Prefronto-thalamic control of cognitive flexibility – from mice to humans

除了处理和传递感觉输入到大脑皮层，有足够的证据表明丘脑在各种认知功能中起着至关重要的作用。这些功能之一是认知灵活性，传统上归因于前额叶皮层（PFC），但根据最近的经验证据，这在很大程度上取决于固定在丘脑内侧背核（MD）的相互连接。例如，当小鼠在不同的学习线索之间做出决定时，这些线索将注意力引导到视觉或听觉目标，来自内侧PFC的反应既反映了个体线索，也反映了它们作为任务规则的重要性。另一方面，MD似乎通过支持或抑制PFC中与兴奋性或抑制性投射相关的任务表征来促进提示上下文之间的切换。这表明MD细胞持续跟踪线索关联的统计规则。MD和前额叶区域之间的这种相互作用是否存在于人类大脑中，以及它们是否具有与小鼠相似的重要性，仍然是推测性的。在拟议的功能性磁共振成像（fMRI）研究中，我们正在解决这个具有挑战性的问题。与Michael Halassa教授（美国剑桥马萨诸塞州麻省理工学院Mc Govern研究所）合作，我们使用先前发表的健康人类受试者fMRI数据重新分析，共同研究了MD和前额叶表征之间有效连接变化的初步证据。与小鼠的结果一致，我们发现，当受试者改变他们的决策策略时，起源于MD的传出投射对参与策略转换的任务相关OFC表示产生兴奋性影响，而负责策略维护的OFC区域则从MD接收抑制性投射。在这里提出的项目中，我们将进一步研究连接MD到其他前额叶和边缘脑区的网络，使用原始的跨模态感觉注意任务的一个变体。新开发的功能磁共振成像设计还允许扩展现有的MD网络模型，通过统计方式将服务于策略切换的行为和大脑网络与允许感知切换的网络分离开来。此外，我们质疑奖励和惩罚调节MD网络相互作用的程度，以及这些过程是否是多巴胺能机制的基础。

Besides processing and relaying sensory inputs to the cerebral cortex, there is ample evidence for the crucial involvement of the thalamus in various cognitive functions. One of these functions is cognitive flexibility, classically attributed to the prefrontal cortex (PFC), but which, according to recent empirical evidence, crucially depends on reciprocal connections anchored in the mediodorsal nucleus (MD) of the thalamus. For example, when mice decide between different sets of learned cues that direct attention to either visual or auditory targets, responses from the medial PFC reflect both the individual cues as well as their importance as task rule. The MD, on the other hand, appears to facilitate switching between cueing contexts by supporting or suppressing task-associated representations in the PFC with excitatory or inhibitory projections. This suggests that MD cells continuously track the statistical rules of cue associations. Whether such interactions between MD and prefrontal regions exist in the human brain, and whether they have comparable importance as those in mice, remains speculative. In the proposed functional magnetic resonance imaging (fMRI) study, we are addressing this challenging question. In collaboration with the group of Prof. Michael Halassa (Mc Govern Institute, Massachusetts Institute of Technology, Cambridge, MA, USA) we jointly investigated preliminary evidence for changes in effective connectivity between the MD and prefrontal representations using re-analyses of previously published fMRI data from healthy human subjects. In agreement with results from mice, we showed that when subjects changed their decision strategy, efferent projections originating in the MD had an excitatory influence on task-associated OFC representations involved in strategy switches, whereas OFC regions, responsible for strategy maintenance, received inhibitory projections from the MD. In the here proposed project, we shall investigate further networks connecting the MD to other prefrontal and limbic brain regions using a variant of the original cross-modal sensory attention task for mice. The newly developed fMRI design also allows to extend the existing MD network model by statistically disentangling behavioral and brain networks that serve strategy switching from those that allow perceptual switching. In addition, we question the extent to which reward and punishment modulate MD network interactions, and whether these processes underlie dopaminergic mechanisms.