Serotonergic modulation of nucleus reuniens in affective and cognitive behaviors

情感和认知行为中团聚核的血清素调节

• 批准号: 10303284
• 负责人: ROBERT Paul Vertes
• 金额: $ 41.11万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10303284
• 关键词: Affect; Affective; Anatomy; Anxiety; Attention; Behavior; Behavior assessment; Behavioral; Behavioral Assay; Behavioral Paradigm; Brain Stem; Cannulas; Central Nervous System Diseases; Clozapine; Cognition; Cognitive; Communication; Deafferentation procedure; Development; Dorsal; Emotional; Executive Dysfunction; Fiber; Fright; Gap Junctions; Glutamates; Goals; Hippocampus (Brain); Impairment; Implant; Investigation; Laboratories; Link; Measures; Mediating; Memory; Mental Depression; Mental disorders; Microinjections; Modeling; Mood Disorders; Mus; Neurobehavioral Manifestations; Neurons; Obsessive-Compulsive Disorder; Odors; Output; Oxides; Pathology; Pathway interactions; Pharmacogenetics; Pharmacology; Population; Positioning Attribute; Prefrontal Cortex; Primates; Process; Prosencephalon; RNA Interference; Rattus; Regulation; Reuniens Thalamic Nucleus; Reversal Learning; Rodent; Role; Sampling; Serotonergic System; Serotonin; Short-Term Memory; Site; System; TPH2; Tactile; Technology; Testing; Thalamic structure; Theta Rhythm; Transgenic Organisms; Update; Viral Vector; Work; anxiety-like behavior; avoidance behavior; behavior test; cognitive function; designer receptors exclusively activated by designer drugs; emotional functioning; executive function; expectation; experimental study; flexibility; insight; nerve supply; neuropsychiatric disorder; neuroregulation; neurotoxin 5; novel therapeutic intervention; raphe nuclei; receptor; recruit; response; virtual

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.

项目摘要 腹部中线丘脑的核团聚（Re）是前额叶 - 海马 沟通。虽然重新选择将其输出定向到包括海马（HF）和 眶前额叶皮层（PFC）收到了一系列潜水员的投入阵列，包括密集的Seratonergic供应（5-- HT）来自背侧（DR）和中位数（MR）Raphe Nuciti的纤维。而博士和先生的表格两个本质上是不同的 不重叠的5-HT途径，RE是收敛的关键站点，因为MR和DR都大量分发到 中线丘脑。虽然RE与PFCàHF电路的互动已与认知行为相关联，但实际上是 关于5-HT在RE中的神经调节作用方面，尚无任何了解。有了本提案，我们打算继续 我们通过利用药物和化学遗传学方法与行为测试一起投资 阐明如何调制参与者在情感，助记符和执行功能中的调制。我们假设 RE的5-HT影响对于灵活的行为和平衡5-HT输入对RE至关重要，将增加回避行为 并损害了执行措施，每种行为都招募了特定的Raphe途径。我们将利用一个 经过验证的大鼠行为评估的全面电池要评估：1。）使用开放场和 高高的迷宫范式； 2.）使用延迟的非匹配样品进行空间工作记忆和行为灵活性 T迷宫范式； 3.）使用气味触觉注意设置转移任务以及注意力和行为灵活性。首先 AIM 1，我们将通过使用神经毒素5,7--局部耗尽5-HT来研究5-HT可用性如何影响行为。 二羟色胺。在AIM 2A中，我们将通过使用DR和MR对RE的不同贡献 抑制性HM4D DREADD接收器有选择地抑制Raphe-Re端子。在AIM 2B中，我们将使用TPH2-CRE 大鼠模型与Dreadd技术结合使用，可有选择地抑制DR或MR的5-羟色胺能项目 关于。这些目标将是第一个概述5-HT输入对行为的特定贡献的贡献。这些结果将会 提供有关raphe-塔拉密斯电路如何促进情感和认知功能的重要信息 重要的是，该系统的变化如何影响抑郁症，焦虑和其他神经精神病学的这种症状 疾病。

项目成果

Projections from the five divisions of the orbital cortex to the thalamus in the rat.

从大鼠眼眶皮层的五个部分到丘脑的投影。

• DOI: 10.1002/cne.25419
• 发表时间: 2023
• 期刊: The Journal of comparative neurology
• 作者: Vertes,RobertP;Hoover,WalterB;Witter,MennoP;Yanik,MehmetFatih;Rojas,AmandaKP;Linley,StephanieB
• 通讯作者: Linley,StephanieB