Developmental Changes in Striatal Neurophysiology through Adolescence

描述(由申请人提供)：从青春期到青壮年的发育阶段与破坏生存(例如冒险行为)并增加出现精神病理(例如药物滥用、情绪障碍和精神分裂症)的风险的脆弱性有关。这些漏洞可能具体与纹状体和多巴胺(DA)功能有关，后者支持动机系统并影响行为。在青春期，多巴胺代谢和纹状体神经生理发生显著变化，纹状体在行为中具有更大的功能意义。到目前为止，关于纹状体动机系统成熟的研究仅限于动物模型、死后研究和间接的神经影像证据，限制了我们理解人类纹状体发育的神经生物学机制的能力。父母的资助发现，在青春期的奖励处理过程中，纹状体功能的增加与感觉寻求指数有关，以及大脑网络的变化，表明青春期具有独特的专业化。我们现在建议探索青春期纹状体变化的神经生物学机制，以及这些机制如何影响大脑系统和行为。我们将使用分子磁共振(MMR)扫描仪对140名12至30岁的健康受试者进行加速纵向研究，该扫描仪提供同时的磁共振成像(MRI)和正电子发射断层扫描(PET)数据。PET方法将量化从年轻到中年的DA的可获得性和释放，而纹状体神经生理学的补充MRI测量将提供纹状体中与奖励相关的神经激活的指标，并通过量化大脑功能和组织铁来间接测量DA的处理(目标1)。纹状体发育变化对大脑系统的影响将通过将纹状体神经生理学措施与功能和结构大脑网络连接联系起来(目标2)来表征。神经生物学变化将与动机的行为测量联系在一起，包括多巴胺能对强化学习的影响的计算模型(目标3)。这项工作将为从青春期到成年期的神经生物学过程模型提供信息，该模型可以阐明在这段时间内精神病理学的发展和风险承担的增加。

DESCRIPTION (provided by applicant): The developmental period from adolescence to young adulthood is associated with vulnerabilities that undermine survival (e.g., risk-taking behaviors) and increase the risk for the emergence of psychopathology (e.g., substance abuse, mood disorders, and schizophrenia). These vulnerabilities may be specifically linked with striatal and dopamine (DA) function, which support motivational systems and influence behavior. During adolescence, DA metabolism and striatal neurophysiology change significantly, and the striatum takes on greater functional significance in behavior. To date, research on the maturation of striatal motivational systems has been restricted to animal models, post mortem studies, and indirect neuroimaging evidence, limiting our ability to understand the neurobiological mechanisms of striatal development in humans. The parent grant identified increases in striatal function during reward processing in the adolescent period that were associated with indices of sensation seeking, as well as changes in brain networks suggesting a unique specialization in adolescence. We now propose to probe the neurobiological mechanisms underlying striatal changes in adolescence and how these affect brain systems and behavior. We will study 140 12- to 30-year-old healthy subjects in an accelerated longitudinal design using a molecular magnetic resonance (mMR) scanner that provides simultaneous magnetic resonance imaging (MRI) and positron emission tomography (PET) data. PET methods will quantify DA availability and release from young to middle adulthood, whereas complementary MRI measures of striatal neurophysiology will provide indices of reward-related neural activation in the striatum and indirect measures of DA processing via quantification of brain function and tissue iron (Aim 1). The effects of developmental changes in the striatum on brain systems will be characterized by linking striatal neurophysiology measures with functional and structural brain network connectivity (Aim 2). Neurobiological changes will be linked with behavioral measures of motivation, including a computational model of dopaminergic effects on reinforcement learning (Aim 3). This work will inform a model of the neurobiological processes underlying the transition from adolescence to adulthood that can clarify the development of psychopathology and increased risk-taking during this time.