AFFERENT REGULATION OF CHOLINERGIC FOREBRAIN NEURONS

这项研究计划的主要目标是了解基底前脑（BF）胆碱能系统是如何 (BFC)在解剖学定义的回路中有助于特定的认知操作。尽管它参与了 皮质激活，注意力和记忆，BF的功能细节还没有得到很好的理解，由于 该区域的解剖复杂性。阿尔茨海默氏病和相关痴呆症患者有显著的 皮质乙酰胆碱（Acetylcholine，ACh）减少，BF胆碱能神经元出现病理改变。 因此，有必要全面了解其职能组织。我们长期以来的核心假设- 长期的解剖学研究表明，胆碱能投射到新皮层不是弥散性的，而是 组织成分离或重叠的投射神经元池。虽然我们早期的模型处理高 密度投射体积仅代表约16-30%的胆碱能投射神经元，我们现在 通过分类局部投影模式包裹整个胆碱能空间。根据这些研究，胆碱能 细胞被分离成投射到功能性连接的皮质靶的簇的拓扑集合。在 在ChAT：：Cre大鼠的各种BF位置中，我们将应用AAV编码的系统性少量注射 抑制性DREADD，以抑制BF亚区内的胆碱能投射群。我们将 研究大部分皮层对BF胆碱能神经元反应的时空EEG变化 以支持我们的想法，即这些簇调节功能相关的皮层区域。在特定 目的2使用高密度硅阵列在眶额，视觉联合皮层和基底前脑， ChAT：：Cre大鼠在基于触摸屏的视觉辨别任务中，我们将研究 神经活动与毫秒精度，以了解胆碱能相关的调制变化， 在特定的行为时期，解剖学定义的神经网络，包括线索检测，短期 记忆、决策和行为执行。最后，在具体目标3中，我们将研究活动如何 在听觉操作期间，纹状体GABA能-胆碱能-听觉皮层回路随时间的变化 条件反射任务，以了解皮层地图可塑性和电生理之间的变化 特定纹状体和胆碱能神经元的分布与胆碱能依赖性听觉可塑性，学习， 记忆和认知灵活性。基底皮层网络功能组织的研究 胆碱能信号在细胞、网络和行为水平上的不同功能将有助于更好地 了解注意力、决策和记忆过程的功能障碍，这些功能障碍是症状的核心 老年痴呆症和其他形式的认知能力下降。

The broad objective of this research program is to understand how the basal forebrain (BF) cholinergic system (BFC) contributes to specific cognitive operations in anatomically defined circuits. Despite its involvement in cortical activation, attention, and memory, the functional details of the BF are not well understood due to the anatomical complexity of the region. Patients with Alzheimer's disease and related dementias have a significant decrease of acetylcholine (ACh) in the cortex and show pathological changes in cholinergic neurons in the BF. Thus, a complete understanding of its functional organization is warranted. The central hypothesis of our long- standing anatomical studies is that cholinergic projections to the neocortex are not diffuse, but instead are organized into segregated or overlapping pools of projection neurons. While our earlier model dealt with high density projection volumes only, which represent only about 16-30% of cholinergic projection neurons, we now parcel the whole cholinergic space by classifying local projection patterns. According to these studies, cholinergic cells are segregated into topographical sets of clusters projecting to functionally connected cortical targets. In Specific Aim 1 in various BF locations in ChAT::Cre rats, we will apply systematic small injections of AAV coding for the inhibitory DREADD in order to inhibit of the cholinergic projection group within subregions of BF. We will investigate spatio-temporal EEG changes in response to BF cholinergic inhibiton over large parts of the cortex in order to lend support to our idea that the clusters modulate functionally related cortical regions. In Specific Aim 2 using high-density silicon arrays in the orbitofrontal, visual association cortex and the basal forebrain in ChAT::Cre rats during a touchscreen-based visual discrimination task, we will investigate the dynamic pattern of neural activity with millisecond precision to understand cholinergic-related modulatory changes within an anatomically defined neuronal network during specific behavioral epochs, including cue detection, short-term memory, decision making, and behavioral execution. Finally, in Specific Aim 3 we will investigate how activity changes over time in the striatal GABAergic-cholinergic–auditory cortical circuits, during an auditory operant conditioning task, in order to understand how changes between cortical map plasticity and electrophysiological profiles of specific striatal and cholinergic neurons relate to cholinergic-dependent auditory plasticity, learning, memory, and cognitive flexibility. The study of the functional organization of the basalo-cortical network and distinct functions of the cholinergic signal at cellular, network and behavior levels will contribute to better understanding of the dysfunction of attention, decision-making, and memory processes, central to the symptoms of Alzheimer's and other forms of cognitive decline.