Zhang Jiajing, Navarrete Meaghan, Wu Yuying, Zhou Yi
Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, United States.
Front Mol Neurosci. 2022 Feb 14;15:817227. doi: 10.3389/fnmol.2022.817227. eCollection 2022.
While hippocampal hyperactivity is implicated in psychosis by both human and animal studies, whether it induces a hyperdopaminergic state and the underlying neural circuitry remains elusive. Previous studies established that region-specific inhibition of 14-3-3 proteins in the dorsal hippocampus CA1 (dCA1) induces schizophrenia-like behaviors in mice, including a novelty-induced locomotor hyperactivity. In this study, we showed that 14-3-3 dysfunction in the dCA1 over-activates ventral tegmental area (VTA) dopaminergic neurons, and such over-activation is necessary for eliciting psychomotor behavior in mice. We demonstrated that such hippocampal dysregulation of the VTA during psychomotor behavior is dependent on an over-activation of the lateral septum (LS), given that inhibition of the LS attenuates over-activation of dopaminergic neurons and psychomotor behavior induced by 14-3-3 inhibition in the dCA1. Moreover, 14-3-3 inhibition-induced neuronal activations within the dCA1-LS-VTA pathway and psychomotor behavior can be reproduced by direct chemogenetic activation of LS-projecting dCA1 neurons. Collectively, these results suggest that 14-3-3 dysfunction in the dCA1 results in hippocampal hyperactivation which leads to psychomotor behavior a dCA1-LS-VTA pathway.
虽然人类和动物研究均表明海马体过度活跃与精神病有关，但它是否会诱发多巴胺能亢进状态以及潜在的神经回路仍不清楚。先前的研究表明，背侧海马体CA1区（dCA1）中14-3-3蛋白的区域特异性抑制会在小鼠中诱发类似精神分裂症的行为，包括新奇诱导的运动活动亢进。在本研究中，我们发现dCA1区的14-3-3功能障碍会过度激活腹侧被盖区（VTA）的多巴胺能神经元，而这种过度激活是引发小鼠精神运动行为所必需的。我们证明，在精神运动行为期间，VTA的这种海马体失调依赖于外侧隔区（LS）的过度激活，因为抑制LS会减弱多巴胺能神经元的过度激活以及dCA1区14-3-3抑制所诱导的精神运动行为。此外，通过直接化学遗传学激活投射到LS的dCA1神经元，可以重现14-3-3抑制诱导的dCA1-LS-VTA通路内的神经元激活和精神运动行为。总体而言，这些结果表明，dCA1区的14-3-3功能障碍会导致海马体过度激活，进而通过dCA1-LS-VTA通路导致精神运动行为。
