Probing the function of hilar mossy cells in hippocampal circuits and dentate gyrus-dependent behaviors

项目总结 海马齿状回(DG)是海马区的一个亚区，与多个 精神疾病，包括精神分裂症。DG的功能包括模式分离、新颖性 检测和先天焦虑的表达，这些都在精神分裂症患者中被扰乱 在精神分裂症小鼠模型中。而包括多巴胺在内的神经调节剂被认为参与了 精神分裂症患者海马区功能障碍的发病机制及缺陷背后的生物学机制 在精神分裂症中，依赖DG的行为尚不清楚。 大多数关于DG功能及其在疾病中的作用的研究都检查了DG的主细胞、颗粒细胞 (GCS)，以及他们经历成人神经发生的独特能力。DG还包含第二组人口 兴奋性神经元被称为苔藓细胞(MCs)，它具有独特的解剖特性和广泛的 海马区的连接使它们处于调节DG活动和影响行为的位置。他们还拥有 最近被认为与精神分裂症有关，在精神分裂症中，精神分裂症相关蛋白dybindin-1定位于 MCS。精神分裂症中MC的参与可能与多巴胺有关，因为它们是唯一的海马体 神经元表达多巴胺D2受体亚型，而多巴胺最近被证明具有 对它们的长时间兴奋作用。考虑到抗精神病药物在D2起作用的事实，这一点意义重大 受体并产生海马区的变化，提示这些变化可能是由MCs介导的。 尽管最近有证据表明，MC有助于临床相关的DG功能，并参与 精神障碍，包括精神分裂症，到目前为止还缺乏直接研究他们的 在DG电路和行为中扮演的角色。这项提议将利用最近开发的Cre转基因小鼠品系 结合依赖Cre的病毒载体回答有关多巴胺的一些悬而未决的问题 MC的输入，MC在DG回路中的作用，以及MC、多巴胺和下列行为之间的联系 失调的失调的，尤指精神分裂症。第一个目标是在密歇根州使用一种改良的狂犬病病毒- 选择性Drd2-Cre小鼠进行单突触逆行示踪以特异性识别单突触 对MC的输入，特别是多巴胺能和神经调节投射。AIM 2将采用特定的 光遗传激活和沉默DRD2-Cre小鼠海马片MC的作用 MC活性对GC输出的影响，以及多巴胺对MC→GC突触的影响。第三个目标将利用 DREADD对DRD2-Cre小鼠MCs的体内沉默作用及其对DG连锁的影响 精神分裂症患者受多巴胺影响并受损的行为。总体而言，这项研究将大大 在电路和行为水平上增强我们对MC解剖和功能的理解，并将有助于 阐明MCs、多巴胺和DG功能障碍在精神分裂症等疾病发病机制中的作用。

PROJECT SUMMARY The dentate gyrus (DG) is a subfield of the hippocampus that has been implicated in multiple psychiatric diseases, including schizophrenia. Functions of the DG include pattern separation, novelty detection, and the expression of innate anxiety, which have all been disrupted in patients with schizophrenia and in schizophrenia mouse models. While neuromodulators including dopamine are thought to be involved in the pathogenesis of hippocampal dysfunction in schizophrenia, the biological mechanisms that underlie defects in DG-dependent behaviors in schizophrenia are unknown. Most studies of DG function and its role in disease have examined the DG principal cells, granule cells (GCs), and their unique ability to undergo adult neurogenesis. The DG also contains a second population of excitatory neurons called mossy cells (MCs), which have unique anatomical properties and extensive hippocampal connections that position them to modulate DG activity and affect behavior. They have also recently been linked to schizophrenia, in which the schizophrenia-associated protein dysbindin-1 localized to MCs. The involvement of MCs in schizophrenia may be tied to dopamine, as they are the only hippocampal neurons to express the dopamine D2 receptor subtype, and dopamine was recently shown to have a prolonged excitatory effect on them. This is significant in light of the fact that antipsychotics act at the D2 receptor and produce hippocampal changes, suggesting that these changes may be mediated by MCs. Despite recent evidence that MCs contribute to clinically relevant DG functions and are involved in psychiatric disorders, including schizophrenia, so far there has been a lack of studies directly examining their role in DG circuitry and in behavior. This proposal will utilize a recently developed Cre-transgenic mouse line in combination with Cre-dependent viral vectors to answer a number of outstanding questions about dopamine inputs to MCs, the role of MCs in the DG circuit, and the link between MCs, dopamine, and behaviors that are dysfunctional in disorders, particularly schizophrenia. The first aim will use a modified rabies virus in MC- selective Drd2-Cre mice to perform monosynaptic retrograde tracing to specifically identify monosynaptic inputs to MCs, especially dopaminergic and neuromodulatory projections. Aim 2 will employ specific optogenetic activation and silencing of MCs in hippocampal slices of Drd2-Cre mice to determine the effect of MC activity on GC output, and the influence of dopamine on the MC → GC synapse. The third aim will utilize DREADD-mediated silencing of MCs in Drd2-Cre mice in vivo, and probe the resulting effects on DG-linked behaviors that are influenced by dopamine and are impaired in schizophrenia. Overall, this research will greatly enhance our understanding of MC anatomy and function at both a circuit and behavioral level, and will help elucidate the role of MCs, dopamine, and DG dysfunction in the pathogenesis of disorders like schizophrenia.