Neuroscience Graduate Program, Emory University, Atlanta, Georgia 30322, USA.
Neuroscience Graduate Program, University of Southern California, Los Angeles, California 90007, USA.
Learn Mem. 2021 Mar 15;28(4):126-133. doi: 10.1101/lm.053041.120. Print 2021 Apr.
Dysfunctions in memory recall lead to pathological fear; a hallmark of trauma-related disorders, like posttraumatic stress disorder (PTSD). Both, heightened recall of an association between a cue and trauma, as well as impoverished recall that a previously trauma-related cue is no longer a threat, result in a debilitating fear toward the cue. Glucocorticoid-mediated action via the glucocorticoid receptor (GR) influences memory recall. This literature has primarily focused on GRs expressed in neurons or ignored cell-type specific contributions. To ask how GR action in nonneuronal cells influences memory recall, we combined auditory fear conditioning in mice and the knockout of GRs in astrocytes in the prefrontal cortex (PFC), a brain region implicated in memory recall. We found that knocking out GRs in astrocytes of the PFC disrupted memory recall. Specifically, we found that knocking out GRs in astrocytes in the PFC (AstroGRKO) after fear conditioning resulted in higher levels of freezing to the CS+ tone when compared with controls (AstroGRintact). While we did not find any differences in extinction of fear toward the CS+ between these groups, AstroGRKO female but not male mice showed impaired recall of extinction training. These results suggest that GRs in cortical astrocytes contribute to memory recall. These data demonstrate the need to examine GR action in cortical astrocytes to elucidate the basic neurobiology underlying memory recall and potential mechanisms that underlie female-specific biases in the incidence of PTSD.
记忆召回功能障碍导致病理性恐惧；这是创伤相关障碍（如创伤后应激障碍（PTSD））的标志。高度回忆线索与创伤之间的关联，以及回忆起以前与创伤相关的线索不再构成威胁的能力下降，都会导致对线索产生衰弱性恐惧。糖皮质激素通过糖皮质激素受体（GR）的介导作用影响记忆召回。这方面的文献主要集中在神经元中表达的 GR 上，或者忽略了细胞类型特异性的贡献。为了探讨非神经元细胞中 GR 作用如何影响记忆召回，我们结合了小鼠的听觉恐惧条件反射和前额叶皮层（PFC）中星形胶质细胞中 GR 的敲除（AstroGRKO），这是一个与记忆召回有关的大脑区域。我们发现，敲除 PFC 星形胶质细胞中的 GR 会破坏记忆召回。具体来说，我们发现，与对照组（AstroGRintact）相比，恐惧条件反射后敲除 PFC 星形胶质细胞中的 GR（AstroGRKO）会导致对 CS+ 音调的冻结水平更高。虽然我们没有发现这些组之间对 CS+ 的恐惧消退有任何差异，但 AstroGRKO 雌性而非雄性小鼠显示出对消退训练的回忆受损。这些结果表明，皮质星形胶质细胞中的 GR 有助于记忆召回。这些数据表明，需要检查皮质星形胶质细胞中的 GR 作用，以阐明记忆召回的基本神经生物学基础以及 PTSD 发生率中潜在的女性特异性偏见的潜在机制。
