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.

项目摘要 学习和记忆涉及多个大脑区域。但是，海马（CA1）和腹侧盖区域 （VTA）是主要参与新颖性检测和上下文歧视的大脑区域。异常 这些大脑区域之间的联系导致定义新颖性行为。几十年来， VTA-CA1在学习中的电路，以及像 精神分裂症，抑郁和成瘾已归因于多巴胺神经元。因为 在这种传统对中脑多巴胺能系统的关注中，谷氨酸途径被忽略了， 在正常的脑功能和神经精神疾病中对不了解。在最近的一项研究中，我们表明 VTA谷氨酸末端在CA1上是解剖学主导的，而VTA多巴胺末端受到限制 到基本的树突层。 VTA-CA1途径的功能跟踪表明VTA的选择性激活 谷氨酸和多巴胺神经元对CA1局部电路具有独特的影响。 VTA的光刺激 谷氨酸 - 但不是多巴胺 - 神经元增加了CA1锥体细胞的爆发发射。同样，刺激 VTA谷氨酸途径增加了CA1中中间神经元（INT）的推定锥体细胞（PYR） 合奏。在自由行为的小鼠中，激活VTA-CA1电路的新颖性检测任务增加了CA1 PYR/INT连接性的抑制作用改变了新颖性的行为。基于初步结果 拟议的研究将阐明海马中VTA Glut→Ca1道的功能意义 编码新颖性依赖性行为，包括上下文歧视和习惯。结果 拟议的研究将增加我们对VTA认知过程的兴奋性调节的理解， 控制适应性行为。