Mechanisms of basal forebrain control over sensory processing

基底前脑对感觉处理的控制机制

• 批准号: 10876118
• 负责人: Elizabeth Hanson Moss
• 金额: $ 24.9万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10876118
• 关键词: Address; Alzheimer' s Disease; Arousal; Attention; Award; Behavioral; Bilateral; Brain; Cells; Cholinergic Receptors; Code; Cognition; Cognitive; Cognitive deficits; Collaborations; Complex; Computing Methodologies; Conscious; Data; Defect; Dementia; Disease; Electrophysiology (science); Esthesia; Fiber; Food; Functional disorder; Future; Goals; Image; Learning; Link; Mediating; Mediator; Mentors; Mentorship; Modeling; Monitor; Motivation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Odors; Olfactory Learning; Olfactory Pathways; Output; Parkinson Disease; Pathway interactions; Pattern; Phase; Photometry; Play; Population; Property; Regulation; Research; Research Personnel; Rewards; Role; Sensory; Signal Transduction; Smell Perception; Speed; Stimulus; Synapses; System; Techniques; Testing; Time; Training; Work; basal forebrain; behavioral response; cell type; cholinergic; cognitive function; computer framework; design; experience; flexibility; genetic manipulation; imaging approach; imaging platform; improved; in vivo; in vivo imaging; in vivo two-photon imaging; mixed dementia; neural circuit; neuropsychiatric disorder; novel; novel therapeutics; olfactory bulb; optogenetics; programs; recruit; response; sensory input; skills; spatiotemporal; targeted treatment; temporal measurement; therapeutic target; two photon microscopy; two-photon

PROJECT SUMMARY A key problem in neuroscience is understanding how internal and external information are integrated in the brain to produce sensory experiences, cognition, and behavioral responses. This integration relies on flexible modulation of sensory processing in response to behavioral states like motivation, attention, and arousal. Neurons in the basal forebrain are key mediators of these behavioral states. At the same time, basal forebrain neurodegeneration in Alzheimer’s and Parkinson’s disease is associated with deficits in both cognitive and sensory processing. Olfactory deficits are especially common across neurodegenerative and neuropsychiatric diseases, particularly those associated with dementia. While it has been hypothesized that olfaction and cognitive processing are linked by common upstream regulatory systems, the circuit mechanisms mediating this control remain unknown. Therefore, the goal of this proposal is to develop a mechanistic understanding of how neural circuits in the basal forebrain impact sensory processing. The proposed Aims test the hypothesis that effects of attention, arousal, and reward prediction on olfactory processing rely on precisely timed, cholinergic signaling within the basal forebrain controlling projection output to the olfactory bulb. In the mentored K99 phase (Aim 1), I will investigate the impact of behavioral state on odor coding in the olfactory bulb using meso-scale, in vivo two-photon imaging. Under the mentorship of Drs. Ben Arenkiel and Paul Pfaffinger, and with the collaboration of Drs. Jacob Reimer and Ankit Patel, I will be trained in the technical aspects of meso-scale two-photon microscopy and computational methods. As I transition to independence in the R00 phase, I will look upstream to processing in the basal forebrain where I will use a combination of electrophysiology, optogenetics, fiber photometry, and targeted genetic manipulations to determine how cell type specific, state-dependent signaling within the basal forebrain influences olfactory learning (Aim 2). Finally, in Aim 3 I will test the hypothesis that basal forebrain cholinergic and GABAergic neurons play distinct roles in olfactory learning, via impacts on odor processing in the olfactory bulb. To test this, I will use a combination of targeted genetic manipulations, olfactory-based behavioral platforms, meso-scale two-photon imaging, and fiber photometry. Together the proposed research will reveal cellular and circuit mechanisms underlying basal forebrain control of olfactory sensory processing in the healthy brain. Ultimately, this addresses the question of how basal forebrain dysfunction impacts sensation and cognition in disease, and it will provide the conceptual framework for a future independent research program.

项目总结 神经科学中的一个关键问题是了解大脑中如何整合内部和外部信息以产生 感官体验、认知和行为反应。这种整合依赖于感官的灵活调节 对动机、注意力和唤醒等行为状态做出反应的处理。基底前脑中的神经元是关键 这些行为状态的中介者。同时，阿尔茨海默病和帕金森病的基底前脑神经退行性变 疾病与认知和感觉处理方面的缺陷有关。嗅觉缺陷在全国范围内尤为常见 神经退行性疾病和神经精神疾病，尤其是与痴呆症有关的疾病。虽然它一直是 假设嗅觉和认知处理通过共同的上游调节系统联系在一起，电路 调节这种控制的机制仍不清楚。因此，这项建议的目标是发展一种机械式的 了解基底前脑中的神经回路如何影响感觉处理。建议的目标将考验 假设注意力、觉醒和奖励预测对嗅觉加工的影响依赖于精确的时间， 基底前脑中的胆碱能信号控制向嗅球的投射输出。在被指导的K99 阶段(目标1)，我将使用中尺度研究行为状态对嗅球气味编码的影响。 活体双光子成像。在本·阿伦基尔博士和保罗·法芬格博士的指导下，与 雅各布·雷默博士和安吉特·帕特尔博士，我将接受中尺度双光子显微镜和 计算方法。当我在R00阶段过渡到独立时，我将着眼于在基本的 前脑，我将使用电生理学、光遗传学、纤维光度学和靶向遗传学的组合 确定基底前脑内特定细胞类型、状态依赖的信号如何影响嗅觉的操作 学习(目标2)。最后，在目标3中，我将测试基底前脑胆碱能和GABA能神经元发挥作用的假设 通过影响嗅球的气味处理，在嗅觉学习中扮演不同的角色。为了测试这一点，我将使用一个组合 靶向基因操作、基于嗅觉的行为平台、中尺度双光子成像和纤维 测光学。这项拟议中的研究将揭示基础前脑控制的细胞和电路机制。 在健康的大脑中进行嗅觉感觉处理。最终，这解决了基础前脑如何 功能障碍影响疾病的感觉和认知，它将为未来提供概念框架 独立研究计划。