Thalamo-prefrontal circuit maturation during adolescence

丘脑-前额叶回路在青春期成熟

• 批准号: 10585031
• 负责人: Christoph Kellendonk
• 金额: $ 50.88万
• 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: 2023-01-27 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585031
• 关键词: ARHGEF5 gene; Address; Adolescence; Adolescent; Adult; Affect; Amygdaloid structure; Anatomy; Area; Attention; Behavior; Cognition; Cognitive deficits; Corpus striatum structure; Data; Development; Disease; Etiology; Impairment; Interneurons; Intervention; Link; Measures; Mental disorders; Mus; Neurobehavioral Manifestations; Neurodevelopmental Disorder; Neurons; Onset of illness; Outcome; Performance; Physiological; Physiology; Prefrontal Cortex; Property; Protocols documentation; Rest; Schizophrenia; Slice; Thalamic Nuclei; Thalamic structure; Time; Training; cell type; cognitive ability; density; early adolescence; imaging study; improved; 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性窗口。在 精神分裂症，成像研究发现，在 疾病发作之前的青春期。功能连接性的下降与认知有关 疾病的症状和病因。多年来，前额叶皮层（PFC）的成熟改变了 与精神障碍的认知缺陷有关，但驱动PFC成熟的机制 在很大程度上未知。由于丘脑输入活性对于感觉皮层的电路成熟很重要，我们 在这里假设丘脑输入活性对于前额叶回路的成熟也很重要。 为了解决青春期是否是敏感的时间周期，在此期间丘脑活动调节 PFC电路的成熟，我们使用了小鼠并比较了丘脑核中还原活性的影响 在产后P20-50期间投射到PFC，成年后（P90-120）。我们发现抑制 青春期期间的丘脑导致丘脑-MPFC投影的密度持续下降 并减少了对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 在成年期间的注意力集转移中，与神经元活性中断有关 MPFC中编码的任务结果。相反，成年期间的丘脑抑制没有长期 对MPFC激发，相关活性，结果编码和行为的后果。令人兴奋的是 在体内神经元活动和认知缺陷中，成年期间的丘脑在成年期间的成年期间。 通过青少年抑制。 尽管这些数据将青春期作为PFC电路成熟的敏感时间窗口 青少年抑制会损害MPFC成熟的机制尚不清楚。为了解决这个问题，首先 需要在青春期表征MPFC电路的发展。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，并且 特定的MPFC投影和中间神经元受青少年丘脑抑制作用调节。第三，将是 重要的是要知道何时出现这种变化以及它们与体内跨相关活动的变化如何相关 和结果编码。我们的数据进一步表明，提高丘脑活动可以为 营救神经发育障碍的认知缺陷。但是，如前所述，只有有益的效果 在刺激丘脑时发生。因此，将需要确定策略，以便更长 认知能力的持久营救。我们将使用三个目标解决这些问题：目标1：确定 青少年丘脑活性在何时何地调节MPFC电路连通性的发展。目标2：到 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。确定丘脑激发是否会导致认知不足的持久救助。