Volen Center for Complex Systems, Neuroscience Program, Department of Biology, Brandeis University, Waltham, MA 02453, USA.
Volen Center for Complex Systems, Neuroscience Program, Department of Psychology, Brandeis University, Waltham, MA 02453, USA; Volen Center for Complex Systems, Neuroscience Program, Program in Neuroscience, Brandeis University, Waltham, MA 02453, USA.
Neurobiol Learn Mem. 2021 Mar;179:107396. doi: 10.1016/j.nlm.2021.107396. Epub 2021 Jan 29.
Working memory deficits are key cognitive symptoms of schizophrenia. Elevated delta oscillations, which are uniquely associated with the presence of the illness, may be the proximal cause of these deficits. Spatial working memory (SWM) is impaired by elevated delta oscillations projecting from thalamic nucleus reuniens (RE) to the hippocampus (HPC); these findings imply a role of the RE-HPC circuit in working memory deficits in schizophrenia, but questions remain as to whether the affected process is the encoding of working memory, recall, or both. Here, we answered this question by optogenetically inducing delta oscillations in the HPC terminals of RE axons in mice during either the encoding or retrieval phase (or both) of an SWM task.
We transduced cells in RE to express channelrhodopsin-2 through bilateral injection of adeno-associated virus, and bilaterally implanted optical fibers dorsal to the hippocampus (HPC). While mice performed a spatial memory task on a Y-maze, the RE-HPC projections were optogenetically stimulated at delta frequency during distinct phases of the task.
Full-trial stimulation successfully impaired SWM performance, replicating the results of the previous study in a mouse model. Task-phase-specific stimulation significantly impaired performance during retrieval but not encoding.
Our results indicate that perturbations in the RE-HPC circuit specifically impair the retrieval phase of working memory. This finding supports the hypothesis that abnormal delta frequency bursting in the thalamus could have a causal role in producing the WM deficits seen in schizophrenia.
工作记忆缺陷是精神分裂症的关键认知症状。与疾病存在密切相关的高频 delta 振荡可能是这些缺陷的近端原因。丘脑束旁核（RE）投射到海马（HPC）的高频 delta 振荡会损害空间工作记忆（SWM）；这些发现表明，RE-HPC 回路在精神分裂症的工作记忆缺陷中起作用，但仍存在一个问题，即受影响的过程是工作记忆的编码、回忆还是两者兼有。在这里，我们通过在 SWM 任务的编码或回忆阶段（或两者）期间光遗传学诱导 RE 轴突的 HPC 末梢中的 delta 振荡，回答了这个问题。
我们通过双侧注射腺相关病毒将细胞转染到 RE 中，以表达通道视紫红质-2，并在海马（HPC）的背侧双侧植入光纤。当小鼠在 Y 型迷宫上执行空间记忆任务时，在任务的不同阶段以 delta 频率对 RE-HPC 投射进行光遗传学刺激。
全试验刺激成功地损害了 SWM 表现，在小鼠模型中复制了先前研究的结果。任务阶段特异性刺激在回忆阶段而非编码阶段显著损害了表现。
我们的结果表明，RE-HPC 回路的干扰会特异性损害工作记忆的回忆阶段。这一发现支持了这样一种假设，即丘脑异常的 delta 频率爆发可能在产生精神分裂症中所见的 WM 缺陷中起因果作用。
