Neuromodulation of cortical circuits and cortical projections to the basal forebrain

皮质回路和皮质投射到基底前脑的神经调节

• 批准号: 9610261
• 负责人: Arielle L Baker
• 金额: $ 3.98万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-11 至 2019-06-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9610261
• 关键词: Acetylcholine; Anatomy; Area; Attention; Axon; Behavior; Brain; Brain Stem; Brain region; Cells; Cerebral cortex; Clinical; Cognition; Complement; Data; Decision Making; Dorsal; Electrophysiology (science); Feedback; Glutamates; Goals; Immunohistochemistry; Individual; Label; Mediating; Mental disorders; Motor output; Neuromodulator; Neurons; Neurotransmitters; Output; Physiological; Pontine structure; Population; Prefrontal Cortex; Presynaptic Receptors; Presynaptic Terminals; Process; Regulation; Schizophrenia; Scientist; Serotonin; Signal Transduction; Specificity; Structure; Synapses; Synaptic Transmission; Techniques; Testing; Travel; Viral Vector; Work; basal forebrain; base; cell type; cholinergic; cholinergic neuron; cognitive function; cognitive process; hippocampal pyramidal neuron; innovation; insight; interest; neuroregulation; neurotransmission; neurotransmitter release; novel; optogenetics; postsynaptic; presynaptic; response; serotonergic regulation; skills

Project Summary The prefrontal cortex (PFC) is the brain area most associated with higher cognition. The “modulatory” neurotransmitters acetylcholine (ACh) and serotonin (5-HT) facilitate these cognitive processes by regulating information flow within cortical circuits, and dysregulation of neuromodulatory input to the cortex is directly implicated in a number of mental health disorders. Despite their clear clinical importance, little is known about the physiological impact of ACh and 5-HT on synaptic transmission and integration within cortical neuron subpopulations. My preliminary data have revealed a reciprocal relationship between ACh and 5-HT in controlling two distinct and non-overlapping cortical output channels. 5-HT selectively inhibits, while ACh preferentially enhances, the output of corticopontine (CPn) neurons projecting to the brainstem, while 5-HT selectively enhances corticocortical (CC) neurons that project to the cerebral cortex. This differential regulation of CPn and CC neurons by 5-HT and ACh suggests circuit-based mechanisms by which these transmitters may influence cognition and behavior. The long-term objective of this project is to define how modulatory neurotransmitters regulate the output of the cerebral cortex through selective, cell-type-specific pre- and postsynaptic actions. The short-term objective proposed here is to evaluate the effect of ACh and 5-HT on synaptic transmission from defined cortical afferents, and to characterize the feedback circuitry from the cortex to the cholinergic center of the basal forebrain. Specific Aim 1 will test the hypothesis that ACh and 5-HT influence transmitter release from axon terminals in ways that complement their actions on cellular excitability. Using innovative labeling strategies to express channelrhodopsin in select cortical projection neuron subpopulations, I will determine the postsynaptic specificity of cortical afferents, test presynaptic modulation of glutamate release from specific cortical afferents, and identify the presynaptic receptors responsible for modulation of synaptic transmission. Specific Aim 2 will test the hypothesis that cortical output to the basal forebrain acts as a negative feedback loop by reducing cholinergic input to the cortex. Using retrograde and viral vector-based neuronal labeling, optogenetics, immunohistochemistry, and electrophysiology, I will identify the population of cortical neurons innervating the basal forebrain, and their net influence on cholinergic circuitry. A growing appreciation of the diversity of cortical neurons, their selective connectivity, and their differential responsivity to neuromodulatory transmitters, is expanding our understanding of cortical circuit function. The proposed project will contribute to that understanding by evaluating the effect of ACh and 5-HT on cortical microcircuits. Findings from this project have the potential to provide insight into how these two neuromodulators facilitate cognitive function, and may identify fundamental and conserved mechanisms contributing to information flow in other brain circuits.

项目摘要 前额叶皮层（PFC）是与高级认知最相关的大脑区域。“调节” 神经递质乙酰胆碱（ACh）和5-羟色胺（5-HT）通过调节这些认知过程， 信息流在皮层回路中，对皮层的神经调节输入的失调直接 与一系列精神疾病有关尽管它们具有明确的临床重要性，但人们对它们知之甚少。 乙酰胆碱和5-羟色胺对皮层神经元突触传递和整合生理影响 亚群我的初步数据显示，ACh和5-HT之间的相互关系， 控制两个不同且不重叠的皮层输出通道。5-HT选择性抑制，而ACh 优先增强投射到脑干的皮质桥脑（CPn）神经元的输出，而5-HT 选择性增强投射到大脑皮层的皮质（CC）神经元。这种差异调节 5-HT和ACh对CPn和CC神经元的作用提示了这些递质 可能影响认知和行为。 该项目的长期目标是确定调节性神经递质如何调节 通过选择性的、细胞类型特异性的突触前和突触后作用来控制大脑皮层。短期目标 本文旨在评价ACh和5-HT对突触传递的影响， 传入，并表征从皮层到基底节胆碱能中心的反馈回路 前脑具体目标1将检验神经递质中的ACh和5-HT从轴突释放的假设 终端的方式，补充他们的行动对细胞的兴奋性。使用创新的标签策略， 表达通道视紫红质在选择皮质投射神经元亚群，我将确定突触后 皮质传入的特异性，测试特定皮质传入的谷氨酸释放的突触前调节， 并确定负责调节突触传递的突触前受体。具体目标2将 测试皮质输出到基底前脑作为一个负反馈回路的假设， 胆碱能输入皮层使用逆行和基于病毒载体的神经元标记，光遗传学， 免疫组织化学和电生理学，我将确定神经支配的皮质神经元的人口。 基底前脑，以及它们对胆碱能回路的影响。 越来越多的人认识到皮层神经元的多样性，它们的选择性连接，以及它们的差异性。 对神经调节递质的反应性，正在扩大我们对皮层回路功能的理解。的 建议的项目将有助于理解，通过评估ACh和5-HT对皮质的影响， 微型电路该项目的发现有可能提供对这两个问题的深入了解。 神经调质促进认知功能，并可能确定基本和保守的机制， 对其他脑回路中的信息流有贡献。