Molecular Maladaptations Following Developmental Loss of D1 Receptor Signaling

D1 受体信号发育丧失后的分子适应不良

基本信息

批准号：
8058643
负责人：
Aliya L. Frederick
金额：
$ 2.65万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8058643
关键词：
AMPA Receptors Acute Adult Affect Agonist Animal Model Attention Deficit Disorder Attenuated Behavior Biochemical Biological Neural Networks Brain Brain region Catecholamines Cell surface Clinical Cocaine Complex Corpus striatum structure Coupled Cyclic AMP-Dependent Protein Kinases DARPP Development Disease Dopamine Dopamine D1 Receptor Equilibrium Exposure to Fetal Cocaine Exposure Functional disorder Gene Expression Genes Genetic Genetic Models Glutamate Receptor Goals Individual Knockout Mice Laboratories Life Link Medial Mediating Mediator of activation protein Mental disorders Methods Modeling Molecular Mus Neurologic Neuronal Differentiation Neurons Oryctolagus cuniculus Pathogenesis Pattern Pharmaceutical Preparations Phosphorylation Population Prosencephalon Proteins Reading Receptor Activation Receptor Signaling Rewards Series Signal Pathway Signal Transduction Signaling Molecule Site Slice Synapses Synaptic Transmission System Testing Therapeutic Uses calmodulin-dependent protein kinase II clinical phenotype cocaine exposure cognitive function design dopamine system executive function frontal lobe in utero in vivo nervous system disorder neuroadaptation neurobehavioral neurochemistry neuropsychiatry neurotransmission novel therapeutic intervention offspring prenatal psychostimulant receptor receptor expression receptor function transmission process

项目摘要

Neurodevelopmental dysregulation of catecholamine neurotransmission in the forebrain contributes to the pathogenesis of neurological and neuropsychiatric disorders, even though clinical phenotypes usually become apparent only later in life. We hypothesize that abnormalities in dopamine signaling initiated developmentally may result in life-long changes in the activation of dopamine-modulated intracellular signaling cascades and underlie neurobehavioral changes observed in adults following disrupted dopamine neurotransmission. We propose two specific aims to test the hypothesis that developmental abnormalities in dopamine D1 receptor signaling result in long-lasting changes in basal and/or receptor-induced activation of dopamine-modulated signaling components. We will investigate changes in phosphorylation of the molecular substrates DARPP-32, CaMKII and the AMPA receptor GluR1 subunit because of their key role in modulating excitatory synaptic transmission in dopaminoceptive brain regions. Aim 1 serves to investigate changes in basal activation of these substrates in a genetic model of constitutive loss of D1 receptor signaling in knockout mice and in hypomorphic models of D1 receptor signaling: rabbits exposed to cocaine in utero, a model in which there is a pharmacologically induced reduction in D1 receptor expression at the cell-surface for signal transduction but not complete loss of D1 receptor signaling, and in D1 receptor haploinsufficient mice. Aim 2 then investigates activation of DARPP-32, CaMKII, and the glutamate receptor GluR1 subunit in cocaine-exposed progeny following D1 receptor stimulation with selective D1 receptor -like agonists and psychostimulant drugs. The elucidation of differential regulatory mechanisms when D1 receptor signaling is diminished in the hypomorphic models compared to complete loss of D1 receptor signaling in the knockout mice will inform our understanding of complex (mal)adaptations to neurodevelopmental insults. In addition, these studies will inform our understanding of the molecular alterations induced by developmental disruptions of dopamine neurotransmission, and how these changes contribute to dysfunctions in neuronal activity and behavior. Beyond the direct issue of understanding (mal)adaptive changes after cocaine exposure in utero within clinical populations of exposed individuals, these studies also hold more general importance for understanding the long-term consequences of how neural networks adapt to developmental disruptions in dopamine signaling.

前脑中儿茶酚胺神经传递的神经发育失调有助于神经和神经精神疾病的发病机理，尽管临床表型通常只在以后的生活中显而易见。我们假设在发育发育中引发的多巴胺信号传导异常可能会导致多巴胺调节的细胞内信号传导级联反应的激活和神经行为的基础变化，而神经行为的基础是多巴胺神经胺传输干扰后在成年人中观察到的。我们提出了两个具体的目的，以检验以下假设：多巴胺D1受体信号传导的发育异常导致基础和/或受体诱导的多巴胺调节信号传导成分激活的长期变化。我们将研究分子底物DARPP-32，CAMKII和AMPA受体GLUR1亚基的磷酸化变化，因为它们在调节多巴哥咖啡脑区域的兴奋性突触传递中的关键作用。 Aim 1 serves to investigate changes in basal activation of these substrates in a genetic model of constitutive loss of D1 receptor signaling in knockout mice and in hypomorphic models of D1 receptor signaling: rabbits exposed to cocaine in utero, a model in which there is a pharmacologically induced reduction in D1 receptor expression at the cell-surface for signal transduction but not complete loss of D1 receptor signaling, and in D1受体单倍型小鼠。 AIM 2然后研究了D1受体刺激在可卡因暴露于可卡因暴露的后代中DARPP-32，CAMKII和谷氨酸受体GlUR1亚基的激活。与敲除小鼠中D1受体信号传导的完全丢失相比，降低了D1受体信号传导时，差异调节机制的阐明将为我们理解对神经发育侮辱的复杂（MAL）适应。此外，这些研究将告知我们对多巴胺神经传递发育中断引起的分子改变的理解，以及这些变化如何导致神经元活性和行为的功能障碍。除了在暴露个人的临床人群中可卡因暴露后的可卡因暴露后的直接理解问题（MAL）自适应变化之外，这些研究对于理解神经网络如何适应多巴胺信号发育破坏的长期后果也具有更重要的重要性。