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时期。在 精神分裂症，影像学研究发现丘脑-前额叶静息状态连接性在 疾病发作前的青春期。功能连接性的下降与认知能力有关 该疾病的症状和病因。多年来，前额皮质（PFC）的成熟度发生了改变 与精神障碍的认知缺陷有关，但驱动 PFC 成熟的机制 很大程度上是未知的。因为丘脑输入活动对于感觉皮层的电路成熟很重要，所以我们 这里假设丘脑输入活动对于前额叶回路的成熟也很重要。 探讨青春期是否是丘脑活动调节的敏感时期 为了 PFC 电路的成熟，我们使用小鼠来比较减少丘脑核活动的影响 出生后 P20-50 与成年期 (P90-120) 投射到 PFC。我们发现抑制 青春期丘脑导致丘脑-mPFC 投射密度长期持续下降 以及 mPFC 神经元的兴奋性驱动减少。青少年丘脑抑制进一步导致认知缺陷 成年期间的注意力转移与相关神经元活动的破坏有关 mPFC 中的任务结果编码。相比之下，成年期的丘脑抑制没有持久的作用。 对 mPFC 兴奋、相关活动、结果编码和行为的影响。引人注目、激动人心 成年期丘脑在设定转移任务期间拯救体内神经元活动和诱发的认知缺陷 通过青春期抑制。 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 青少年抑制损害 mPFC 成熟的机制仍不清楚。为了解决这个问题，首先， mPFC 电路的发育需要在青春期进行表征。其次，重要的是 确定青春期抑制是否会引起内在 mPFC 回路的长期变化，以及哪些变化 特定的 mPFC 投射和中间神经元受到青少年丘脑抑制的调节。第三，这将是 重要的是要知道这些变化何时发生以及它们与体内交叉相关活动的变化有何关系 和结果编码。我们的数据进一步表明，促进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，有益效果仅 当丘脑受到刺激时发生。因此，需要确定能够延长更长时间的策略 认知能力的持久拯救。我们将通过三个目标来解决这些问题： 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缓解。