Hoffman Ann N, Watson Sonya L, Makridis Anna S, Patel Anisha Y, Gonzalez Sarah T, Ferguson Lindsay, Giza Christopher C, Fanselow Michael S
Neurosurgery, Brain Injury Research Center, University of California, Los Angeles, Los Angeles, CA, United States.
Psychology, University of California, Los Angeles, Los Angeles, CA, United States.
Front Neurol. 2020 Nov 25;11:553190. doi: 10.3389/fneur.2020.553190. eCollection 2020.
Traumatic brain injury (TBI) is associated with high rates of post-injury psychiatric and neurological comorbidities. TBI is more common in males than females despite females reporting more symptoms and longer recovery following TBI and concussion. Both pain and mental health conditions like anxiety and post-traumatic stress disorder (PTSD) are more common in women in the general population, however the dimorphic comorbidity in the TBI population is not well-understood. TBI may predispose the development of maladaptive anxiety or PTSD following a traumatic stressor, and the impact of sex on this interaction has not been investigated. We have shown that white noise is noxious to male rats following fluid percussion injury (FPI) and increases fear learning when used in auditory fear conditioning, but it is unclear whether females exhibit a similar phenotype. Adult female and male rats received either lateral FPI or sham surgery and 48 h later received behavioral training. We first investigated sex differences in response to 75 dB white noise followed by white noise-signaled fear conditioning. FPI groups exhibited defensive behavior to the white noise, which was significantly more robust in females, suggesting FPI increased auditory sensitivity. In another experiment, we asked how FPI affects contextual fear learning in females and males following unsignaled footshocks of either strong (0.9 mA) or weaker (0.5 mA) intensity. We saw that FPI led to rapid acquisition of contextual fear compared to sham. A consistent pattern of increased contextual fear after TBI was apparent in both sexes across experiments under differing conditioning protocols. Using a light gradient open field task we found that FPI females showed a defensive photophobia response to light, a novel finding supporting TBI enhanced sensory sensitivity across modalities in females. General behavioral differences among our measures were observed between sexes and discussed with respect to interpretations of TBI effects for each sex. Together our data support enhanced fear following a traumatic stressor after TBI in both sexes, where females show greater sensitivity to sensory stimuli across multiple modalities. These data demonstrate sex differences in emergent defensive phenotypes following TBI that may contribute to comorbid PTSD, anxiety, and other neurological comorbidities.
创伤性脑损伤（TBI）与伤后较高的精神和神经共病发生率相关。尽管女性在TBI和脑震荡后报告的症状更多、恢复时间更长，但TBI在男性中比女性更常见。在普通人群中，疼痛以及焦虑和创伤后应激障碍（PTSD）等心理健康状况在女性中更为常见，然而，TBI人群中的这种二态共病现象尚未得到充分理解。TBI可能会使个体在遭受创伤性应激源后更容易出现适应不良的焦虑或PTSD，而性别对这种相互作用的影响尚未得到研究。我们已经表明，白噪声对液体冲击伤（FPI）后的雄性大鼠有害，并且在听觉恐惧条件反射中使用时会增加恐惧学习，但尚不清楚雌性大鼠是否表现出类似的表型。成年雌性和雄性大鼠接受了侧方FPI或假手术，48小时后接受行为训练。我们首先研究了对75分贝白噪声的反应以及随后白噪声信号恐惧条件反射中的性别差异。FPI组对白噪声表现出防御行为，雌性大鼠的这种行为明显更强烈，这表明FPI增加了听觉敏感性。在另一项实验中，我们研究了FPI如何影响雌性和雄性大鼠在未发出信号的不同强度（强0.9毫安或弱0.5毫安）足底电击后的情境恐惧学习。我们发现，与假手术组相比，FPI组导致情境恐惧的快速习得。在不同的条件反射方案下，TBI后情境恐惧增加的一致模式在两个性别中均很明显。使用光梯度旷场任务，我们发现FPI雌性大鼠对光表现出防御性畏光反应，这一新颖发现支持TBI增强了雌性大鼠跨多种感觉模态的感觉敏感性。我们观察到不同性别在各项测量指标上存在一般行为差异，并针对每种性别的TBI效应解释进行了讨论。我们的数据共同支持了TBI后两性在遭受创伤性应激源后恐惧增强，其中雌性对多种感觉刺激表现出更高的敏感性。这些数据证明了TBI后出现的防御性表型存在性别差异，这可能导致共病的PTSD、焦虑和其他神经共病。
