 TrkB在特定发育时期的活动，以确定行动的关键时期。在子目标中，我们将 将SIFC任务中的任何效果与传统的巴甫洛夫-仪器转换(PIT)任务中的效果进行比较 揭示神经营养因子信号对社会性与非社会性坑道行为的分离效应，如果它们存在的话。 目标3：在社会孤立后恢复SIFC。早年的逆境可以深刻地影响认知和 晚年的社会功能。我们发现青少年的社会隔离导致TrkB基因过早上调 全长异构体和应力相关的辅助因素，并阻碍SIFC。我们将检验这样的假设：选择 血乳酸中的因素对SIFC有因果影响，过度表达阻碍SIFC，抑制归一化 社会决策。

SUMMARY Social interactions impact everyday decisions, even decisions lacking explicit social content. How mammals process social information is intensively investigated. Still, how prior social experiences influence later decision making is not well-understood, likely due in part to a dearth of assays for use in malleable model organisms. My team developed a task referred to as social incentivization of future choice (SIFC). Mice are trained to respond in operant conditioning chambers for two equally preferred foods, then one food is paired with the opportunity to interact with a novel conspecific. The other food is paired with a novel object. We find that mice will later respond more for the conspecific-associated food, even in the absence of that conspecific. Thus, prior social experience appears to confer value to familiar rewards and incentivize choosing that reward over another – akin to one repeatedly favoring a particular restaurant because it’s where one had a first date. The medial orbitofrontal cortex (MO) is necessary for generating reward-seeking actions when the motivating features of possible rewards are not available and must be envisioned – as in SIFC, when mice must recall social interactions. Brain-derived Neurotrophic Factor (BDNF) is integral to MO development, and we recently found that neuronal Bdnf depletion in the MO early in life obstructs SIFC. Many unanswered questions remain. We will: Aim 1: Determine whether BDNF in the developing MO impacts social value processing via MO-BLA connections. We will test the hypothesis that MO-BLA connections require neuronally-derived BDNF for maturation, such that Bdnf silencing in developing MO neurons, but not other cell types, will: 1) diminish MO terminal densities in the BLA and 2) occlude learning-dependent dendritic spine plasticity on excitatory BLA neurons. 3) We will test the hypothesis that dendritic spine plasticity in the BLA is necessary for SIFC to occur. Aim 2: Dissociate the roles of pre- vs. post-synaptic trkB in SIFC. BDNF is subject to anterograde transport; thus, where BDNF must bind to its ubiquitously expressed high-affinity receptor, tropomyosin receptor kinase B (trkB), to control SIFC remains unclear. We will test the hypothesis that BDNF-trkB in the MO and not BLA is necessary for mice to integrate social information into decision-making behavior. We will then replace trkB activity during specific developmental epochs to identify critical periods of action. In a sub-aim, we will compare any effects in the SIFC task to those in a traditional Pavlovian-to-instrumental transfer (PIT) task to reveal dissociable effects of neurotrophin signaling on social vs. non-social PIT behavior, if they exist. Aim 3: Recover SIFC following social isolation. Early-life adversity can profoundly impact cognitive and social function later in life. We find that adolescent social isolation causes the premature up-regulation of trkB full-length isoforms and stress-related co-factors and obstructs SIFC. We will test the hypothesis that select factors in the BLA causally influence SIFC, with overexpression obstructing SIFC and inhibition normalizing social decision-making.