Neural Mechanisms of Generalization in the Ventral Hippocampus

腹侧海马泛化的神经机制

• 批准号: 2303305
• 负责人: Isabel Muzzio
• 金额: $ 80.38万
• 依托单位: University of Iowa
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2303305&HistoricalAwards=false
• 关键词: Neural; Mechanisms; Generalization; Ventral; Hippocampus

The tendency to respond in similar ways to different situations, known as generalization, can be adaptive or maladaptive, depending on the context. For example, feeling apprehension when walking down a dark alley in any place in the world can be important for survival; however, displaying fear in well-lit streets is detrimental. These examples illustrate that the context or surroundings can signal when fear generalization is adaptive. The ventral hippocampus, an area involved in memory and anxiety, is in a key position to code contextual valence and use this information to generate selective versus generalized responses. Yet little is known about how this area modulates the expression of these behaviors. The goal of this project is to determine if different cells types within the ventral hippocampus modulate the expression of selective vs. generalized emotional responses. Understanding the mechanisms that control the selectivity of emotional behavior is extremely important because it can serve to explain anxiety behaviors, such as phobias or post-traumatic stress, where fear is continuously expressed in inappropriate contexts. Moreover, understanding the computations underlying generalization extends beyond emotional learning, having potential impact on artificial intelligence and machine learning. To address this question, this project uses cutting-edge techniques, including in vivo recordings of selective populations of cells while animals are learning. Since UTSA is a minority serving institution, this research also provides training opportunities to underrepresented groups and inform the community at large about current scientific issues through an ongoing podcast that serves to showcase prominent neuroscientists.The ventral hippocampus has reciprocal connections with the basolateral amygdala, an area involved in fear learning and extinction, and it is the main hippocampal region sending projections to the prelimbic and infralimbic cortices, areas of the medial prefrontal cortex involved in fear expression and extinction, respectively. Additionally, ventral hippocampus principal cells display large, overlapping firing fields that are ideal for generalization processes. The overarching hypothesis of this proposal is that the ventral hippocampus modulates selective vs. generalized responses though the activity of distinct subpopulations of projection neurons with different physiological and computational properties. This idea is assessed by combining in vivo single unit and local field potential recordings along with pathway-specific chemogenetic silencing/activation and in vitro patch clamping techniques along with optogenetic circuit analysis to answer the following questions: 1) How do subpopulations of ventral hippocampal cells respond and synchronize with target regions when animals discriminate or generalize emotional responses? 2) What is the role of different ventral hippocampus projection cells in generalization/discrimination and how do ventral representations change when distinct subpopulations are selectively activated or inhibited? 3) What are the computational and synaptic properties of different ventral hippocampus projection cells? Since too narrow or too broad generalization can have extremely negative consequences for survival, understanding the neural mechanisms that produce fine calibration of generalization processes is very important.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.

对不同情况以相似方式作出反应的倾向，即泛化，可以是适应的，也可以是不适应的，这取决于环境。例如，在世界上任何地方走在黑暗的小巷里时，感到恐惧对生存都很重要；然而，在光线充足的街道上表现出恐惧是有害的。这些例子说明，当恐惧泛化是适应性的时候，背景或环境可以发出信号。腹侧海马体，一个涉及记忆和焦虑的区域，是编码情境效价并使用这些信息产生选择性和广义反应的关键位置。然而，我们对这个区域如何调节这些行为的表达知之甚少。该项目的目的是确定腹侧海马体内不同类型的细胞是否调节选择性和广义情绪反应的表达。理解控制情绪行为选择性的机制是极其重要的，因为它可以用来解释焦虑行为，如恐惧症或创伤后应激，在这些行为中，恐惧在不适当的环境中不断表达。此外，理解泛化背后的计算超越了情感学习，对人工智能和机器学习有潜在的影响。为了解决这个问题，该项目使用了尖端技术，包括在动物学习时对选择性细胞群的体内记录。由于UTSA是一个为少数群体服务的机构，这项研究也为代表性不足的群体提供了培训机会，并通过正在进行的播客向广大社区介绍当前的科学问题，以展示杰出的神经科学家。腹侧海马体与基底外侧杏仁核相互连接，基底外侧杏仁核负责恐惧学习和消除，是向内侧前额叶皮层的边缘前皮层和边缘下皮层分别负责恐惧表达和消除的主要海马区域。此外，腹侧海马主细胞显示出大的、重叠的放电场，这是泛化过程的理想条件。这一提议的首要假设是，腹侧海马体通过具有不同生理和计算特性的不同投射神经元亚群的活动调节选择性和广义反应。通过结合体内单个单元和局部场电位记录、途径特异性化学发生沉默/激活、体外斑块夹紧技术和光遗传电路分析来评估这一想法，以回答以下问题：1)当动物区分或概括情绪反应时，腹侧海马细胞亚群如何响应并与目标区域同步？2)不同的海马腹侧投射细胞在泛化/区分中的作用是什么？当不同的亚群被选择性地激活或抑制时，腹侧表征是如何变化的？3)海马腹侧不同投射细胞的计算和突触特性是什么？由于太窄或太宽的泛化都会对生存产生极其负面的影响，因此理解产生精细校准泛化过程的神经机制非常重要。该奖项反映了美国国家科学基金会的法定使命，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。

项目成果

Defibrinogenation Ameliorates Retinal Microgliosis and Inflammation in A CX3CR1-Independent Manner.

除纤维蛋白原以与CX3CR1无关的方式改善视网膜小胶质细胞增多症和炎症。

• DOI: 10.1177/17590914221131446
• 发表时间: 2022-01
• 期刊: ASN NEURO
• 影响因子: 4.7
• 作者: Sarker, Borna;Cardona, Sandra M.;Church, Kaira A.;Vanegas, Difernando;Velazquez, Priscila;Rorex, Colin;Rodriguez, Derek;Mendiola, Andrew S.;Kern, Timothy S.;Domingo, Nadia D.;Stephens, Robin;Muzzio, Isabel A.;Cardona, Astrid E.
• 通讯作者: Cardona, Astrid E.