Serotonergic modulation of nucleus reuniens in affective and cognitive behaviors

项目摘要 丘脑腹侧中线的连合核（nucleus reuniens，RE）是额前-海马神经元的非平行联系 通信而RE选择性地将其输出定向到皮质边缘靶，包括海马体（HF）和海马体。 在眶内侧前额叶皮层（PFC），RE接受各种各样的输入，包括密集的多巴胺能（5- HT）纤维来自中缝背核（DR）和中缝正中核（MR）。虽然DR和MR本质上形成两种不同的 不重叠的5-HT通路，RE作为会聚的关键部位，因为MR和DR都大量分布于 丘脑中线虽然RE与PFCàHF回路的相互作用与认知行为有关，但实际上， 关于5-HT在RE中的神经调节作用还不清楚。根据目前的建议，我们打算继续 我们通过药理学和化学遗传学方法结合行为测试对RE进行了研究 阐明RE的5-HT调节如何参与情感、记忆和执行功能。我们假设 RE对5-HT的影响是灵活行为的关键，抑制RE的5-HT输入将增加回避行为 并损害执行措施，这些行为中的每一个都招募特定的中缝通路。我们将利用 全面的经验证的大鼠行为测定组合以评估：1.）焦虑/回避行为使用开放领域和 高架十字迷宫模式; 2.）使用延迟非匹配样本的空间工作记忆和行为灵活性 t-迷宫范例; 3.）和注意力和行为灵活性使用气味触觉注意力转移任务。第一 目的1，我们将研究RE中5-HT的可用性如何通过使用神经毒素5，7- 二羟色胺在目标2a中，我们将通过使用 抑制性hM 4D DREADD受体选择性抑制中缝核-RE末端。在目标2b中，我们将使用TPH 2-Cre 结合DREADD技术选择性抑制从DR或MR到 RE.这些目标将是第一个概述5-HT输入对RE行为的具体贡献。这些结果将 提供中缝丘脑回路如何促进情绪和认知功能的重要信息， 重要的是，这个系统的改变如何影响抑郁症、焦虑症和其他神经精神疾病的神经病学。 紊乱

PROJECT SUMMARY The nucleus reuniens (RE) of the ventral midline thalamus sits as the nonpareil nexus of prefrontal-hippocampal communication. While RE selectively directs its output to cortical limbic targets including the hippocampus (HF) and orbitomedial prefrontal cortex (PFC), RE receives a diverse array of inputs, including a dense supply of serotonergic (5- HT) fibers from the dorsal (DR) and median (MR) raphe nuclei. While DR and MR form two distinct essentially nonoverlapping 5-HT pathways, RE serves as a key site of convergence as MR and DR both distribute heavily to the midline thalamus. While RE's interactions with PFCàHF circuitry have been linked to cognitive behaviors, virtually nothing is known regarding the neuromodulatory role of 5-HT in RE. With the present proposal, we intend to continue our investigation of RE by utilizing pharmacological and chemogenetic approaches in conjunction with behavioral testing to elucidate how 5-HT modulation of RE participates in affective, mnemonic, and executive functioning. We hypothesize that 5-HT influence of RE is essential to flexible behavior and quelling 5-HT input to RE will increase avoidance behavior and impair executive measures, with each of these behaviors recruiting specific raphe pathways. We will utilize a comprehensive battery of validated rat behavioral assays to assess: 1.) anxiety/avoidance behavior using an open field and elevated plus maze paradigm; 2.) spatial working memory and behavioral flexibility using a delayed nonmatch to sample t-maze paradigm; 3.) and attention and behavioral flexibility using an odor tactile attentional set shifting task. First in Aim 1, we will examine how 5-HT availability in RE affects behavior by locally depleting 5-HT using the neurotoxin 5,7- dihydroxytryptamine. In Aim 2a, we will examine the distinct contributions of DR and MR on RE on behavior by using the inhibitory hM4D DREADD receptor to selectively suppress raphe-RE terminals. In Aim 2b, we will use a TPH2-Cre rat model in combination with DREADD technology to selectively inhibit serotoninergic projections from DR or MR to RE. These aims will be the first to outline the specific contributions of 5-HT input to RE on behavior. These results will provide important information on how raphe-thalamic circuitry contributes to emotional and cognitive functioning and importantly how alterations of this system impact this symptomology in depression, anxiety, and other neuropsychiatric disorders.