Neurochemical modulation of high level cognition

改变行为以适应新的环境条件的能力对生存至关重要。这种纠偏能力取决于我们抑制给定行为的能力，以及建立新的行为策略以应对偶然性变化的能力。在动物模型中，可以通过多种方式研究行为灵活性，包括使用触摸屏的复杂的高级认知任务。这种方法允许使用不同的测试来探测行为灵活性背后的特定组件。乙酰胆碱(ACh)和多巴胺(DA)在纹状体具有复杂的关系，这两种神经调节剂都与行为灵活性有关。然而，ACh和多巴胺之间的动态关系如何有助于行为灵活性尚不清楚。造成这种认识差距的原因之一是，到目前为止，观察这些神经化学物质在行为过程中的变化是极其困难的。纤维光度法可与新一代基于GPCR的神经递质传感器相结合，可用于测量毫秒级分辨率的神经化学活动。我的总体研究计划旨在阐明神经递质和神经调节剂是如何调节高级认知的。我这个项目的短期目标是了解背侧纹状体中乙酰胆碱/多巴胺的动态变化，以及这些神经调节剂是如何促进行为灵活性的。为了测量与行为灵活性有关的认知域，我们将使用触摸屏测试。基于已发表的和初步的数据，我们假设背侧纹状体中的胆碱能信号通过提供对多巴胺释放的空间受限调节来调节行为灵活性。为了验证这一假设，我们将追求以下短期目标：1-在进行触摸屏行为灵活性测试的小鼠中，绘制DMS和DLS中ACh/DA释放的动力学图。2-在行为灵活性测试中，确定胆碱能活动降低对DMS和DLS多巴胺能信号动力学的影响程度。3-确定增加多巴胺能信号是否可以逆转Vacht-KO小鼠纹状体的行为和神经化学缺陷。这项研究计划将使用独特的遗传模型，在衡量行为灵活性的触摸屏测试中记录行为动物的神经化学活动。因果操作将测试神经化学张力的特定变化是否会调节行为的灵活性。这些实验将使我们更深入地了解神经化学张力的变化与行为灵活性及其因果关系的关系。该计划的开发还将允许对HQP进行小鼠遗传学、神经化学、免疫细胞化学和高级认知测试方面的培训。

The ability to change behavior in response to a new environmental condition is critical for survival. This course-correction ability depends on our capacity to inhibit a given behavior and to establish a new behavioral strategy to respond to the change in contingency. Behavioral flexibility can be studied in a variety of ways in animal models, including by sophisticated higher-order cognitive tasks using touchscreens. This approach allows for different tests to be used to probe specific components underlying behavioural flexibility. Acetylcholine (ACh) and dopamine (DA) have an intricated relationship in the striatum and both neuromodulators have been implicated in behavioral flexibility. However, how the dynamic relationship between ACh and dopamine contribute to behavioral flexibility is not understood. One of the reasons for this gap of knowledge is the fact that up to now it has been extremally difficult to observe changes in these neurochemicals during behavioral processes. Fibre photometry can be combined with a new generation of GPCR-based neurotransmitter sensors that can be used to measure neurochemical activity with millisecond resolution. My overarching research program aims to elucidate how neurotransmitters and neuromodulators regulate high-level cognition. The short-term objective of my program is to understand acetylcholine/dopamine dynamics in the dorsal striatum and how these neuromodulators contribute to behavioral flexibility. To measure cognitive domains involved in behavioral flexibility we will use touchscreen tests. Based on published and preliminary data, we hypothesized that cholinergic signaling in the dorsal striatum regulates behavioral flexibility by providing spatially restricted regulation of dopamine release. To test this hypothesis, we will pursue the following short-term objectives: 1-Map the dynamics of ACh/DA release in the DMS and DLS in mice performing touchscreen behavioral flexibility tests. 2-Determine the extent by which decreased cholinergic activity affects the dynamics of DMS and DLS dopaminergic signaling during behavioral flexibility tests. 3-Determine whether increasing dopaminergic signaling can reverse behavioral and neurochemical deficits in the striatum in VAChT-KO mice. This research program will use unique genetic models, recording of neurochemical activity in behaving animals during touchscreen tests measuring behavioral flexibility. Causal manipulations will test whether specific changes in neurochemical tone regulate behavioral flexibility. These experiments will allow a deeper understanding of how changes in neurochemical tone relate to behavioral flexibility and their causal relationships. Development of this program will also allow for training of HQP in mouse genetics, neurochemistry, immunocytochemistry and high-level cognitive testing.