Investigating the Role of the Dorsal Hippocampus to Nucleus Accumbens Pathway in Regulating Social Interaction

研究背侧海马到伏核通路在调节社会互动中的作用

• 批准号: 10195843
• 负责人: Dane M Chetkovich
• 金额: $ 25.95万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10195843
• 关键词: Affect; Amygdaloid structure; Animal Behavior; Animal Model; Animals; Antidepressive Agents; Awareness; Behavior; Behavior Therapy; Behavioral; Behavioral Model; Brain region; Cations; Characteristics; Chronic; Chronic stress; Cyclic Nucleotides; Data; Disease; Dorsal; Epilepsy; Exhibits; Fiber; Functional disorder; HCN1 gene; Health; Hippocampus (Brain); Human; Impairment; Lead; Link; Magnetic Resonance Imaging; Major Depressive Disorder; Mediating; Molecular; Mus; Neurons; Nucleus Accumbens; Pathway interactions; Patients; Pharmacology; Photometry; Play; Prefrontal Cortex; Property; Public Health; Regulation; Research Personnel; Residual state; Resistance; Rewards; Role; Social Behavior; Social Interaction; Stress; Sucrose; Symptoms; Task Performances; Testing; Viral; Work; autism spectrum disorder; base; behavioral response; cognitive function; cyclic-nucleotide gated ion channels; design; disability; disabling symptom; experience; experimental study; genetic approach; hippocampal pyramidal neuron; human disease; improved outcome; motivated behavior; neuronal excitability; new therapeutic target; novel; object recognition; response; social; social defeat; social deficits; therapeutic target; way finding

Abstract Major Depressive Disorder (MDD) is a major public health problem across the globe. Despite growing awareness and treatment, existing antidepressant therapies often leave patients with residual symptoms. Moreover, some of the most debilitating symptoms of MDD, such as impaired social interaction, lack specific pharmacologic therapies entirely. Targeting these symptoms could improve outcomes not only in MDD, but also in other disorders where social interaction is affected, such as Autism Spectrum Disorder. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have recently been identified as a possible therapeutic target for the treatment of behavioral changes related to chronic stress. These nonspecific cation channels play a role in regulating neuronal excitability. Antagonizing HCN channels in the dorsal hippocampus (dHC) promotes excitability and limits behavioral changes in response to chronic stress in animal models. However, the dHC is mostly known for its role in spatial navigation and early investigators did not find evidence of projections from the dHC to brain regions involved in the regulation of behaviors that are affected by chronic stress. As such, it remains unclear why altering dHC excitability through changes in HCN channel expression would influence animal behavior. Recent work has emphasized the role of a projection from the dHC to the nucleus accumbens (NAcc) in the regulation of motivated behavior to a sucrose reward. Unlike the dHC, activity in the NAcc has previously been shown to influence social interaction behavior. As a result, we hypothesize that the dHC to NAcc projection plays an essential role in regulating social interaction and we will investigate this hypothesis in two aims. In Aim 1, we will perform fiber photometry (FP) in order to study the activity of projections from the dHC to the NAcc. These experiments will utilize animals subjected to chronic social defeat (CSD), a chronic stress paradigm that leads to impaired social interaction behavior in a subset of mice (termed ‘susceptible’ mice). In Aim 2 we will utilize a novel viral approach to enhance cellular excitability in the dHC to NAcc pathway in order to try and rescue social interaction behavior after CSD in susceptible mice. We predict that by altering the excitability of the dHC to NAcc pathway, we will be able to rescue the behavioral changes that occur following CSD. These experiments will help define a new function of the dHC in health and in response to chronic stress.

摘要 严重抑郁障碍(MDD)是全球范围内的重大公共卫生问题。尽管不断增长 意识和治疗方面，现有的抗抑郁疗法往往会给患者留下残留的症状。 此外，MDD的一些最令人衰弱的症状，如社交互动障碍，缺乏具体的 完全是药物疗法。针对这些症状不仅可以改善MDD的预后，而且 在社会互动受到影响的其他障碍中也是如此，例如自闭症谱系障碍。 超极化激活的环核苷酸门控(HCN)通道最近被发现是一种 治疗慢性应激相关行为改变的可能治疗靶点。这些 非特异性阳离子通道在调节神经元兴奋性方面起着重要作用。拮抗HCN通道的实验研究 背侧海马区(DHC)促进兴奋性并限制对慢性应激反应的行为改变 在动物模型中。然而，DHC最为人所知的是它在空间导航和早期调查中的作用 没有发现DHC向参与行为调控的大脑区域投射的证据 都会受到慢性压力的影响。因此，尚不清楚为什么通过改变DHC兴奋性 HCN通道表达的改变会影响动物的行为。 最近的工作强调了从DHC到伏核(NAcc)的投射的作用。 在对蔗糖奖励的动机行为的调节上。与DHC不同，NAcc中的活动具有 之前的研究表明，这会影响社交互动行为。因此，我们假设DHC 对NAcc的投射在调节社交互动方面起着至关重要的作用，我们将对此进行调查 假设有两个目的。在目标1中，我们将进行纤维光度(FP)以研究其活性 从DHC到NAcc的投射。这些实验将利用长期群居的动物 失败(CSD)，这是一种慢性应激范式，导致部分小鼠的社交行为受损 (称为“易感”小鼠)。在目标2中，我们将利用一种新的病毒方法来增强细胞的兴奋性 DHC到NAcc通路，以试图挽救CSD易感小鼠的社交行为。 我们预测，通过改变DHC到NAcc通路的兴奋性，我们将能够拯救 CSD后发生的行为变化。这些实验将有助于定义DHC的新功能 对健康和对长期压力的反应。