Behavioral and mechanistic dissection of a cognitive thalamo-cortical network

摘要 皮质和丘脑之间的相互作用对感觉、行动和认知至关重要。虽然 丘脑在感觉处理中的作用已经得到了很好的研究，它在认知中的作用才刚刚开始 阐明。这项建议将集中在内侧背丘脑（MD），其中一个最大的丘脑核团， 哺乳动物的大脑，在调节前额叶皮层（PFC）活动的认知控制和灵活性。MD-PFC 已知相互作用在精神分裂症中受到干扰，但治疗选择有限，因为回路 这些相互作用的机制尚不清楚。在本提案中，我们将测试一个总体模型， MD调节PFC连接模式，以通过增强 上下文相关的活动模式和上下文无关的抑制。具体来说，我们的模型假设 MD神经元通过选择性地加强PFC输入来产生特定于上下文的信号，PFC输入携带基本的 这些信号的元素，但不显式地编码上下文。两种MD细胞类型似乎产生 这种信号，其中一个使用它来增强上下文一致的PFC活动，而另一个则抑制 上下文不一致的活动。最后，我们的模型假设这些不同的丘脑效应是由 不同的PFC电路图案，分别是兴奋性/去抑制性和抑制性。在目标I中，我们将测试 假设MD神经元基于来自PFC的上下文非特定输入生成上下文特定输出。 在目的II中，我们将测试两种MD功能细胞类型映射到不同遗传类型的假设。在 目的三，我们将测试的假设，这两个MD依赖的影响PFC，增强和抑制 的活动模式，是由不同的本地电路图案。总的来说，我们的工作应该澄清电路 MD影响PFC活性的机制，为检查其普遍性提供了一个起点 在不同的任务转换范式以及与更高层次的丘脑功能的关系， 大致上我们的工作也应该与NIH的中心使命相关，即理解 治疗潜力

Abstract Interactions between the cortex and thalamus are essential for sensation, action and cognition. Although the role of the thalamus in sensory processing is well-studied, its role in cognition is just beginning to be elucidated. This proposal will focus on the mediodorsal thalamus (MD), one of the largest thalamic nuclei of the mammalian brain, in regulating prefrontal cortex (PFC) activity in cognitive control and flexibility. MD-PFC interactions are known to be perturbed in schizophrenia, but therapeutic options are limited because the circuit mechanisms underlying these interactions are unknown. In this proposal, we will test an overarching model that the MD regulates PFC connectivity patterns to match the behavioral context through enhancement of context-relevant activity patterns and suppression of context-irrelevant ones. Specifically, our model posits that MD neurons generate context-specific signals by selectively strengthening PFC inputs that carry the basic elements of these signals but do not encode the context explicitly. Two MD cell types appear to generate such signals, one of which uses it to enhance context-congruent PFC activity while the other suppresses context incongruent activity. Lastly, our model posits that these distinct thalamic effects are mediated by different PFC circuit motifs, an excitatory/disinhibitory and an inhibitory, respectively. In Aim I, we will test the hypothesis that MD neurons generate context-specific output based on context non-specific inputs from PFC. In Aim II, we will test the hypothesis that the two MD functional cell types map onto distinct genetic types. In Aim III, we will test the hypothesis that the two MD-dependent effects on PFC, enhancement and suppression of activity patterns, are implemented by distinct local circuit motifs. Overall, our work should clarify the circuit mechanisms by which the MD influences PFC activity, providing a starting point for examining their generality across different task switching paradigms as well as relationship to higher order thalamus function more broadly. Our work should also be relevant to central mission of the NIH in understanding mechanisms with therapeutic potential.