Maturation of flexible cognitive behavior as result of age-dependent formation of prefrontal ensembles in juvenile mice

大多数有助于认知灵活性的功能，如工作记忆，被认为是与前额叶回路的发育同时成熟的，因此，从童年到青年阶段，逐渐增强，直到中年之后才下降。然而，认知灵活性的某些方面，如决策策略，已被发现在青少年时期达到最大的表现。一般来说，控制认知灵活性出现的原理与相应的神经元集合有关，特别是在发育过程中工作记忆和决策的表现差异，人们知之甚少。我们之前对啮齿动物的研究表明，出生后不久，内侧前额叶皮层，即认知灵活性的大脑回路核心，经历了深刻的功能成熟。新生儿前额叶回路进入振荡节律对年轻人的行为表现至关重要；另一方面，在精神疾病的小鼠模型中，早期时间协调的破坏是功能障碍的标志。除了新生儿发育，青少年时期/青春期也被认为是神经回路（重新）组织和复杂认知能力出现的关键敏感时间窗口。本研究旨在研究不同青少年工作记忆和决策过程中前额叶整体的动态组装，并通过海马体和丘脑输入识别其任务依赖模式。为此，我们将结合电生理学和光遗传学在最近开发的行为设置监测青少年的行为。我们假设在整个青少年发展过程中，在工作记忆和决策任务中，前额叶集合的组织和输入控制是不同的。首先，我们将监测PFC前边缘细分的单个神经元和时间协调集合如何编码工作记忆和决策任务中的年龄依赖性表现。与核心假设1一致，我们提出前额叶神经元通过不同神经元间种群的年龄依赖性嵌入而组织的同步连接是行为表现的基础。其次，根据核心假设3，我们将探索海马体和丘脑输入对工作记忆和决策任务中神经元集合形成的贡献。最后，我们将探讨前少年/少年时期边缘系统的时间协调是否能预测成人的认知表现。我们期望所获得的见解将确定认知灵活性的发展原则与前额叶集合的动态形成有关。

Most functions contributing to cognitive flexibility, such as working-memory, are thought to mature in parallel with the development of prefrontal circuits and therefore, to progressively augment from childhood to young adulthood, and to decline only after middle age. However, some aspects of cognitive flexibility, such as decision-making strategies, have been found to reach a maximal performance at juvenile age. The principles that govern the emergence of cognitive flexibility in relationship to corresponding neuronal ensembles, in general, and the performance differences for working-memory and decision-making during development, in particular, are poorly understood. Our previous studies in rodents showed that shortly after birth, the medial prefrontal cortex, the core of the brain circuit underlying cognitive flexibility, undergoes profound functional maturation. The entrainment of neonatal prefrontal circuits into oscillatory rhythms is critical for behavioral performance of young adults; on a flip side, disruption of early temporal coordination is a signature of dysfunction in mouse models of mental illness. Besides neonatal development, juvenile period / adolescence has been proposed as a time window of critical sensitivity for (re)organization of circuits and emergence of complex cognitive abilities. Here, we aim to tackle the dynamic assembling of prefrontal ensembles during working-memory and decision-making at different juvenile ages and identify their task-dependent patterning by hippocampal and thalamic inputs. For this, we will combine electrophysiology and optogenetics in a recently developed behavioral setup for monitoring juvenile behavior. We hypothesize that prefrontal ensembles are differently organized and input controlled during working memory and decision making tasks across juvenile development. First, we will monitor how single neurons and temporally-coordinated ensembles in the prelimbic subdivision of PFC encode the age-dependent performance in working-memory and decision-making tasks. In line with the core hypothesis 1, we propose that synchrony-based linking of prefrontal neurons organized through age-dependent embedding of different interneuronal populations underlies the behavioral performance. Second, following the core hypothesis 3, we will explore the contribution of hippocampal and thalamic inputs to the formation of neuronal ensembles during working-memory and decision-making tasks across development. Finally, we will interrogate whether the temporal coordination of prelimbic ensembles at pre-juvenile / juvenile age is predictive of the adult cognitive performance. We expect that the gained insights will identify the developmental principles of cognitive flexibility in relation with the dynamic formation of prefrontal ensembles.