The role of excitatory VTA projections in novelty-dependent behavior

兴奋性 VTA 投射在新奇依赖行为中的作用

• 批准号: 10720976
• 负责人: Olalekan Michael Ogundele
• 金额: $ 36.53万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720976
• 关键词: Adaptive Behaviors; Anatomy; Architecture; Area; Behavior; Bipolar Depression; Brain; Brain region; Cell Nucleus; Cells; Cognitive; Dendrites; Desire for food; Detection; Discrimination; Disease; Dopamine; Electrophysiology (science); Extinction; Food; Frequencies; Future; Glutamates; Goals; Hallucinations; Hippocampus; Interneurons; Knowledge; Learning; Link; Medial; Memory; Mental Depression; Methods; Midbrain structure; Mus; Nature; Neurons; Neurotransmitters; Noise; Pathway interactions; Pattern; Physiological; Positive Valence; Prefrontal Cortex; Pyramidal Cells; Research; Rewards; Role; Schizophrenia; Stimulus; System; Ventral Tegmental Area; addiction; autism spectrum disorder; behavioral phenotyping; cognitive control; cognitive process; dopaminergic neuron; experimental study; gamma-Aminobutyric Acid; habituation; in vivo; learned behavior; neural; neural circuit; neuropsychiatric disorder; novel; optogenetics; social; social contact

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.

项目概要 学习和记忆涉及多个大脑区域。然而，海马体（CA1）和腹侧被盖区 （VTA）是主要参与新颖性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会导致新奇行为的缺陷。几十年来，该功能 学习中的 VTA-CA1 回路，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 这种对中脑多巴胺能系统的传统关注，谷氨酸途径被忽视了 对于正常脑功能和神经精神疾病的了解较少。在最近的一项研究中，我们表明 VTA 谷氨酸末端在 CA1 中占解剖学主导地位，而 VTA 多巴胺末端有限 到基底树突层。 VTA-CA1 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 CA1 局部回路具有明显的影响。 VTA 光刺激 谷氨酸（而非多巴胺）神经元增加了 CA1 锥体细胞的爆发放电。同样，刺激 VTA 谷氨酸途径的增加增加了 CA1 中假定的锥体细胞 (PYR) 中间神经元 (INT) 的兴奋 合奏团。在自由行为的小鼠中，激活 VTA-CA1 电路的新奇检测任务增加了 CA1 PYR/INT 连接性而其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中 VTA glut→CA1 束的功能意义 编码依赖新奇的行为，包括情境歧视和习惯化。结果 拟议的研究将增加我们对认知过程的 VTA 兴奋性调节的理解 适应性行为的控制。