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

摘要 重度抑郁症（MDD）是地球仪的主要公共卫生问题。尽管越来越多 认识和治疗，现有的抗抑郁治疗往往留下残留症状的患者。 此外，MDD的一些最令人衰弱的症状，如社会交往障碍，缺乏特异性的治疗。 完全的药物治疗。针对这些症状不仅可以改善MDD的结局， 还有其他影响社会互动的疾病，如自闭症谱系障碍。 超极化激活的环核苷酸门控（HCN）通道最近被确定为一种新的通道。 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中起作用。拮抗HCN通道 背侧海马（dHC）促进兴奋性，限制慢性应激反应的行为变化 在动物模型中。然而，dHC主要以其在空间导航和早期研究中的作用而闻名。 没有发现证据表明，从dHC到参与行为调节的大脑区域的投射， 受到慢性压力的影响。因此，目前尚不清楚为什么通过改变dHC兴奋性， HCN通道表达的变化会影响动物的行为。 最近的工作强调了从dHC到丘脑核（NAcc）的投射的作用 在调节蔗糖奖励的动机行为方面。与dHC不同，NAcc中的活性 以前被证明会影响社会互动行为。因此，我们假设dHC NAcc投射在调节社会互动中起着至关重要的作用，我们将对此进行研究 假设有两个目标。在目标1中，我们将进行纤维光度法（FP）以研究 从dHC到NAcc的预测。这些实验将利用动物进行慢性社会 失败（CSD），一种慢性应激范式，导致小鼠亚组的社会互动行为受损 （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，以尝试拯救易感小鼠CSD后的社会互动行为。 我们预测，通过改变dHC到NAcc通路的兴奋性，我们将能够挽救 行为改变发生在CSD之后。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。

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.