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之外，有充分的证据表明丘脑在各种认知功能中起着至关重要的作用。其中一项功能是认知灵活性，通常被认为是前额叶皮层（PFC）的功能，但根据最近的经验证据，认知灵活性在很大程度上取决于丘脑中背核（MD）的相互连接。例如，当老鼠在不同的学习线索中做出选择，将注意力引导到视觉或听觉目标时，内侧PFC的反应既反映了单个线索，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中具有兴奋性或抑制性投射的任务相关表征来促进线索上下文之间的切换。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，以及它们是否与小鼠具有相当的重要性，仍然是推测性的。在功能性磁共振成像（fMRI）研究中，我们正在解决这个具有挑战性的问题。我们与Michael Halassa教授（麻省理工学院mcgovern研究所，Cambridge， MA， USA）小组合作，通过重新分析先前发表的健康人类受试者的功能磁共振成像数据，共同调查了MD和前额叶表征之间有效连接变化的初步证据。与小鼠实验结果一致，我们发现当受试者改变决策策略时，源自MD的传出投射对涉及策略转换的任务相关OFC表征具有兴奋性影响，而负责策略维持的OFC区域则收到来自MD的抑制性投射。我们将使用一种原始的小鼠跨模态感觉注意任务的变体，进一步研究连接MD与其他前额叶和边缘脑区域的网络。新开发的fMRI设计还允许扩展现有的MD网络模型，通过统计分离为策略转换服务的行为和大脑网络与允许感知转换的网络。此外，我们质疑奖惩调节MD网络相互作用的程度，以及这些过程是否构成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.