Optogenetic dissection of thalamo-prefontal circuitry supporting working memory

描述(申请人提供)：术语工作记忆描述的是我们记忆系统的活跃部分。例如，当我们忽视环境中的干扰，以便进行必要的心理计算，在餐厅账单上留下小费时，它就会被使用。无法执行这样的任务是精神分裂症最具破坏性的症状之一。事实上，不仅患者工作记忆损伤的严重程度高度预测了该患者的长期预后，而且目前的治疗方法对改善这种缺陷也几乎没有起到什么作用。为了开发更好的治疗这些缺陷的方法，必须首先了解支持工作记忆的神经机制。实现这一目标的一个基本方法是使用动物模型，在动物模型中，神经活动可以被可逆地操纵，并建立活动和复杂行为之间的因果关系。脑成像研究表明，精神分裂症患者在执行工作记忆任务时，丘脑内侧背侧核(MD)的活动水平降低。MD与前额叶皮质(PFC)共享一组密集的相互联系，形成紧密联系的丘脑-皮质环路。这一大脑回路的功能障碍被认为是精神分裂症工作记忆缺陷的基础。为了因果检验MD在工作记忆中的作用，我们最近建立了一个MD神经活动减少的小鼠模型。我们的发现表明，MD活动的减少足以导致工作记忆任务中的缺陷。有趣的是，这些缺陷与工作记忆执行过程中MD和PFC内侧亚核之间的同步活动中断有关。虽然有重要的发现，但有两个限制限制了解释的范围。首先，我们的实验扰乱了所有MD投射的活动，包括对多个PFC亚核的投射。因此，目前尚不清楚是否只有MD到内侧PFC的投射对工作记忆是重要的。其次，虽然我们任务中的工作记忆过程是以秒为时间尺度进行的，但我们的实验在几个小时的时间尺度上扰乱了MD的活动。为了了解MD-PFC活动对工作记忆的贡献，有必要知道在我们的任务中MD-PFC活动增加的准确时间点，以及它是否与适当的性能紧密相关。该信息对于理解MD-PFC活动对于编码信息、检索信息或基于检索的信息执行行为是否重要是必不可少的。为了获得解决这些问题所需的空间和时间分辨率，这一建议利用了最近在小鼠身上开发的光遗传工具。通过可逆地操纵已定义的MD-PFC投影中的神经活动，以毫秒级的精度，拟议的实验将揭示该电路如何在我们之前的实验不可能实现的机械细节水平上支持工作记忆，也不可能在人类受试者中实现。这些实验的发现将为理解这种神经元回路的中断如何导致精神分裂症等障碍的工作记忆缺陷奠定基础。

DESCRIPTION (provided by applicant): The term working memory describes the active part of our memory system. It is put to use, for example, when we ignore distractions in our environment in order to perform the mental calculations necessary for leaving a tip on a restaurant bill. An inability to carry out such tasks is one of the most devastating symptoms of schizophrenia. Indeed, not only is the severity of a patient's working memory impairment highly predictive for that individual's long-term prognosis, but current treatments also do little to ameliorate such deficits. In order to develop better treatments for these deficits, the neural mechanisms that support working memory must first be understood. An essential approach towards this end is the use of animal models, in which neural activity can be reversibly manipulated and causal relationships between activity and complex behavior established. Brain imaging studies have revealed that patients with schizophrenia have decreased levels of activity in the mediodorsal thalamus (MD) when performing working memory tasks. The MD shares a dense set of reciprocal connections with the prefrontal cortex (PFC), forming a closely-knit thalamo-cortical circuit. Dysfunction in this brain circuit has been hypothesized to underlie the working memory deficits of schizophrenia. To causally test the involvement of the MD in working memory we recently generated a mouse model with decreased neural activity in the MD. Our findings revealed that decreasing MD activity was sufficient to cause deficits in a working memory task. Interestingly, these deficits correlated with disruptions in synchronous activity between MD and the medial subnucleus of the PFC during working memory performance. While important findings, two limitations constrain the scope of interpretation. First, our experiments disrupted activity in all MD projections, including projections made to multiple PFC subnuclei. It is thus unclear whether only projections from the MD to the medial PFC are important for working memory. Second, while working memory processes in our task take place at a time-scale of seconds, our experiments disrupted MD activity at a time scale of hours. In order to understand how MD-PFC activity contributes to working memory it is necessary to know the precise time point during our task when MD-PFC activity increases and if it is tightly linked to proper performance. This information is essential for understanding whether MD-PFC activity is important for encoding information, retrieving information or executing behavior based on retrieved information. To obtain the spatial and temporal resolution necessary to address these questions, this proposal takes advantage of recently developed optogenetic tools in mice. By reversibly manipulating neural activity in defined MD-PFC projections with millisecond-time scale precision, the proposed experiments will reveal how this circuit supports working memory at a level of mechanistic detail not possible by our previous experiments, nor in human subjects. Findings from these experiments will lay the groundwork for understanding how disruption of this neuronal circuit can lead to working memory deficits in disorders like schizophrenia.