Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962.
Department of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962.
J Neurosci. 2021 Mar 17;41(11):2475-2495. doi: 10.1523/JNEUROSCI.1724-20.2021. Epub 2021 Jan 20.
The dentate gyrus (DG) of the hippocampus is important for cognition and behavior. However, the circuits underlying these functions are unclear. DG mossy cells (MCs) are potentially important because of their excitatory synapses on the primary cell type, granule cells (GCs). However, MCs also activate GABAergic neurons, which inhibit GCs. We used viral delivery of designer receptors exclusively activated by designer drugs (DREADDs) in mice to implement a gain- and loss-of-function study of MCs in diverse behaviors. Using this approach, manipulations of MCs could bidirectionally regulate behavior. The results suggest that inhibiting MCs can reduce anxiety-like behavior and improve cognitive performance. However, not all cognitive or anxiety-related behaviors were influenced, suggesting specific roles of MCs in some, but not all, types of cognition and anxiety. Notably, several behaviors showed sex-specific effects, with females often showing more pronounced effects than the males. We also used the immediate early gene c-Fos to address whether DREADDs bidirectionally regulated MC or GC activity. We confirmed excitatory DREADDs increased MC c-Fos. However, there was no change in GC c-Fos, consistent with MC activation leading to GABAergic inhibition of GCs. In contrast, inhibitory DREADDs led to a large increase in GC c-Fos, consistent with a reduction in MC excitation of GABAergic neurons, and reduced inhibition of GCs. Together, these results suggest that MCs regulate anxiety and cognition in specific ways. We also raise the possibility that cognitive performance may be improved by reducing anxiety. The dentate gyrus (DG) has many important cognitive roles as well as being associated with affective behavior. This study addressed how a glutamatergic DG cell type called mossy cells (MCs) contributes to diverse behaviors, which is timely because it is known that MCs regulate the activity of the primary DG cell type, granule cells (GCs), but how MC activity influences behavior is unclear. We show, surprisingly, that activating MCs can lead to adverse behavioral outcomes, and inhibiting MCs have an opposite effect. Importantly, the results appeared to be task-dependent and showed that testing both sexes was important. Additional experiments indicated what MC and GC circuitry was involved. Together, the results suggest how MCs influence behaviors that involve the DG.
海马齿状回（DG）在认知和行为中起着重要作用。然而，这些功能的潜在机制尚不清楚。DG 苔藓细胞（MCs）因其与主要细胞类型颗粒细胞（GCs）的兴奋性突触而具有潜在的重要性。然而，MCs 也会激活 GABA 能神经元，从而抑制 GCs。我们使用病毒传递专门被设计药物激活的设计受体（DREADDs），在小鼠中进行了 MCs 在各种行为中的功能获得和功能丧失研究。使用这种方法，MCs 的操作可以双向调节行为。结果表明，抑制 MCs 可以减少焦虑样行为并改善认知表现。然而，并非所有认知或焦虑相关行为都受到影响，这表明 MCs 在某些但不是所有类型的认知和焦虑中具有特定作用。值得注意的是，几种行为表现出性别特异性效应，女性的影响通常比男性更为明显。我们还使用即时早期基因 c-Fos 来解决 DREADDs 是否双向调节 MC 或 GC 活性。我们证实兴奋性 DREADDs 增加了 MC 的 c-Fos。然而，GC 的 c-Fos 没有变化，这与 MC 激活导致 GABA 能神经元对 GCs 的抑制一致。相反，抑制性 DREADDs 导致 GC 的 c-Fos 大量增加，这与 MC 对 GABA 能神经元的兴奋减少以及对 GCs 的抑制减少一致。总之，这些结果表明 MCs 以特定方式调节焦虑和认知。我们还提出了通过降低焦虑来提高认知表现的可能性。齿状回（DG）具有许多重要的认知作用，并且与情感行为有关。这项研究探讨了称为苔藓细胞（MCs）的谷氨酸能 DG 细胞类型如何有助于各种行为，这是及时的，因为已知 MCs 调节主要 DG 细胞类型颗粒细胞（GCs）的活性，但 MC 活性如何影响行为尚不清楚。令人惊讶的是，我们发现激活 MCs 会导致不良的行为结果，而抑制 MCs 则会产生相反的效果。重要的是，结果似乎是任务依赖性的，并表明测试两性都很重要。额外的实验表明涉及哪些 MC 和 GC 电路。总之，这些结果表明 MCs 如何影响涉及 DG 的行为。
