Thalamo-Prefrontal Circuit Maturation During Adolescence

青春期是易患精神分裂症和其他精神疾病的窗口期。在 精神分裂症，成像研究发现，丘脑-前额叶静息状态连接减少， 发病前的青春期。这种功能连接的减少与认知功能有关。 症状和疾病的病因。多年来，前额叶皮层（PFC）的成熟改变 与精神障碍的认知缺陷有关，但驱动PFC成熟的机制 大部分都是未知的。由于丘脑输入活动对感觉皮层回路的成熟很重要， 在此假设丘脑输入活动对前额回路成熟也很重要。 为了解决青春期是否是一个敏感的时间段，在此期间，丘脑活动调节， 成熟的PFC电路，我们使用小鼠和比较的影响，减少活动在丘脑核 P20-50与P90-120之间的差异有统计学意义。我们发现抑制 青春期的丘脑导致丘脑-mPFC投射密度的长期持续下降 减少了对mPFC神经元的兴奋性驱动。青少年丘脑抑制进一步导致认知缺陷 在成年期的注意力转移中，这些注意力转移与相关神经元活动中断有关， 在mPFC中的任务结果编码。相比之下，成年期的丘脑抑制并不持久， 对mPFC兴奋、相关活动、结果编码和行为的影响。令人惊讶的是， 丘脑在成年期的设置转换任务期间拯救体内神经元活动和认知缺陷诱导 青少年的压抑 虽然这些数据表明青春期是PFC电路成熟的敏感时间窗口，但潜在的 青春期抑制损害mPFC成熟的机制尚不清楚。为了解决这个问题，首先， mPFC电路的发展需要在青春期进行表征。其次，重要的是， 确定青少年抑制是否会引起内在mPFC电路的长期变化，以及 特定的mPFC投射和中间神经元受青少年丘脑抑制的调节。第三，将 重要的是知道这些变化何时出现以及它们如何与体内交叉相关活性的变化相关 和结果编码。我们的数据进一步表明，增强丘脑活动可以提供一种策略， 挽救神经发育障碍中的认知缺陷。然而，正如所介绍的， 是在丘脑受到刺激时发生的因此，需要确定战略， 持久拯救认知能力。我们将通过三个目标来解决这些问题：目标1：确定 何时何地青少年丘脑活动调节mPFC电路连接的发展。目标2： 确定青少年丘脑抑制对认知的影响是否需要mPFC的成熟。 目标3。确定丘脑兴奋是否可以导致认知缺陷的长期拯救。

Adolescence is a window of vulnerability for the development of schizophrenia and other mental disorders. In schizophrenia, imaging studies have found that thalamo-prefrontal resting state connectivity is reduced during adolescence prior to disease onset. This decrease in functional connectivity has been linked to cognitive symptoms and the etiology of the disorder. For many years, an altered maturation of the prefrontal cortex (PFC) has been implicated in the cognitive deficits of mental disorders yet the mechanisms that drive PFC maturation are largely unknown. Because thalamic input activity is important for circuit maturation in sensory cortices, we hypothesize here that thalamic input activity is also important for prefrontal circuit maturation. To address whether adolescence is a sensitive time-period during which thalamic activity regulates the maturation of PFC circuitry, we used mice and compared the effects of reducing activity in the thalamic nuclei projecting to the PFC during postnatal days P20-50 with that in adulthood (P90-120). We found that inhibiting the thalamus during adolescence leads to a long-lasting decrease in the density of thalamo-mPFC projections and a reduced excitatory drive to mPFC neurons. Adolescent thalamic inhibition further causes cognitive deficits in attentional set shifting during adulthood that are associated with disrupted correlated neuronal activity and task outcome encoding in the mPFC. In contrast, thalamic inhibition during adulthood has no long-lasting consequences on mPFC excitation, correlated activity, outcome encoding and behavior. Strikingly, exciting the thalamus in adulthood during the set shifting task rescues in vivo neuronal activity and cognitive deficits induced by adolescent inhibition. While these data point to adolescence as a sensitive time window for PFC circuit maturation the underlying mechanisms by which adolescent inhibition impairs mPFC maturation are still unclear. To address this, first, the development of mPFC circuitry needs to be characterized during adolescence. Second, it will be important to determine whether adolescent inhibition induces long-lasting changes in intrinsic mPFC circuitry, and which specific mPFC projections and interneurons are regulated by adolescent thalamic inhibition. Third, it will be important to know when such changes arise and how they relate to the changes in in vivo cross correlated activity and outcome encoding. Our data further suggest that boosting thalamic activity could provide a strategy for rescuing cognitive deficits in neurodevelopmental disorders. However, as presented, the beneficial effect only occurs while the thalamus is stimulated. Therefore, strategies will need to be identified that allow for a longer lasting rescue of the cognitive abilities. We will address these questions using three aims: Aim 1: To determine when and where adolescent thalamic activity regulates the development of mPFC circuit connectivity. Aim 2: To determine whether the impact of adolescent thalamic inhibition on cognition requires maturation of the mPFC. Aim 3. To determine whether thalamic excitation can lead to a long-lasting rescue of the cognitive deficit.