Optogenetic dissection of thalamo-prefontal circuitry supporting working memory

描述（由申请人提供）：工作记忆这个术语描述了我们记忆系统中活跃的部分。例如，当我们忽略环境中的干扰，以便在餐馆账单上留下小费时进行必要的心算时，就会用到它。无法完成这些任务是精神分裂症最具破坏性的症状之一。事实上，不仅患者工作记忆障碍的严重程度可以高度预测个人的长期预后，而且目前的治疗方法对改善这种缺陷也几乎没有作用。为了更好地治疗这些缺陷，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，活动和复杂行为之间建立因果关系。脑成像研究表明，精神分裂症患者在执行工作记忆任务时，其丘脑中背侧（MD）的活动水平下降。MD与前额叶皮层（PFC）共享一组密集的相互连接，形成一个紧密结合的丘脑-皮层回路。这个脑回路的功能障碍被假设为精神分裂症工作记忆缺陷的基础。为了检验MD与工作记忆的因果关系，我们最近建立了一个MD神经活动减少的小鼠模型。我们的研究结果表明，MD活动减少足以导致工作记忆任务的缺陷。有趣的是，这些缺陷与工作记忆表现期间前额叶前部和内侧亚核之间同步活动的中断有关。虽然重要的发现，两个限制限制了解释的范围。首先，我们的实验破坏了所有MD投射的活动，包括对多个PFC亚核的投射。因此，尚不清楚是否只有从MD到内侧PFC的投射对工作记忆重要。第二，虽然我们的任务中的工作记忆过程是在几秒钟的时间尺度上发生的，但我们的实验在几个小时的时间尺度上破坏了大脑皮层的活动。为了了解MD-PFC活动如何促进工作记忆，有必要知道在我们的任务中MD-PFC活动增加的确切时间点，以及它是否与适当的表现紧密相关。这些信息对于理解MD-PFC活动对于编码信息、检索信息或基于检索信息执行行为是否重要至关重要。为了获得解决这些问题所需的空间和时间分辨率，本提案利用了最近开发的小鼠光遗传学工具。通过以毫秒级的精度可逆地操纵MD-PFC投影中的神经活动，所提出的实验将揭示该回路如何在机械细节层面上支持工作记忆，这是我们以前的实验无法做到的，也无法在人类受试者中实现。这些实验的发现将为理解这种神经回路的破坏如何导致精神分裂症等疾病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.