Neuromodulation of cortical circuits in health and disease

健康和疾病中皮质回路的神经调节

• 批准号: 8576665
• 负责人: Allan T Gulledge
• 金额: $ 40.5万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-16 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8576665
• 关键词: Adult; Agonist; Amygdaloid structure; Animals; Anxiety; Behavior; Behavioral; Brain; Cerebral cortex; Cerebrum; Clinical; Cognition; Cognitive; Coupled; Data; Disease; Extinction (Psychology); Fright; Functional disorder; Glutamates; Goals; HTR2A gene; Health; Human; Knowledge; Label; Laboratory Finding; Medial; Mediating; Mental Depression; Mental disorders; Minority; Mission; Mus; National Institute of Mental Health; Neocortex; Neurons; Neurotransmitters; Output; Performance; Physiological; Population; Prefrontal Cortex; Process; Public Health; Research; Role; Schizophrenia; Serotonin; Serotonin Agents; Signal Transduction; Structure; Synapses; Synaptic Transmission; Testing; Tracer; Variant; atypical antipsychotic; base; clinically significant; cognitive function; conditioned fear; conditioning; density; executive function; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; human CCXCR1 receptor; in vivo; information processing; innovation; insight; mouse model; neuroregulation; optogenetics; postsynaptic; public health relevance; receptor; response; selective expression; tool

DESCRIPTION (provided by applicant): Cortical microcircuits, comprising specialized neuron subpopulations and their selective synaptic connections, form functionally segregated output channels to other cortical and subcortical targets. The activity of cortical microcircuits is regulated by a number of "modulatory" neurotransmitters, such as serotonin (5-HT), that optimize circuit performance for specific cognitive tasks, and which are implicated in a wide spectrum of mental health disorders. For instance, disrupted 5-HT signaling contributes to schizophrenia, depression, and anxiety, while serotonergic drugs are widely used to treat these disorders. However, despite their functional and clinical importance, little is known about how modulatory transmitters selectively regulate the activity of cortical neuron subpopulations subserving specific functional roles within cortical microcircuits. Our long-term goal is to characterize the functional impact of modulatory neurotransmitters on cortical microcircuit function. The research proposed here represents an important first step toward this goal by identifying key cellular and synaptic components of cortical microcircuits differentially regulated by 5-HT. Serotonergic signaling in excitatory cortical neurons relies primarily on two G-protein coupled receptors, 5-HT1A (1A) and 5-HT2A (2A), that have opposing influences on neuron excitability. Based on recent results showing commissural/callosal (COM) projection neurons are selectively excited by 5-HT, our central hypothesis is that endogenous 5-HT acts to selectively enhance the activity of neurons participating in specific executive functions, while suppressing the bulk of cortical output to subcortical structures. Our first aim is to identify the cellular components of cortical circuits that are functionally excited or inhibited by endogenous 5-HT. This will be accomplished in a mouse model in which channelrhodopsin-2 is selectively expressed in 5-HT neurons, and using fluorescent retrograde tracers delivered in vivo. Our second aim is to characterize synaptic connectivity among populations of 5-HT-excited neurons to determine whether they form networks capable of the sustained activity associated with executive functions. Finally, our third aim will confirm in behaving animals preferential activatio of COM or other 5-HT-excited neuron populations by 2A agonists, fear conditioning, and extinction of conditioned fear. These aims are innovative in combining anatomical, physiological, optogenetic, and behavioral approaches to characterize selective modulation of cellular components and synaptic connections underlying functionally defined cortical output channels. The results will be significant in providing a framework for understanding the functional role of 5 HT in regulating the output of cortical circuits. The new knowledge gained will provide insight into how 5-HT facilitates normal cognition and behavior, and why dysregulation of serotonergic signaling in the cerebral cortex leads to the behavioral deficits observed in schizophrenia, depression, and other mental health disorders.

描述（由申请人提供）：皮层微电路，包括专门的神经元亚群和它们的选择性突触连接，形成功能隔离的输出通道到其他皮层和皮层下目标。皮层微回路的活动受到许多“调节性”神经递质的调节，如血清素（5-HT），它可以优化特定认知任务的回路性能，并与广泛的精神健康障碍有关。例如，5-羟色胺信号被破坏会导致精神分裂症、抑郁症和焦虑症，而5-羟色胺能药物被广泛用于治疗这些疾病。然而，尽管它们具有功能和临床重要性，但对于调节递质如何选择性地调节皮层微回路中服务于特定功能角色的皮层神经元亚群的活动知之甚少。我们的长期目标是表征调节性神经递质对皮质微回路功能的功能影响。这里提出的研究通过识别皮层微回路差异调节的关键细胞和突触成分，代表了实现这一目标的重要的第一步