The role of excitatory VTA projections in novelty-dependent behavior

项目总结 学习和记忆涉及多个大脑区域。然而，海马区(CA1)和腹侧被盖区 (VTA)是主要涉及新奇事物检测和背景辨别的大脑区域。异常 这些大脑区域之间的联系会导致新奇行为的缺陷。几十年来，世界银行的功能 学习中的VTA-CA1回路，以及中脑神经递质系统的失调 精神分裂症、抑郁症和成瘾(主要)都归因于多巴胺神经元。因为 在这种对中脑多巴胺能系统的传统关注中，谷氨酸途径被忽视了， 对于正常的大脑功能和神经精神障碍则知之甚少。在最近的一项研究中，我们表明 在解剖上，VTA-谷氨酸终末在CA1中占主导地位，而VTA-多巴胺终末在解剖上是有限的 至基础树枝晶层。对VTA-CA1通路的功能示踪表明，VTA选择性激活 谷氨酸和多巴胺神经元对CA1局部回路有明显的影响。VTA的光刺激效应 谷氨酸--而不是多巴胺--神经元增加了CA1锥体细胞的突发性放电。同样，刺激 VTA谷氨酸通路增强CA1区中间神经元(INT)对锥体细胞的兴奋作用 合唱团。在行为自由的小鼠中，激活VTA-CA1电路的新奇检测任务增加了CA1 PYR/INT连接，而它的抑制改变了与新颖性相关的行为。根据初步结果， 拟议的研究将阐明海马区Vta Glut→CA1区的功能意义 对新奇依赖行为的编码，包括环境歧视和习惯化。评选结果 拟议的研究将增加我们对VTA对认知过程和 适应行为的控制。

PROJECT SUMMARY Learning and memory involve multiple brain areas. However, the hippocampus (CA1) and ventral tegmental area (VTA) are the brain regions primarily involved in novelty detection and context discrimination. Abnormal connection between these brain regions leads to deficits in novelty behavior. For decades, the function of the VTA-CA1 circuit in learning, and the dysregulation of midbrain neurotransmitter systems in diseases like schizophrenia, depression, and addictions have been attributed (primarily) to the dopamine neurons. Because of this traditional focus on the midbrain dopaminergic systems, the glutamate pathway has been overlooked and is less understood in normal brain function and neuropsychiatric disorders. In a recent study, we showed that the VTA glutamate terminals are anatomically dominant in the CA1 while VTA dopamine terminals were limited to the basal dendrite layer. Functional tracing of the VTA-CA1 pathway shows that selective activation of VTA glutamate and dopamine neurons has distinguishable effects on CA1 local circuits. Photostimulation of VTA glutamate – but not the dopamine – neurons increased burst firing of CA1 pyramidal cells. Likewise, stimulation of the VTA glutamate pathway increased putative pyramidal cells (PYR) excitation of interneurons (INT) in CA1 ensembles. In freely behaving mice, novelty detection tasks that activate the VTA-CA1 circuit increased CA1 PYR/INT connectivity while its inhibition altered novelty-linked behavior. Based on preliminary results, the proposed research will elucidate the functional significance of the VTA glut→CA1 tract in the hippocampal encoding of novelty-dependent behavior including context discrimination and habituation. The results of the proposed research will increase our understanding of VTA excitatory modulation of cognitive processes and control of adaptive behavior.