Genetic and Functional dissection of frontal thalamocortical circuitry

摘要 精神分裂症是一种使人衰弱的疾病，其治疗在过去几十年中停滞不前。尽管 在治疗其阳性症状（幻觉和妄想）方面取得了一些成功，约40%的患者 几乎所有人都表现出认知功能障碍。精神分裂症的目标认知是一个巨大的 未得到满足的公共卫生需求，有可能使全球约1%的人口恢复劳动力。 前额叶皮层（PFC）功能异常是精神分裂症认知缺陷的核心， 但最近的证据表明，PFC与其主要成分之间的相互作用存在额外的异常， 皮质下伙伴，内侧背丘脑（MD）。这一观点得到了研究的支持，研究表明， 在患者和相关动物模型中，这两种结构之间的结构和功能连接。 该提案旨在围绕拯救MD的想法建立一个基础科学和转化基础， PFC相互作用是精神分裂症认知增强的可行策略。我们的动力来自于我们的 基于SCHEMA研究的新小鼠模型的产生，提供了与疾病的强遗传联系， 随着新任务的发展，可以选择性地访问该电路的不同功能特征， 完整的动物。在目的一，我们将描述一个SCHEMA模型，Grin 2a halposufficiency在两个 依赖于MD-PFC相互作用的不同切换任务，识别该网络的功能签名 功能障碍，可以通过救援方法的目标。在目标II中，我们会问， 沿着在Grin 2a小鼠中观察到的两种模型，Gria 3和Setd 1A， 表征其MD-PFC网络的结构和功能特征。在Aim III中，我们将深入 MD的分子表征，使用scRNA测序鉴定新的细胞类型， 人鱼。最后，在Aim IV中，我们将使用CELLREADR技术在有希望的细胞类型中驱动视蛋白， 在这些动物模型中确定未来的干预目标。

Abstract Schizophrenia is a debilitating disorder whose treatment has stagnated over the last several decades. Despite some success in treating its positive symptoms (hallucinations and delusions), ~40% of patients are treatment-resistant and almost all exhibit cognitive dysfunction. Targeting cognition in schizophrenia is a huge unmet public health need, with a potential to restore around 1% of global population to the workforce. Abnormal prefrontal cortex (PFC) function is known to be central for the cognitive deficits in schizophrenia, but recent evidence suggests additional abnormalities in the interactions between the PFC and its major subcortical partner, the mediodorsal thalamus (MD). This idea is supported by studies showing reduced structural and functional connectivity between these two structures in patients and in relevant animal models. This proposal aims to build a basic science and translational foundation around the idea that rescuing MD- PFC interactions is a viable strategy for cognitive enhancement in schizophrenia. We are motivated by our generation of new mouse models based on the SCHEMA study, which offer a strong genetic link to the illness, and with the development of new tasks that can selectively access different funcitonal features of this circuitry in intact animals. In Aim I, we will characterize one SCHEMA model, the Grin2a halpoinsufficiency in two distinct switching tasks that rely on MD-PFC interactions, identifying funcitonal signatures of this networks dysfunction that can be targeted by rescue methodology. In Aim II, we will ask whether the preliminary deficits observed in Grin2a mice generalize to two other models, Gria3 and Setd1A, along with a broader characterization of structural and functional features of their MD-PFC network. In Aim III, we will perform deep molecular characterization of the MD, identifying novel cell types using scRNA sequencing and validation with MERFISH. Lastly, in Aim IV, we will use CELLREADR technology to drive opsins in promising cell types to identify future targets of intervention in these animal models.