Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
Department of Psychology, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
Biol Sex Differ. 2022 Jul 23;13(1):42. doi: 10.1186/s13293-022-00450-2.
Females are more likely to present with anxiety disorders such as post-traumatic stress disorder (PTSD) compared to males, which are associated with disrupted hippocampal integrity. Sex differences in the structure and function of hippocampus exist. Here, we examined sex differences in contextual pattern separation, functional connectivity, and activation of new neurons during fear memory.
Two-month-old male and female Sprague-Dawley rats were injected with the DNA synthesis markers, iododeoxyuridine (IdU) and chlorodeoxyuridine (CldU) 3 weeks and 4 weeks before perfusion, respectively. One week after CldU injection, the rats underwent a context discrimination task in which rats were placed in context A (shock) and context A' (no shock) every day for 12 days. On the test day, rats were placed in the shock context (context A) to measure fear memory and expression of zif268, an immediate early gene across 16 different limbic and reward regions. Repeated-measures or factorial analysis of variance was conducted on our variables of interest. Pearson product-moment calculations and principal component analyses on zif268 expression across regions were also performed.
We found that females, but not males, showed contextual discrimination during the last days of training. On the test day, both sexes displayed similar levels of freezing, indicating equivalent fear memory for context A. Despite similar fear memory, males showed more positive correlations of zif268 activation between the limbic regions and the striatum, whereas females showed more negative correlations among these regions. Females showed greater activation of the frontal cortex, dorsal CA1, and 3-week-old adult-born dentate granular cells compared to males.
These results highlight the importance of studying sex differences in fear memory and the contribution of adult neurogenesis to the neuronal network and may contribute to differences in susceptibility to fear-related disorders such as post-traumatic stress disorder. Highlights Female rats, but not male rats, show faster discrimination during a contextual pattern separation task. Three-week-old adult-born neurons are more active in response to fear memory in females compared to males. Females had greater neural activation compared to males in the frontal cortex and dorsal CA1 region of the hippocampus in response to fear memory. Males and females show distinct patterns in functional connectivity for fear memory across limbic regions. Males have many positive correlations between activated new neurons of different ages between the dorsal and ventral hippocampus, while females show more correlations between activated new neurons and other limbic regions.
与男性相比，女性更有可能出现创伤后应激障碍（PTSD）等焦虑症，这与海马体完整性受损有关。海马体在结构和功能上存在性别差异。在这里，我们研究了在恐惧记忆过程中，情景模式分离、功能连接和新神经元激活方面的性别差异。
两个月大的雄性和雌性 Sprague-Dawley 大鼠分别在灌注前 3 周和 4 周注射 DNA 合成标记物碘脱氧尿苷（IdU）和氯脱氧尿苷（CldU）。在 CldU 注射后一周，大鼠进行了情景辨别任务，每天将大鼠置于情景 A（电击）和情景 A'（无电击）中 12 天。在测试日，将大鼠置于受电击的情景（情景 A）中，以测量恐惧记忆和 zif268 的表达，zif268 是一种在 16 个不同的边缘和奖励区域中表达的即刻早期基因。对我们感兴趣的变量进行重复测量或方差分析。还对 zif268 在不同区域的表达进行了皮尔逊积矩计算和主成分分析。
我们发现，只有雌性大鼠，而不是雄性大鼠，在训练的最后几天表现出情景辨别。在测试日，雌雄大鼠均表现出相似水平的冻结，表明对情景 A 的恐惧记忆相同。尽管恐惧记忆相似，但雄性大鼠显示出边缘区域与纹状体之间的 zif268 激活的相关性更强，而雌性大鼠则显示出这些区域之间的相关性更差。与雄性大鼠相比，雌性大鼠的前额皮质、背侧 CA1 和 3 周龄新生颗粒细胞表现出更高的激活。
这些结果强调了研究恐惧记忆中性别差异以及成年神经发生对神经元网络的贡献的重要性，这可能导致对创伤后应激障碍等与恐惧相关的疾病的易感性存在差异。
