Biltz Rebecca G, Yin Wenyuan, Goodman Ethan J, Wangler Lynde M, Davis Amara C, Oliver Braedan T, Godbout Jonathan P, Sheridan John F
Department of Neuroscience, The Ohio State University Wexner Medical Center, USA.
Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, USA.
Brain Behav Immun Health. 2024 Nov 29;43:100908. doi: 10.1016/j.bbih.2024.100908. eCollection 2025 Feb.
Chronic stress increases the incidence of psychiatric disorders including anxiety, depression, and posttraumatic stress disorder. Repeated Social Defeat (RSD) in mice recapitulates several key physiological, immune, and behavioral changes evident after chronic stress in humans. For instance, neurons in the prefrontal cortex, amygdala, and hippocampus are involved in the interpretation of and response to fear and threatful stimuli after RSD. Therefore, the purpose of this study was to determine how stress influenced the RNA profile of hippocampal neurons and neurons that project into the hippocampus from threat appraisal centers. Here, RSD increased anxiety-like behavior in the elevated plus maze and reduced hippocampal-dependent novel object location memory in male mice. Next, pan-neuronal (Baf53 b-Cre) RiboTag mice were generated to capture ribosomal bound mRNA (i.e., active translation) activated by RSD in the hippocampus. RNAseq revealed that there were 1694 differentially expressed genes (DEGs) in hippocampal neurons after RSD. These DEGs were associated with an increase in oxidative stress, synaptic long-term potentiation, and neuroinflammatory signaling. To further examine region-specific neural circuitry associated with fear and anxiety, a retrograde-adeno-associated-virus (AAV2rg) expressing Cre-recombinase was injected into the hippocampus of male RiboTag mice. This induced expression of a hemagglutinin epitope in neurons that project into the hippocampus. These AAV2rg-RiboTag mice were subjected to RSD and ribosomal-bound mRNA was collected from the amygdala for RNA-sequencing. RSD induced 677 DEGs from amygdala projections. Amygdala neurons that project into the hippocampus had RNA profiles associated with increased synaptogenesis, interleukin-1 signaling, nitric oxide, and reactive oxygen species production. Using a similar approach, there were 1132 DEGs in neurons that project from the prefrontal cortex. These prefrontal cortex neurons had RNA profiles associated with increased synaptogenesis, integrin signaling, and dopamine feedback signaling after RSD. Collectively, there were unique RNA profiles of stress-influenced projection neurons and these profiles were associated with hippocampal-dependent behavioral and cognitive deficits.
慢性应激会增加包括焦虑症、抑郁症和创伤后应激障碍在内的精神疾病的发病率。小鼠反复遭受社会挫败（RSD）会重现人类慢性应激后出现的一些关键生理、免疫和行为变化。例如，前额叶皮质、杏仁核和海马体中的神经元参与了RSD后对恐惧和威胁性刺激的解读与反应。因此，本研究的目的是确定应激如何影响海马神经元以及从威胁评估中心投射到海马体的神经元的RNA谱。在此，RSD增加了雄性小鼠在高架十字迷宫中的焦虑样行为，并降低了海马依赖性新物体定位记忆。接下来，构建了全神经元（Baf53 b-Cre）RiboTag小鼠，以捕获RSD在海马体中激活的核糖体结合mRNA（即活跃翻译）。RNA测序显示，RSD后海马神经元中有1694个差异表达基因（DEG）。这些DEG与氧化应激增加、突触长时程增强和神经炎症信号传导有关。为了进一步研究与恐惧和焦虑相关的区域特异性神经回路，将表达Cre重组酶的逆行腺相关病毒（AAV2rg）注入雄性RiboTag小鼠的海马体。这诱导了投射到海马体的神经元中血凝素表位的表达。对这些AAV2rg-RiboTag小鼠进行RSD处理，并从杏仁核收集核糖体结合mRNA进行RNA测序。RSD诱导杏仁核投射产生677个DEG。投射到海马体的杏仁核神经元的RNA谱与突触发生增加、白细胞介素-1信号传导、一氧化氮和活性氧产生有关。使用类似的方法，从前额叶皮质投射的神经元中有1132个DEG。这些前额叶皮质神经元在RSD后的RNA谱与突触发生增加、整合素信号传导和多巴胺反馈信号传导有关。总体而言，应激影响的投射神经元有独特的RNA谱，这些谱与海马依赖性行为和认知缺陷有关。
