Parr Ashley C, Perica Maria I, Calabro Finnegan J, Foran Will, Moon Chan Hong, Hetherington Hoby, Luna Beatriz
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
Mol Psychiatry. 2025 Jun;30(6):2558-2572. doi: 10.1038/s41380-024-02860-7. Epub 2024 Dec 9.
Developmental changes in prefrontal cortex (PFC) excitatory (glutamatergic, Glu) and inhibitory (gamma- aminobutryic acid, GABA) neurotransmitter balance (E:I) have been identified during human adolescence, potentially reflecting a critical period of plasticity that supports the maturation of PFC-dependent cognition. Animal models implicate increases in dopamine (DA) in regulating changes in PFC E:I during critical periods of development, however, mechanistic relationships between DA and E:I have not been studied in humans. Here, we used high field (7T) echo planar imaging (EPI) in combination with Magnetic Resonance Spectroscopic Imaging (MRSI) to assess the role of basal ganglia tissue iron-reflecting DA neurophysiology-in longitudinal trajectories of dorsolateral PFC Glu, GABA, and their relative levels (Glu:GABA) and working memory performance from adolescence to adulthood in 153 participants (ages 10-32 years old, 1-3 visits, 272 visits total). Using generalized additive mixed models (GAMMs) that capture linear and non-linear developmental processes, we show that basal ganglia tissue iron increases during adolescence, and Glu:GABA is biased towards heightened Glu relative to GABA early in adolescence, decreasing into adulthood. Critically, variation in basal ganglia tissue iron was linked to different age-related trajectories in Glu:GABA and working memory. Specifically, individuals with higher levels of tissue iron showed a greater degree of age-related declines in Glu and Glu:GABA, resulting in lower Glu relative to GABA (i.e., higher GABA relative to Glu) in young adulthood. Variation in tissue iron additionally moderated working memory trajectories, as higher levels of tissue iron were associated with steeper age-related improvements and better performance into adulthood. Our results provide novel evidence for a model of critical period plasticity whereby individual differences in DA may be involved in fine-tuning PFC E:I and PFC-dependent cognitive function at a critical transition from adolescence into adulthood.
人类青春期期间，前额叶皮质（PFC）兴奋性（谷氨酸能，Glu）和抑制性（γ-氨基丁酸，GABA）神经递质平衡（E:I）出现了发育变化，这可能反映了支持PFC依赖性认知成熟的可塑性关键期。动物模型表明，多巴胺（DA）增加在发育关键期调节PFC的E:I变化，然而，DA与E:I之间的机制关系尚未在人类中进行研究。在此，我们使用高场（7T）回波平面成像（EPI）结合磁共振波谱成像（MRSI），评估基底神经节组织铁（反映DA神经生理学）在153名参与者（年龄10 - 32岁，1 - 3次访视，共272次访视）从青春期到成年期背外侧PFC的Glu、GABA及其相对水平（Glu:GABA）纵向轨迹以及工作记忆表现中的作用。使用捕捉线性和非线性发育过程的广义相加混合模型（GAMMs），我们发现基底神经节组织铁在青春期增加，并且Glu:GABA在青春期早期偏向于Glu相对于GABA升高，成年期下降。至关重要的是，基底神经节组织铁的变化与Glu:GABA和工作记忆中不同的年龄相关轨迹相关。具体而言，组织铁水平较高的个体在Glu和Glu:GABA方面与年龄相关的下降程度更大，导致成年早期Glu相对于GABA较低（即GABA相对于Glu较高）。组织铁的变化还调节了工作记忆轨迹，因为较高水平的组织铁与成年期更陡峭的年龄相关改善和更好的表现相关。我们的结果为关键期可塑性模型提供了新证据，即DA的个体差异可能在从青春期到成年期的关键转变中参与微调PFC的E:I和PFC依赖性认知功能。
