Thalamo-Prefrontal Circuit Maturation During Adolescence

青春期丘脑-前额叶回路的成熟

• 批准号: 10818866
• 负责人: Christoph Kellendonk
• 金额: $ 6.18万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818866
• 关键词: Address; Adolescence; Adolescent; Adult; Area; Attention; Behavior; Cognition; Cognitive deficits; Data; Development; Disease; Etiology; Impairment; Interneurons; Link; Mental disorders; Mus; Neurobehavioral Manifestations; Neurodevelopmental Disorder; Neurons; Onset of illness; Outcome; Prefrontal Cortex; Rest; Schizophrenia; Thalamic Nuclei; Thalamic structure; Time; cognitive ability; density; imaging study; in vivo; postnatal; sensory cortex

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.

青春期是精神分裂症和其他精神障碍发展的脆弱窗口。在……里面 精神分裂症，成像研究发现丘脑-前额叶休息状态的连接性在 发病前的青春期。这种功能连接性的下降与认知能力有关 症状和疾病的病因学。多年来，前额叶皮质(PFC)的成熟改变 与精神障碍的认知缺陷有关，但推动PFC成熟的机制 在很大程度上是未知的。因为丘脑的输入活动对感觉皮层的回路成熟很重要，所以我们 假设丘脑的输入活动对前额叶回路的成熟也很重要。 为了解决青春期是否是丘脑活动调节 PFC回路的成熟，我们用小鼠比较了降低丘脑核团活动的效果 出生后20~50天投射至PFC，成年期投射至PFC(P90~120)。我们发现抑制作用 青春期的丘脑导致丘脑-mPFC投射密度的长期下降 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障碍 在成年期注意定势转移中，与相关神经元活动中断和 MPFC中的任务结果编码。相比之下，丘脑在成年期的抑制不会持续很长时间 对mPFC兴奋、相关活动、结果编码和行为的影响。引人注目的是，令人兴奋的是 成年期设定转移任务丘脑对体内神经元活动和认知功能障碍的挽救作用 青春期的抑制。 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成熟的机制仍不清楚。为了解决这个问题，首先， MPFC回路的发育需要在青春期确定特征。其次，重要的是 确定青少年抑制是否会导致内在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，它将是 重要的是要知道这种变化是什么时候发生的，以及它们如何与体内交叉相关活动的变化相关 和结果编码。我们的数据进一步表明，增强丘脑活动可以为 挽救神经发育障碍中的认知缺陷。然而，如上所述，有益的影响只是 发生在丘脑受到刺激的时候。因此，将需要确定允许更长时间的战略 认知能力的持久拯救。我们将通过三个目标解决这些问题：目标1：确定 青少年丘脑活动何时何地调节mPFC回路连通性的发展。目标2：实现 确定青少年丘脑抑制对认知的影响是否需要mPFC的成熟。 目的3.确定丘脑兴奋是否能导致认知缺陷的长期恢复。