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.

抽象的 重度抑郁症（MDD）是全球主要的公共卫生问题。尽管增长 意识和治疗，现有的抗抑郁药疗法通常会使患者患有残留症状。 此外，MDD的一些最令人衰弱的症状，例如社交互动受损，缺乏特定的 药理学疗法完全是。针对这些症状不仅可以改善MDD的结果，而且可以改善 在其他受影响的社会互动的疾病中，例如自闭症谱系障碍。 超极化激活的循环核苷酸门控（HCN）通道最近被确定为一个 治疗与慢性应激有关的行为变化的可能治疗靶标。这些 非特异性阳离子渠道在调节神经元令人兴奋的情况下发挥了作用。对抗HCN通道 背侧海马（DHC）促进了兴奋性，并限制了对慢性应激的响应的行为变化 在动物模型中。但是，DHC主要以其在空间导航和早期研​​究人员中的作用而闻名 没有找到从DHC到参与行为调节的大脑区域的项目的证据 受慢性压力的影响。因此，尚不清楚为什么通过通过 HCN通道表达的变化会影响动物行为。 最近的工作强调了DHC投射到伏隔核（NACC）的作用。 在调节蔗糖奖励的动机行为中。与DHC不同，NACC的活动具有 以前已显示出影响社会互动行为。结果，我们假设DHC NACC投影在确定社会互动中起着至关重要的作用，我们将调查这一点 两个目标的假设。在AIM 1中，我们将执行光纤光度法（FP），以研究 从DHC到NACC的项目。这些实验将利用受到慢性社会的动物 失败（CSD），这是一种慢性压力范式，导致小鼠一部分社会互动行为受损 （称为“易感”小鼠）。在AIM 2中，我们将利用一种新型的病毒方法来增强激动人心的细胞 DHC到NACC途径，以尝试在易感小鼠中CSD后挽救社交互动行为。 我们预测，通过将DHC的兴奋更改为NACC途径，我们将能够营救 CSD后发生的行为变化。这些实验将有助于定义DHC的新功能 在健康和应对慢性压力方面。