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

多巴胺能中额叶回路的青少年可塑性：细胞机制和行为作用

• 批准号: 10228964
• 负责人: Rianne Stowell
• 金额: $ 7.05万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228964
• 关键词: Address; Adolescence; Adolescent; Adolescent Development; Adult; Animal Model; Antipsychotic Agents; Attention; Automobile Driving; Axon; Behavior; Behavioral; Behavioral Paradigm; Bipolar Disorder; Brain region; Cells; Chronic; Cognitive; Cognitive deficits; Complex; Delusions; Development; Disease; Dopamine; Elements; Genetic Models; Hallucinations; Head; Image; Immune; Mediating; Mental disorders; Microglia; Microscope; Midbrain structure; Modification; Morphology; Mus; Neuraxis; Neurobehavioral Manifestations; Neurodevelopmental Disorder; Neuroglia; Neuronal Plasticity; Neurons; Participant; Pathway interactions; Patients; Pharmacological Treatment; Pharmacotherapy; Play; Population; Process; Psychoses; Research; Role; Schizophrenia; Signal Transduction; Structure; Symptoms; Synaptic plasticity; System; Systems Development; Techniques; Testing; Therapeutic; Therapeutic Intervention; Ventral Tegmental Area; Work; calcium indicator; cognitive function; developmental disease; developmental plasticity; dopamine system; dopaminergic neuron; effective therapy; excitatory neuron; experimental study; imaging approach; improved; in vivo; in vivo calcium imaging; in vivo imaging; in vivo two-photon imaging; inhibitory neuron; innovation; insight; mature animal; mouse genetics; mouse model; neural circuit; neuronal circuitry; neuropsychiatric disorder; new therapeutic target; optogenetics; postsynaptic; presynaptic; psychostimulant; relating to nervous system; response; two photon microscopy

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.

最近的证据表明，许多精神疾病（例如精神分裂症）是发育性的 以神经元回路的复杂改变为特征的疾病。多巴胺长期以来被认为是一种 精神疾病的关键参与者和许多当前的精神病治疗策略都针对多巴胺能 系统。虽然许多这些疗法有效地针对患者的妄想和幻觉，但没有有效的方法 现有疗法可以控制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，中额叶多巴胺能回路异常与认知缺陷有关 在精神疾病中。我们实验室之前的工作已经确定了青少年活动依赖的独特可塑性 成年动物所缺乏的中额叶多巴胺能投射。然而，这背后的机制 青少年的可塑性过程仍不清楚。我们实验室之前的工作和初步实验表明 腹侧被盖区活动引起突触前轴突布顿生长和突触后皮质 神经元活动。在目标 1 中，我将进一步描述皮质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突触前所必需的 通过突触后兴奋性和抑制性神经元的光/化学遗传学沉默来实现可塑性。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响应 多巴胺能活性的变化以及小胶质细胞是否介导中额叶多巴胺能可塑性。最后，为了 阐明中额叶神经活动在正常发育中所起的未知作用，在目标 3 中我会扰乱 青春期期间的中额叶活动的化学遗传学，并评估对额叶皮层活动的影响 和额叶皮质依赖性行为。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发育提供重要见解。随着对 中额叶回路的发育和功能，可以确定和治疗干预的新途径 在神经发育精神疾病的背景下进行了测试。