Institute of Anatomy, Otto-von-Guericke-University, Leipziger Str. 44, 39120 Magdeburg, Germany.
Institute of Biology, Otto-von-Guericke-University, Leipziger Str. 44, 39120 Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Universitätsplatz 2, 39106 Magdeburg, Germany.
Neurobiol Dis. 2023 Jul;183:106165. doi: 10.1016/j.nbd.2023.106165. Epub 2023 May 23.
Anxiety disorders have been linked to a disbalance of excitation and inhibition in a network of brain structures comprising frontal cortical regions, the amygdala and the hippocampus, among others. Recent imaging studies suggest sex differences in the activation of this anxiety network during the processing of emotional information. Rodent models with genetically altered ϒ-amino butyric acid (GABA) neurotransmission allow studying the neuronal basis of such activation shifts and their relation to anxiety endophenotypes, but to date sex effects have rarely been addressed. Using mice with a null mutation of the GABA synthetizing enzyme glutamate decarboxylase 65 (GAD65-/-), we started to compare anxiety-like behavior and avoidance in male vs. female GAD65-/- mice and their wildtype littermates. In an open field, female GAD65-/- mice displayed increased activity, while male GAD65-/- mice showed an increased adaptation of anxiety-like behavior over time. GAD65-/- mice of both sexes had a higher preference for social interaction partners, which was further heightened in male mice. In male mice higher escape responses were observed during an active avoidance task. Together, female mice showed more stable emotional responses despite GAD65 deficiency. To gain insights into interneuron function in network structures controlling anxiety and threat perception, fast oscillations (10-45 Hz) were measured in ex vivo slice preparations of the anterior cingulate cortex (ACC). GAD65-/- mice of both sexes displayed increased gamma power in the ACC and a higher density of PV-positive interneurons, which are crucial for generating such rhythmic activity. In addition, GAD65-/- mice had lower numbers of somatostatin-positive interneurons in the basolateral amygdala and in the dorsal dentate gyrus especially in male mice, two key regions important for anxiety and active avoidance responses. Our data suggest sex differences in the configuration of GABAergic interneurons in a cortico-amygdala-hippocampal network controlling network activity patterns, anxiety and threat avoidance behavior.
焦虑障碍与包括额皮质区域、杏仁核和海马体在内的脑结构网络中的兴奋和抑制失衡有关。最近的影像学研究表明，在处理情绪信息时，这个焦虑网络的激活存在性别差异。具有改变的 γ-氨基丁酸（GABA）神经传递的遗传改变的啮齿动物模型允许研究这种激活转变的神经元基础及其与焦虑表型的关系，但迄今为止，很少有研究涉及性别效应。使用谷氨酸脱羧酶 65（GAD65-/-）缺乏的 GABA 合成酶的基因敲除小鼠，我们开始比较雄性和雌性 GAD65-/- 小鼠及其野生型同窝仔鼠的焦虑样行为和回避。在开阔场中，雌性 GAD65-/- 小鼠表现出增加的活动，而雄性 GAD65-/- 小鼠表现出随着时间的推移焦虑样行为的适应性增加。两种性别的 GAD65-/- 小鼠对社交互动伙伴的偏好更高，而雄性小鼠的这种偏好更高。在主动回避任务中，雄性小鼠观察到更高的逃避反应。总的来说，尽管缺乏 GAD65，雌性小鼠表现出更稳定的情绪反应。为了深入了解控制焦虑和威胁感知的网络结构中的中间神经元功能，我们在额前扣带皮层（ACC）的离体切片中测量了快速振荡（10-45 Hz）。两种性别的 GAD65-/- 小鼠在 ACC 中显示出更高的伽马功率和更高密度的 PV 阳性中间神经元，这对于产生这种节律性活动至关重要。此外，GAD65-/- 小鼠的基底外侧杏仁核和背齿状回中的生长抑素阳性中间神经元数量较少，特别是在雄性小鼠中，这两个区域对于焦虑和主动回避反应很重要。我们的数据表明，在控制网络活动模式、焦虑和威胁回避行为的皮质-杏仁核-海马网络中，GABA 能中间神经元的配置存在性别差异。
