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.

项目概要 社会记忆受损是许多神经精神疾病的核心，包括精神分裂症 (SZD) 该应用研究了啮齿类动物海马 CA2 区域的嗅觉处理过程。 对社会记忆的贡献——编码和回忆另一个同种的能力对于社会来说是必要的。 啮齿类动物的记忆；在最初的社交互动过程中抑制背侧 CA2 (dCA2) 会破坏小鼠的记忆能力 但 CA2 究竟如何促进编码和检索仍不清楚。 由于小鼠依靠嗅觉来调查社会目标，我认为小鼠 CA2 对于整合至关重要 以及在试点中提供有关不同同种动物的有价值信息的社会嗅觉线索的辨别。 使用限水雌性小鼠的研究，我发现用抑制性视蛋白沉默 CA2 活性呈现出趋势 损害小鼠在头部固定、Go/No-中区分一只雄性小鼠尿液与另一只雄性小鼠尿液的能力 Go 气味辨别任务，其中使用 2 光子钙成像将 GO 气味与水奖励配对。 我和一位合作者在七只小鼠中发现 dCA2 可以处理社交和非社交气味。 接下来，我将使用 2 光子成像来测试 CA2 如何使用嗅觉信息来区分 气味刺激并将气味与条件或非条件化合价联系起来，以及如何扰动这一点 在目标 1 中，我正在识别 CA2 功能中的性别差异（如果有）。 关于五种气味的编码——两种天然价的男性尿液（社会气味）、丁酸甲酯和 醋酸乙酯（非价非社会气味）和模拟气味（涉及水）——在“三相范式”（TPP）中 在目标 2 中，我将比较社交和非社交的主动气味辨别之前和之后的被动气味传递。 TPP 中 dCA2 和 dCA1 的气味处理功能（已知处理非社会气味奖励关联） 我还将训练多个解码器来根据 2 光子钙成像数据预测刺激特性， 寻找对每个区域重要的刺激类型（社交、非社交、奖励或非奖励气味） 基于解码器性能，目标 3 检查人类 22q11.2 缺失的 SZD 遗传小鼠模型。 综合症——Df(16)A+/-小鼠——在第二次气味辨别中表现出严重的社会记忆缺陷。 在初步研究中，我发现 Df(16)A+/- 雌性小鼠的表现与 CA2 沉默小鼠的表现相似 区分两种社会气味的能力受损因此，我将使用 2 光子成像来比较 CA2。 此外，我将尝试将这种小鼠模型对气味刺激的反应与它们的神经典型笼中伙伴的反应进行比较。 通过注射 TREK-1 显性失活病毒来挽救这种社会气味辨别缺陷，该病毒已 已被证明可以改善这些细胞所携带的病理性超极化 CA2 神经元的神经元放电 总而言之，我的研究结果将提供对小鼠如何使用感官线索的深入了解。 区分社会主体并促进社会认可。 人类如何通过 CA2 处理其他社会感觉模式（例如视觉、听觉和触觉）。