Mechanisms of basal forebrain control over sensory processing

项目摘要 神经科学中的一个关键问题是了解内部和外部信息如何在大脑中整合， 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的反应。基底前脑的神经元是关键 这些行为状态的中介。与此同时，阿尔茨海默氏症和帕金森氏症的基底前脑神经退行性病变 疾病与认知和感觉处理的缺陷有关。嗅觉缺陷在以下人群中尤为常见： 神经变性和神经精神疾病，特别是与痴呆相关的那些。虽然已经 假设嗅觉和认知过程是由共同的上游调节系统连接的， 调节这种控制的机制仍然未知。因此，本提案的目标是开发一种 了解基底前脑的神经回路如何影响感觉处理。拟议的目标是检验 假设注意力、唤醒和奖励预测对嗅觉处理的影响依赖于精确的时间， 基底前脑内的胆碱能信号传导控制向嗅球的投射输出。在K99的指导下 阶段（目标1），我将研究行为状态的影响，气味编码的嗅球使用中尺度， 活体双光子成像在Ben Arenkiel和Paul Pfaffinger博士的指导下，并与 Drs. Jacob Reimer和Ankit Patel，我将接受中尺度双光子显微镜技术方面的培训， 计算方法当我在R00阶段过渡到独立性时，我将在基础阶段中向上看处理 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 操作，以确定细胞类型特异性，基底前脑内的状态依赖信号如何影响嗅觉 学习（目标2）。最后，在目标3中，我将检验基底前脑胆碱能神经元和GABA能神经元发挥作用的假设。 通过影响嗅球中的气味处理，在嗅觉学习中发挥不同的作用。为了验证这一点，我将使用一个组合 有针对性的基因操作，嗅觉为基础的行为平台，中尺度双光子成像，和纤维 测光法这项研究将揭示基底前脑控制的细胞和电路机制 嗅觉感觉处理的过程。最终，这解决了基底前脑 功能障碍会影响疾病中的感觉和认知，它将为未来的研究提供概念框架。 独立研究计划。

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.