GABA Neuron Subpopulation and the Regulation of Cortical Neuronal and Behavior

GABA 神经元亚群与皮质神经元和行为的调节

• 批准号: 7879283
• 负责人: Holly Marie Moore
• 金额: $ 21.75万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7879283
• 关键词: ARHGEF5 gene; Address; Affect; Affective Symptoms; Affinity; Age; Agonist; Animals; Archives; Autistic Disorder; Axon; Behavior; Behavioral; Benzodiazepine Receptor; Benzodiazepines; Bicuculline; Binding; Biostatistics Core; Brain; Brain Diseases; Cell division; Cell membrane; Cells; Cerebral cortex; Chloride Ion; Chlorides; Cognition; Cognitive; Cognitive deficits; Convulsants; Coupled; Cues; Data; Development; Disease; Dose; Epilepsy; Erinaceidae; Event; Exhibits; Frequencies; Fright; Functional disorder; GABA Receptor; Gene Expression; Genetic Models; Genotype; Goals; Growth; Hand; Hippocampus (Brain); Holly; Immediate-Early Genes; In Vitro; Interneurons; Knockout Mice; Lead; Learning; Ligands; Measures; Mediating; Memory; Methods; Modeling; Molecular; Mood Disorders; Mus; Mutant Strains Mice; Neocortex; Neurobiology; Neurons; Parvalbumins; Pattern; Phenotype; Physiologic pulse; Physiological; Physiology; Population; Positioning Attribute; Predisposition; Probability; Process; Regulation; Relative (related person); Research Support; Rodent; Role; Schizophrenia; Seizures; Services; Severities; Slice; Somatostatin; Sonic Hedgehog Pathway; Stimulus; Synapses; Synaptic Transmission; System; Telemetry; Testing; Universities; Visuospatial; Voltage-Clamp Technics; Wages; Water; Work; age related; awake; base; behavior test; conditioned fear; conditioning; cyclin D2; disability; extracellular; follow-up; frontal lobe; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; hippocampal subregions; human SMO protein; in vivo; mood regulation; mutant; neocortical; nerve supply; neuromechanism; neuron loss; neuronal cell body; neurophysiology; postnatal; postsynaptic; pre-clinical research; presynaptic; programs; receptor; relating to nervous system; research study; response; secondary outcome; synaptic inhibition; tool; transmission process

The overarching goal of Project 4 is to characterize disease-relevant neurophysiological and behavioral phenotypes in two genetic models of developmental interneuronopathies: Cyclin D2 nulls and the Six3- Cre:Smo(FI/FI) conditional nulls of the sonic hedgehog (Shh) pathway developed in Projs. 1 and 2, respectively. Anatomical data provided by Projs 1,2 and 4 and Core B indicate that these two genetic models differ in terms of their impact on MGE-derived interneurons in at least 2 important aspects: 1) relative decreases in parvalbumin-expressing (Pv+) vs. somatostatin-expressing (SSN+) subpopulations and 2) differential effects on neocortical and hippocampal subregions. Specifically, the cyclin D2 model exhibits a loss of Pv+ but not SSN+ interneurons in the cortex; moreover the hippocampus shows a more marked reduction in Pv+ interneurons, relative to neocortical regions. On the other hand, the Six3-Cre:Smo(FI/FI) model shows a loss of both Pv+ and SSN+ interneurons in both neocortex and hippocampus. In Project 4, the impact of these different patterns of interneuron deficits will be determined using a combination of electophysiological, functional-anatomical, and behavioral experiments. Electrophysiological experiments will test the hypothesis that local GABA transmission is reduced in the neocortex and hippocampus of these mutant mice. The behavioral experiments will characterize changes in seizure threshold and fear-related behaviors in response to decreases in efficacy of the GABAA-benzodiazepine receptor. Correlations between behavior and cortical neuron activity will be assessed by telemetry-based EEGs in behaving animals and by quantifying induction patterns of the immediate early gene c-fos following administration of ligands that negatively modulate the GABAA-BZ receptor. Together these studies will characterize the impact of the "maldevelopment" of specific interneuron subpopulations on the functional postnatal development of prefrontal and limbic cortical circuitry mediating mood regulation (specifically, fear) and seizure susceptibility. Pathological development of interneuron populations of the neocortex and hippocampus are thought to contribute to several developmental brain disorders including seizures, cognitive disabilities, autism and schizophrenia. Preclinical research supports the idea that the affective symptoms and cognitive deficits that often accompany these disorders may also be, in part, mediated by a disruption of cortical GABA transmission or its developmental consequences. Thus Project 4 has broad relevance for epilepsy and disorders of mood and cognition.

项目4的总体目标是表征与疾病相关的神经生理学和行为 发育间间疾病的两个遗传模型中的表型：Cyclin d2 nulls和Six3-- CRE：SMO（FI/FI）在Projs中开发的Sonic Hedgehog（SHH）途径的条件零。分别为1和2。 ProJS 1,2和4和核心B提供的解剖学数据表明，这两个遗传模型在 至少有2个重要方面，它们对MGE衍生的中间神经元的影响术语：1）相对减少 表达白蛋白的（PV+）与表达生长抑素的（SSN+）亚群和2）差异效应 在新皮层和海马子区域。具体而言，细胞周期蛋白D2模型表现出PV+的损失，但没有 皮质中的SSN+中间神经元；此外，海马显示PV+的降低更为明显 中间神经元相对于新皮质区域。另一方面，Six3-Cre：SMO（FI/FI）模型显示出损失 NeoCortex和Hippocampus中的PV+和SSN+中间神经元。在项目4中，这些影响 中间缺陷的不同模式将使用电论生理学的组合确定 功能性动态和行为实验。电生理实验将检验假设 这些突变小鼠的新皮层和海马中减少了局部GABA的传播。这 行为实验将表征癫痫发作阈值和与恐惧相关的行为的变化。 为了降低Gabaa-Benzodiazepine受体的功效。行为与皮质之间的相关性 神经元的活性将通过基于遥测的脑电图评估，并通过量化诱导来评估 服用配体后立即产生早期基因C-Fos的模式，该配体对调节 GABAA-BZ受体。这些研究共同表征了特定的“玛尔德开发”的影响 关于前额叶和边缘皮质回路功能后发育的功能性产后发育 介导情绪调节（特别是恐惧）和癫痫发作的敏感性。 新皮层和海马的中间神经元种群的病理发展被认为是 促进多种发育性脑部疾病，包括癫痫发作，认知障碍，自闭症和 精神分裂症。临床前研究支持这样的观念，即情感症状和认知缺陷 这些疾病通常也可能部分是由于皮质GABA的破坏而介导的 传输或其发育后果。因此，项目4与癫痫和 情绪和认知障碍。