The role of excitatory VTA projections in novelty-dependent behavior

项目摘要 学习和记忆涉及多个大脑区域。然而，海马（CA 1）和腹侧被盖区 (VTA)是主要参与新奇检测和上下文辨别的大脑区域。异常 这些大脑区域之间的联系导致新奇行为的缺陷。几十年来， VTA-CA 1回路在学习中的作用，以及中脑神经递质系统在疾病中的失调， 精神分裂症、抑郁症和成瘾症（主要）归因于多巴胺神经元。因为 传统上集中在中脑多巴胺能系统，谷氨酸途径被忽视， 在正常脑功能和神经精神疾病中了解较少。在最近的一项研究中，我们发现， 腹侧被盖区谷氨酸终末在CA 1中占优势，而腹侧被盖区多巴胺终末有限 到基底枝晶层。对VTA-CA 1通路的功能追踪表明，VTA的选择性激活 谷氨酸和多巴胺神经元对CA 1局部回路有不同的影响。腹侧被盖区的光刺激 谷氨酸-而不是多巴胺-神经元增加CA 1锥体细胞的爆发放电。同样，刺激 VTA谷氨酸途径增加了CA 1中中间神经元（INT）的假定锥体细胞（PYR）兴奋 合奏。在行为自由的小鼠中，新奇的检测任务激活了VTA-CA 1回路，增加了CA 1 PYR/INT连接，而它的抑制改变了新奇联系的行为。根据初步结果， 拟议的研究将阐明VTA glut→ CA 1束在海马中的功能意义， 新奇依赖行为的编码，包括情境辨别和习惯化。的结果 拟议的研究将增加我们对认知过程的VTA兴奋性调制的理解， 控制适应性行为。

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.