Adolescent plasticity of the dopaminergic mesofrontal circuit: cellular mechanisms and behavioral roles

最近的证据表明，许多精神疾病，如精神分裂症，都是发育性的。 以复杂的神经元回路改变为特征的疾病。长期以来，多巴胺一直被认为是一种 精神疾病的关键角色和许多目前精神病的治疗策略以多巴胺能为靶点 系统。虽然这些疗法中的许多有效地针对患者的妄想和幻觉，但没有有效的 存在治疗方法来管理精神分裂症等疾病的认知症状。对两名患者的研究 动物模型表明，前额叶中脑多巴胺能回路异常与认知障碍有关。 在精神疾病方面。我们实验室之前的工作已经确定了一种独特的青少年活动依赖可塑性 成年动物缺乏的前额叶中脑多巴胺能投射。然而，这背后的机制 青春期的可塑性过程仍不清楚。我们实验室以前的工作和初步实验证明 腹侧被盖区活动引起突触前轴突突起和突触后皮质 神经元活动。在目标1中，我将进一步描述皮层兴奋性和抑制性神经元对 中额叶活动并确定皮质突触后活动是否是中额叶前突触所必需的 突触后兴奋性和抑制性神经元的光/化学沉默可塑性。小胶质细胞， 中枢神经系统的先天免疫细胞也被确定为神经元的关键参与者。 可塑性、发育和神经发育障碍。在目标2中，我将确定小胶质细胞是否对 多巴胺能活性的变化和IF小胶质细胞介导前额叶中脑多巴胺能可塑性。最后，为了 阐明中额叶神经活动在正常发育中扮演的未知角色，在目标3中我将感到不安 青春期中额叶化学发生活动及其对双侧额叶皮质活动的影响 以及额叶皮质依赖行为。从这些互补但独立的目标中获得的结果 将为青少年多巴胺能系统的发育提供关键的见解。通过更好地理解 中额叶回路的发育和功能，可以确定治疗干预的新途径，并 在神经发育性精神疾病的背景下进行测试。

Recent evidence suggests that many psychiatric disorders such as schizophrenia are developmental disorders characterized by complex alterations in neuronal circuits. Dopamine has long been recognized as a key player in psychiatric illness and many current therapeutic strategies for psychosis target the dopaminergic system. While many of these therapeutics effectively target delusions and hallucinations in patients, no effective therapies exist to manage the cognitive symptoms of illnesses such as schizophrenia. Research in both patients and animal models indicates that mesofrontal dopaminergic circuit abnormalities are involved in cognitive deficits in psychiatric illnesses. Prior work in our lab has identified a unique adolescent activity-dependent plasticity in the mesofrontal dopaminergic projections that is lacking in adult animals. However, the mechanisms behind this adolescent plasticity process remain unclear. Previous work and preliminary experiments in our lab demonstrate that ventral tegmental area activity elicits both presynaptic axonal bouton outgrowth and postsynaptic cortical neuronal activity. In Aim 1 I will further characterize the response of cortical excitatory and inhibitory neurons to mesofrontal activity and determine if cortical postsynaptic activity is necessary for mesofrontal presynaptic plasticity through opto/chemogenetic silencing of postsynaptic excitatory and inhibitory neurons. Microglia, the innate immune cells of the central nervous system, have also been identified as key participants in neuronal plasticity, development, and neurodevelopmental disorders. In Aim 2 I will determine if microglia respond to changes in dopaminergic activity and if microglia mediate mesofrontal dopaminergic plasticity. Finally, to elucidate the unknown role that mesofrontal neural activity plays in normal development, in Aim 3 I will perturb mesofrontal activity chemogenetically during adolescence and evaluate the impact on both frontal cortical activity and frontal cortical dependent behaviors. The results obtained from these complementary, but independent aims will provide key insights into adolescent dopaminergic system development. With an improved understanding of mesofrontal circuit development and function, new pathways for therapeutic intervention can be identified and tested in the context of neurodevelopmental psychiatric diseases.