The Role of Sensory Inputs and Cholinergic Modulation for the Coding of Location and Movement Speed in the Entorhinal Cortex

本研究的目的是探讨感觉输入和胆碱能调制在产生位置和运动速度的神经编码中的潜在机制作用。这些结果有望支持精神疾病网络机制模型的发展。空间位置和运动速度的表示对于路径整合和记忆引导的导航是重要的。在光和完全黑暗的条件下，自由探索小鼠的内侧内嗅皮层中的网格细胞和θ振荡的记录将首先解决这样一个问题：在没有视觉输入的情况下，通过网格细胞放电确定位置的神经元代码和通过θ频率确定运动速度的代码在工作记忆中保留了多长时间。对所获得的数据的分析将检验空间周期性网格单元放电的变化在时间上与θ频率与运行速度关系的变化相关的假设。这些分析的预期结果将用于通知路径整合的计算模型，包括网格单元放电模型。具体目标#2下的实验将使用纤维光度法监测内侧内嗅皮层中的胆碱能活动，以解决胆碱能调制在存在和不存在视觉线索的情况下形成和保存位置和运动速度代码的作用。分析将测试感觉输入、神经元活动和胆碱能调节的变化是否在不同的时间尺度上相关。这些分析将进一步加深我们对与空间记忆相关的广泛认知过程的编码原则的机械理解。网格细胞和胆碱能调节在当前的空间记忆和记忆引导导航模型中是必不可少的。具体目标#3下的实验将使用内侧隔中胆碱能投射神经元的光遗传学抑制结合内侧内嗅皮层中的网格细胞记录来测试胆碱能信号传导对于网格细胞的空间周期性放电是必要的这一假设。最后，具体目标#4下的实验将调查听觉和嗅觉线索是否足以支持通过内侧内嗅皮层中的网格细胞放电形成认知空间图。在完全黑暗中，在存在或不存在听觉或嗅觉线索的情况下，同时记录内侧内嗅皮层中的网格细胞和通过纤维光度法监测胆碱能活性，将测试以下假设：孤立的听觉和嗅觉输入可用于形成支持路径整合的认知地图，并且胆碱能调节支持基于这些地图的记忆引导导航。 在该项目的培训期间开发的实验和计算技能以及神经数据科学和计算建模方面的额外理论培训对于实现拟议的短期和长期科学目标至关重要，并将成为未来独立研究人员工作的基础。

The goal of this project is to investigate potential mechanistic roles of sensory inputs and cholinergic modulation for generating neural coding of location and movement speed. The results are expected to support development of models of network mechanisms underlying psychiatric disorders. Representations for spatial location and movement speed are important for path integration and memory-guided navigation. Recordings of grid cells and theta oscillations in the medial entorhinal cortex in freely exploring mice under conditions of light and complete darkness will first address the question how long the neuronal code for location by grid cell firing and the code for movement speed by theta frequency are preserved in working memory in the absence of visual inputs. Analysis of the acquired data will test the hypothesis that changes in spatial periodic grid cell firing correlate in time with changes in the theta frequency vs. running speed relationship. The expected outcomes of these analyses will be used to inform computational models of path integration, including models of grid cell firing. Experiments under Specific Aim #2 will use fiber photometry for monitoring cholinergic activity in the medial entorhinal cortex to address the role of cholinergic modulation in forming and preserving codes for location and movement speed in the presence and absence of visual cues. Analyses will test if changes in sensory inputs, neuronal activity, and cholinergic modulation correlate at different time scales. These analyses will further our mechanistic understanding of coding principles underlying a broad range of cognitive processes associated with spatial memory. Both grid cells and cholinergic modulation are essential in current models of spatial memory and memory-guided navigation. Experiments under Specific Aim #3 will use optogenetic inhibition of cholinergic projection neurons in the medial septum in combination with grid cell recordings in the medial entorhinal cortex to test the hypothesis that cholinergic signaling is necessary for spatial periodic firing of grid cells. Finally, experiments under Specific Aim #4 will investigate if auditory and olfactory cues are sufficient to support the formation of a cognitive spatial map by grid cell firing in the medial entorhinal cortex. Simultaneous recording of grid cells in the medial entorhinal cortex and monitoring of cholinergic activity by fiber photometry in complete darkness during the presence or absence of auditory or olfactory cues will test the hypotheses that auditory and olfactory inputs in isolation can be used to form a cognitive map that supports path integration and that cholinergic modulation supports memory-guided navigation based on these maps. The experimental and computational skills developed during the training period of this project and the additional theoretical training in neural data science and computational modeling will be crucial for the accomplishment of the proposed short- and long-term scientific goals and will become the foundation for the future work as an independent researcher.