Neural Mechanisms of Generalization in the Ventral Hippocampus

腹侧海马泛化的神经机制

• 批准号: 1924732
• 负责人: Isabel Muzzio
• 金额: $ 80.38万
• 依托单位: University of Texas at San Antonio
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1924732&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.

对不同情况做出类似反应的倾向，也就是所谓的泛化，可以是适应性的，也可以是不适应性的，这取决于具体的环境。例如，在世界上任何地方走在黑暗的小巷中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，背景或环境可以发出信号。腹侧海马体是一个与记忆和焦虑有关的区域，它在编码情境效价方面处于关键地位，并利用这些信息来产生选择性反应和广义反应。然而，人们对这个区域如何调节这些行为的表达知之甚少。这个项目的目标是确定腹侧海马内不同类型的细胞是否调节选择性与广义情绪反应的表达。理解控制情绪行为选择性的机制是非常重要的，因为它可以用来解释焦虑行为，如恐惧症或创伤后应激，其中恐惧在不适当的环境中持续表达。此外，理解泛化背后的计算超出了情感学习，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进行体内记录。由于UTSA是一个为少数族裔服务的机构，这项研究还为代表性不足的群体提供培训机会，并通过持续的播客向整个社区通报当前的科学问题，该播客旨在展示杰出的神经科学家。腹侧海马体与基底有相互联系外侧杏仁核，一个参与恐惧学习和灭绝的区域，它是海马体的主要区域，负责向前边缘皮层和下边缘皮层发送投射，这两个皮层分别是内侧前额叶皮层中与恐惧表达和消退有关的区域。此外，腹侧海马主细胞显示大，重叠的放电领域是理想的泛化过程。这个提议的首要假设是，腹侧海马通过具有不同生理和计算特性的投射神经元的不同亚群的活动来调节选择性与广义反应。通过结合体内单个单位和局部场电位记录沿着与通路特异性化学遗传沉默/激活和体外膜片钳技术沿着与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靶区域同步？2)不同的腹侧海马投射细胞在泛化/辨别中的作用是什么？当不同的亚群被选择性激活或抑制时，腹侧表征是如何改变的？3)不同的腹侧海马投射细胞的计算和突触特性是什么？由于过于狭窄或过于宽泛的泛化都可能对生存产生极其负面的后果，因此了解产生泛化过程精细校准的神经机制非常重要。该奖项反映了NSF的法定使命，并通过使用基金会的智力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

Navigable Space and Traversable Edges Differentially Influence Reorientation in Sighted and Blind Mice

• DOI: 10.1177/09567976211055373
• 发表时间: 2022-05
• 期刊: Psychological Science
• 影响因子: 8.2
• 作者: M. Normandin;Maria C Garza;M. Ramos-Alvarez;J. Julian;Tuoyo Eresanara;Nishanth Punjaala;J. H. Vasquez-J.

Differential effect of sleep deprivation on place cell representations, sleep architecture, and memory in young and old mice.

• DOI: 10.1016/j.celrep.2021.109234
• 发表时间: 2021-06-15
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Yuan RK;Lopez MR;Ramos-Alvarez MM;Normandin ME;Thomas AS;Uygun DS;Cerda VR;Grenier AE;Wood MT;Gagliardi CM;Guajardo H;Muzzio IA
• 通讯作者: Muzzio IA