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

项目总结 社会记忆障碍是许多神经精神障碍的核心，包括精神分裂症 (SZD)。这项应用研究了啮齿动物海马区CA2区的嗅觉处理及其 对社会记忆的贡献--编码和回忆另一个同种生物的能力。CA2是社交网络所必需的 啮齿动物的记忆；在最初的社会互动中抑制背部CA2(DCA2)会扰乱小鼠的 形成并回忆起那段社会记忆。但CA2究竟如何对编码和检索做出贡献仍不清楚。 由于小鼠依赖嗅觉来研究社会目标，我假设小鼠的CA2对整合至关重要 以及对社会嗅觉线索的辨别，这些线索提供了关于不同共同特征的有价值的信息。在试行中 利用限水雌性小鼠进行的研究发现，用抑制性视蛋白沉默CA2活性显示出一种趋势 为了削弱小鼠区分雄性小鼠尿液的能力，在头部固定的Go/No- Go气味辨别任务，在任务中，Go气味与水奖励配对。使用双光子钙成像 在七只小鼠身上，我和一位合作者发现，dCA2同时处理社交和非社交气味。 接下来，我将使用双光子成像来测试CA2如何使用嗅觉信息来区分 气味刺激，并将气味与条件性或非条件性价态联系起来，以及这一点的扰动 在疾病中，加工会影响社会记忆。在目标1中，我正在识别CA2功能中的性别差异 关于五种气味的编码--两种天然价男性尿液(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)-在涉及以下内容的“三相范例”(TPP)中 主动气味辨别前后的被动气味传递。在目标2中，我将比较社会性和非社会性 TPP中dCA2和dCA1的气味处理功能(已知处理非社会性气味-奖赏关联) 气味任务。我还将训练多个解码器从双光子钙成像数据中预测刺激身份， 寻找哪些类型的刺激对每个地区都很重要(社会性、非社会性、奖励或不奖励的气味) 基于解码器的性能。目的3研究人类22q11.2缺失的SZD遗传性小鼠模型 综合症-DF(16)A+/-小鼠-显示出严重的社会记忆缺陷。在第二次气味辨别中 试点研究，我发现DF(16)A+/-雌性小鼠的表现与CA2沉默的小鼠相似。 辨别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CA2 在这个小鼠模型中，对气味刺激的反应是对它们的神经典型笼子的反应。此外，我会尝试 通过注射Trek-1显性阴性病毒来挽救这种社会气味歧视缺陷，这种病毒已经 已被证明可以改善病理性超极化CA2神经元的神经元放电。 杂合子小鼠。总而言之，我的研究结果将为我们深入了解老鼠如何利用感觉线索 区分社会主体，促进社会认同。我的调查结果将启动对 其他社会感官形式--如视觉、听觉和触觉--是如何在人类体内通过CA2进行处理的。

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.