Control of dentate gyrus function and context discrimination by CCK+ interneurons

CCK 中间神经元对齿状回功能和环境辨别的控制

• 批准号: 2228988
• 负责人: Simon Pieraut
• 金额: $ 80万
• 依托单位: Board of Regents, NSHE, obo University of Nevada, Reno
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2228988&HistoricalAwards=false
• 关键词: Control; dentate; gyrus; function; context

Efficient memory processes rely on our brain's ability to store similar experiences as distinct memories. This process, performed in part by a structure in the brains of mammals called hippocampus, facilitates memory discrimination and is affected in brain disorders like dementia and post-traumatic stress disorders. As a result, animals and people suffering from these disorders experience difficulties recalling or accurately retrieving memories. Our understanding of how the hippocampus encodes similar experiences as distinct memories, allowing for easy discrimination during recall, is still limited. Recent advancements in neuroscience suggest that coordinated activity between excitatory and inhibitory neurons enables a specific computation known as pattern separation within the hippocampal circuit. This computation transforms similar input patterns into highly dissimilar output patterns and is thought to be the basis for memory discrimination. In the proposed research, the investigators aim to determine the contribution of a specific type of inhibitory neurons called cholecystokinin-expressing (CCK) neurons to the hippocampal circuit’s function. Their long-term goal is to enhance our understanding of critical computations, like pattern separation, performed by this brain region, which are crucial for memory discrimination. As part of this project, the investigators also provide a strong educational and training environment to students and new generations of scientists with a strong emphasis in recruiting and training minorities and under-represented groups in STEM, and they participate in outreach programs, such as the Big Brother Big Sister event organized by the Reno Museum of Natural History, which they use as a platform to share their research with the general public and students of all ages.The investigators aim to determine the contribution of CCK neurons to hippocampal circuit function, focusing on the plasticity of CCK neurons during the developmental period of juvenile mice. Their previous work demonstrates that environmental enrichment (EE) leads to increased synapses formed by CCK neurons in the dentate gyrus, suggesting their involvement in the maturation of hippocampal function and pattern separation. For the proposed work, they use an EE paradigm in mice and take advantage of viral mediated gene delivery technique combined with optogenetic approaches to manipulate the activity of the CCK neurons. They determine how the remodeling of the inhibitory CCK network adjusts the computation in the DG. In the first Objective of the project, they determine the contribution of CCK neurons to feedback and feedforward inhibitory microcircuits, both of which can impact pattern separation. In the second Objective, they measure the change in pattern separation and filtering performance of the DG induced by the EE using a novel in-vitro electrophysiological protocol. Together their research aims to unravel the mechanisms underlying pattern separation by exploring the involvement of CCK neurons in the hippocampal circuit. By increasing our understanding of these fundamental computations, they will shed light on the processes that support efficient memory functioning and potentially contribute to the development of novel therapeutic approaches for memory-related disorders.This project is jointly funded by the Modulation Program of the Neural Systems Cluster in the BIO Directorate and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

高效的记忆过程依赖于我们大脑将相似经历存储为不同记忆的能力。这一过程部分是由哺乳动物大脑中一种叫做海马体的结构完成的，它有助于记忆辨别，并在痴呆症和创伤后应激障碍等大脑疾病中受到影响。因此，患有这些疾病的动物和人难以回忆或准确检索记忆。我们对海马体如何将相似的经历编码为不同的记忆，从而在回忆过程中容易区分的理解仍然有限。神经科学的最新进展表明，兴奋性神经元和抑制性神经元之间的协调活动使海马回路内的模式分离成为可能。这种计算将相似的输入模式转换为高度不相似的输出模式，被认为是记忆辨别的基础。在拟议的研究中，研究人员的目标是确定一种特定类型的抑制性神经元（称为胆囊收缩素表达（CCK）神经元）对海马回路功能的贡献。他们的长期目标是增强我们对关键计算的理解，比如由这个大脑区域执行的模式分离，这对记忆辨别至关重要。 作为该项目的一部分，调查人员还为学生和新一代科学家提供了一个强大的教育和培训环境，重点是招募和培训STEM中的少数民族和代表性不足的群体，他们参加了外展计划，例如由自然历史博物馆里诺组织的大哥哥大姐姐活动，研究人员的目标是确定CCK神经元对海马回路功能的贡献，重点是CCK神经元在发育期的可塑性。他们以前的工作表明，环境富集（EE）导致齿状回中CCK神经元形成的突触增加，这表明它们参与了海马功能和模式分离的成熟。对于拟议的工作，他们在小鼠中使用EE范例，并利用病毒介导的基因递送技术结合光遗传学方法来操纵CCK神经元的活性。它们决定了抑制性CCK网络的重构如何调整DG中的计算。在该项目的第一个目标中，他们确定了CCK神经元对反馈和前馈抑制微电路的贡献，这两者都可以影响模式分离。在第二个目标中，他们使用一种新的体外电生理方案测量EE诱导的DG的模式分离和过滤性能的变化。他们的研究旨在通过探索CCK神经元参与海马回路来揭示模式分离的机制。通过增加我们对这些基本计算的理解，他们将阐明支持有效记忆功能的过程，并可能有助于开发记忆相关疾病的新治疗方法。该项目由BIO董事会神经系统集群调制计划和刺激竞争研究的既定计划（EPSCoR）联合资助。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。