Odor-Reward Association Encoding in CA2 and its Contribution to Social Memory

CA2 中的气味奖励关联编码及其对社会记忆的贡献

• 批准号: 10475028
• 负责人: Shivani Bigler
• 金额: $ 4.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475028
• 关键词: 22q11; Action Potentials; Affect; Animals; Behavioral; Calcium; Code; Cues; Data; DiGeorge Syndrome; Dimensions; Discrimination; Disease; Dominant-Negative Mutation; Dorsal; Down-Regulation; Face; Female; Friends; Fright; Functional disorder; Genetic; Head; Hearing; Hippocampus (Brain); Human; Image; Impairment; Individual; Injections; Investigation; Link; Memory; Memory impairment; Modality; Mus; Neurons; Odors; Opsin; Pathologic; Patients; Pattern; Performance; Persons; Phase; Pilot Projects; Play; Population; Process; Research; Retrieval; Rewards; Rodent; Role; Schizophrenia; Sensory; Sex Differences; Signal Transduction; Smell Perception; Social Discrimination; Social Interaction; Stimulus; Techniques; Testing; Touch sensation; Training; Up-Regulation; Urine; Virus; Vision; Water; base; entorhinal cortex; ethyl acetate; hippocampal pyramidal neuron; improved; in vivo; insight; male; memory encoding; methyl butyrate; mouse model; neuropsychiatric disorder; novel; olfactory bulb; olfactory receptor; olfactory stimulus; optogenetics; potassium channel protein TREK-1; recruit; relating to nervous system; response; sensory input; sex; sexual dimorphism; social; social integration; trend; two-photon

PROJECT SUMMARY Impairments in social memories are central to many neuropsychiatric disorders, including Schizophrenia (SZD). This application investigates olfactory processing in the CA2 region of the rodent hippocampus and its contribution to social memory—the ability to encode and recall another conspecific. CA2 is necessary for social memory in rodents; inhibiting dorsal CA2 (dCA2) during an initial social interaction disrupts a mouse’s ability to form and recall that social memory. But how CA2 precisely contributes to encoding and retrieval remains unclear. Since mice rely on olfaction to investigate social targets, I hypothesize that murine CA2 is vital to the integration and discrimination of social olfactory cues that provide valent information about different conspecifics. In a pilot study using water-restricted female mice, I found that silencing CA2 activity with inhibitory opsins showed a trend towards impairing the mice’s abilities to distinguish one male mouse urine from another in a head-fixed, Go/No- Go Odor Discrimination Task, in which GO odors are paired with a water reward. Using 2-photon calcium imaging in seven mice, a collaborator and I have discovered that dCA2 processes both social and nonsocial odors. Moving forward, I am using 2-photon imaging to test how CA2 uses olfactory information to discriminate between odor stimuli and to associate odors with conditioned or unconditioned valences, and how perturbation of this processing affects social memory in disease. In Aim 1, I am identifying sex differences, if any, in CA2 function with respect to the encoding of five odors—two naturally valent male urines (social odors), methyl butyrate and ethyl acetate (nonvalent nonsocial odors), and a mock odor (water)—in a “three-phase paradigm” (TPP) involving passive odor delivery before and after active odor discrimination. In Aim 2, I will compare the social and nonsocial odor processing functions of dCA2 and dCA1 (known to process nonsocial odor-reward associations) in the TPP odor task. I will also train multiple decoders to predict stimulus identity from 2-photon calcium imaging data, looking for what kinds of stimuli are important to each region (social, nonsocial, rewarded, or nonrewarded odors) based on decoder performance. Aim 3 examines an SZD genetic mouse model of the human 22q11.2 deletion syndrome—Df(16)A+/- mice—which shows a profound deficit in social memory. In a second odor discrimination pilot study, I found that Df(16)A+/- female mice resemble the performance of the CA2-silenced mice in their impaired ability to distinguish between two social odors. Hence, I will use 2-photon imaging to compare CA2 responses to odor stimuli in this mouse model to that of their neurotypical cagemates. Furthermore, I will attempt to rescue this social odor discrimination deficit with injection of a TREK-1 dominant-negative virus, which has been shown to improve neuronal firing in the pathologically hyperpolarized CA2 neurons harbored by these heterozygous mice. All in all, the results of my research will provide insight into how mice use sensory cues to discriminate between social subjects and facilitate social recognition. My findings will initiate investigations into how other social sensory modalities—like vision, hearing, and touch—are processed through CA2 in humans.

项目摘要 社会记忆的损伤是许多神经精神疾病的核心，包括精神分裂症 （SZD）.本申请研究了啮齿动物海马CA 2区的嗅觉加工及其与海马神经元的关系。 对社会记忆的贡献-编码和回忆另一个同种的能力。CA 2是社会所必需的 啮齿类动物的记忆;在最初的社会交往中抑制背侧CA 2（dCA 2）会破坏小鼠的能力， 形成并回忆起社会记忆。但是，CA 2如何精确地参与编码和提取仍然不清楚。 由于小鼠依赖嗅觉来研究社会目标，我假设小鼠CA 2对整合至关重要。 和社会嗅觉线索的歧视，提供有关不同同种的价格信息。以试点 在一项使用限水雌性小鼠的研究中，我发现用抑制性视蛋白沉默CA 2活性显示出一种趋势， 在一个头部固定的，去/不- Go气味辨别任务，其中GO气味与水奖励配对。使用双光子钙成像 在7只小鼠中，我和一位合作者发现dCA 2既处理社会气味，也处理非社会气味。 下一步，我将使用双光子成像来测试CA 2如何使用嗅觉信息来区分 气味刺激和关联气味与条件或非条件价，以及如何扰动这一点， 加工影响疾病中的社会记忆。在目标1中，我确定了CA 2功能的性别差异（如果有的话） 关于五种气味的编码--两种自然价的男性尿液（社会气味）、丁酸甲酯和 乙酸乙酯（非价非社会气味）和模拟气味（水）-在“三相范式”（TPP）中， 在主动气味辨别之前和之后的被动气味递送。在目标2中，我将比较社会和非社会 TPP中dCA 2和dCA 1的气味处理功能（已知处理非社会性气味奖励关联） 气味任务我还将训练多个解码器来预测来自双光子钙成像数据的刺激身份， 寻找哪种刺激对每个区域都很重要（社交、非社交、奖励或非奖励气味） 基于解码器性能。目的3：建立人22q11.2缺失的SZD遗传小鼠模型 综合征-Df（16）A+/-小鼠-其显示社交记忆的严重缺陷。在第二种气味辨别中， 在初步研究中，我发现Df（16）A+/-雌性小鼠在其生长发育中的表现与CA 2沉默小鼠相似。 区分两种社会气味的能力受损。因此，我将使用双光子成像来比较CA 2 在这个小鼠模型中对气味刺激的反应与它们的神经典型笼状体的反应相同。此外，我将尝试 通过注射TREK-1显性阴性病毒来挽救这种社会气味辨别缺陷， 已经显示出改善由这些神经元所携带的病理性超极化CA 2神经元中的神经元放电。 杂合子小鼠总而言之，我的研究结果将提供深入了解老鼠如何使用感官线索， 区分社会主体，促进社会认同。我的发现将启动对 其他的社会感觉模式，如视觉、听觉和触觉，是如何通过人类的CA 2来处理的。