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展平行成熟的，因此，从童年到青年逐渐增加，只有在中年之后才下降。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表现。一般来说，认知灵活性与相应的神经元集合之间的关系，以及工作记忆和决策在发育过程中的表现差异，这些原则的出现还知之甚少。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（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的夹带对年轻成年人的行为表现至关重要;另一方面，早期时间协调的中断是精神疾病小鼠模型功能障碍的标志。除了新生儿的发展，少年期/青春期已被提出作为一个时间窗口的关键敏感性（重组）组织的电路和复杂的认知能力的出现。在这里，我们的目标是解决动态组装的前额叶合奏在工作记忆和决策在不同的青少年年龄，并确定其任务依赖的模式，海马和丘脑的输入。为此，我们将结合联合收割机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，前额叶合奏不同的组织和输入控制过程中的工作记忆和决策任务在青少年发展。首先，我们将监测单个神经元和时间协调的合奏在前额叶皮层细分编码的工作记忆和决策任务的年龄依赖性性能。与核心假设1一致，我们提出，通过年龄依赖性嵌入不同的interneuronal种群组织的前额叶神经元的同步连接的行为表现的基础。其次，根据核心假设3，我们将探讨海马和丘脑输入的神经元合奏在整个发展过程中的工作记忆和决策任务的形成的贡献。最后，我们将询问是否在前青少年/青少年年龄的前边缘系统合奏的时间协调是预测的成年认知性能。我们期望，所获得的见解将确定认知灵活性的发展原则与动态形成的前额叶合奏。

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.