Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142.
McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
Proc Natl Acad Sci U S A. 2022 May 17;119(20):e2118712119. doi: 10.1073/pnas.2118712119. Epub 2022 May 10.
Alterations in the structure and functional connectivity of anterior thalamic nuclei (ATN) have been linked to reduced cognition during aging. However, ATN circuits that contribute to higher cognitive functions remain understudied. We found that the anteroventral (AV) subdivision of ATN is necessary specifically during the maintenance phase of a spatial working memory task. This function engages the AV→parasubiculum (PaS)→entorhinal cortex (EC) circuit. Aged mice showed a deficit in spatial working memory, which was associated with a decrease in the excitability of AV neurons. Activation of AV neurons or the AV→PaS circuit in aged mice was sufficient to rescue their working memory performance. Furthermore, rescued aged mice showed improved behavior-induced neuronal activity in prefrontal cortex (PFC), a critical site for working memory processes. Although the direct activation of PFC neurons in aged mice also rescued their working memory performance, we found that these animals exhibited increased levels of anxiety, which was not the case for AV→PaS circuit manipulations in aged mice. These results suggest that targeting AV thalamus in aging may not only be beneficial for cognitive functions but that this approach may have fewer unintended effects compared to direct PFC manipulations.
前丘脑核（ATN）结构和功能连接的改变与衰老过程中的认知能力下降有关。然而，有助于更高认知功能的 ATN 回路仍未得到充分研究。我们发现，ATN 的前腹侧（AV）亚区在空间工作记忆任务的维持阶段是必需的。这一功能涉及 AV→副隔核（PaS）→内嗅皮层（EC）回路。老年小鼠表现出空间工作记忆缺陷，这与 AV 神经元兴奋性降低有关。激活老年小鼠的 AV 神经元或 AV→PaS 回路足以挽救其工作记忆表现。此外，挽救的老年小鼠在前额叶皮层（PFC）中表现出改善的行为诱导神经元活动，这是工作记忆过程的关键部位。尽管直接激活老年小鼠的 PFC 神经元也挽救了它们的工作记忆表现，但我们发现这些动物表现出焦虑水平的增加，而在老年小鼠中对 AV→PaS 回路进行操作则没有这种情况。这些结果表明，针对衰老中的 AV 丘脑不仅可能有益于认知功能，而且与直接 PFC 操作相比，这种方法可能具有更少的意外影响。
