Behavioral and mechanistic dissection of a cognitive thalamo-cortical network

摘要 大脑皮质和丘脑之间的相互作用对感觉、行动和认知是必不可少的。尽管 丘脑在感觉处理中的作用已经被很好地研究了，它在认知中的作用才刚刚开始 已澄清。这项提案将重点放在丘脑内侧背侧核(MD)上，它是丘脑最大的核团之一 哺乳动物的大脑，在调节前额叶皮质(PFC)活动中的认知控制和灵活性。MD-PFC 众所周知，精神分裂症患者的相互作用会受到干扰，但治疗选择有限，因为电路 这些相互作用背后的机制尚不清楚。在本提案中，我们将测试一个总体模型 MD通过增强PFC连接模式以匹配行为上下文 语境相关的活动模式和语境无关的活动模式的抑制。具体来说，我们的模型假设 MD神经元通过选择性地加强PFC输入来产生上下文特定信号，PFC输入携带基本的 这些信号的元素，但不对上下文进行显式编码。两种MD细胞类型似乎产生了 这样的信号，其中一个用它来增强上下文一致的PFC活动，而另一个抑制 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电路模体，分别是兴奋性/非抑制性和抑制性。在AIM 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产生上下文特定的输出。 在AIM II中，我们将检验这两种MD功能细胞类型映射到不同遗传类型的假设。在……里面 目的III，我们将检验两种MD依赖的PFC效应，增强效应和抑制效应 活动模式，是由不同的局部回路主题实现的。总体而言，我们的工作应该澄清电路 MD影响PFC活动的机制，为研究其普遍性提供了一个起点 跨越不同的任务切换范例以及与更高级别丘脑功能的关系 大体上说。我们的工作也应该与美国国立卫生研究院的核心使命相关，以理解 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.