Bidirectional Regulation of Cognitive and Anxiety-like Behaviors by Dentate Gyrus Mossy Cells in Male and Female Mice
Bidirectional Regulation of Cognitive and Anxiety-like Behaviors by Dentate Gyrus Mossy Cells in Male and Female Mice
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DOI：
10.1523/jneurosci.1724-20.2021
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发表时间：
2021-03-17
影响因子：
5.3
通讯作者：
Scharfman, Helen E.
中科院分区：
文献类型：
--
作者：
Botterill, Justin J.;Vinod, K. Yaragudri;Scharfman, Helen E.
齿状回 (DG) 具有许多重要的认知作用并与情感行为相关。这项研究探讨了称为苔藓细胞 (MC) 的谷氨酸 DG 细胞类型如何促进不同的行为，这是及时的，因为众所周知 MC 调节主要 DG 细胞类型颗粒细胞 (GC) 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 MC 会导致不良行为结果，而抑制 MC 海马齿状回 (DG) 对于认知和行为很重要。然而，这些功能背后的电路尚不清楚。 DG 苔藓细胞 (MC) 具有潜在的重要性，因为它们对初级细胞类型颗粒细胞 (GC) 具有兴奋性突触。然而，MC 也会激活 GABA 能神经元，从而抑制 GC。我们在小鼠体内使用专门由设计药物 (DREADD) 激活的设计受体的病毒递送来实施 MC 在不同行为中的功能获得和丧失的研究。使用这种方法，对 MC 的操纵可以双向调节行为。结果表明，抑制 MC 可以减少焦虑样行为并提高认知能力。然而，并非所有认知或焦虑相关行为都受到影响，这表明 MC 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，一些行为表现出性别特异性的影响，女性往往比男性表现出更明显的影响。我们还使用立即早期基因 c-Fos 来解决 DREADD 是否双向调节 MC 或 GC 活性。我们证实兴奋性 DREADD 会增加 MC c-Fos。然而，GC c-Fos 没有变化，这与 MC 激活导致 GC 的 GABA 能抑制一致。相反，抑制性 DREADD 导致 GC c-Fos 大幅增加，与 GABA 能神经元 MC 兴奋的减少一致，并减少 GC 的抑制。总之，这些结果表明 MC 以特定方式调节焦虑和认知。我们还提出了通过减少焦虑来改善认知表现的可能性。
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 MCsThe 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.