Dataset for: Sex matters: Females in proestrus show greater diazepam anxiolysis and BDNF- and parvalbumin-positive neurons than males

In humans and animal models, sex differences are reported for anxiety-like behavior and response to anxiogenic stimuli. In the current work, we studied anxiety-like behavior and response to the prototypical anti-anxiety drug, diazepam. We used 6th generation outbred lines of adult Long Evans rats with high and low anxiety-like behavior phenotypes to investigate the impact of proestrus on the baseline and diazepam-induced behavior. At three doses of diazepam (0, 0.1 and 1.0 mg/kg, i.p.), we measured anxiogenic responses on the elevated plus maze of adult male and female rats. We assessed parvalbumin and brain-derived neurotrophin protein levels in forebrain and limbic structures implicated in anxiety/stress using immunohistochemistry. At baseline, we saw significant differences between anxiety lines, with high anxiety lines displaying less time on the open arms of the elevated plus maze, and less open arm entries, regardless of sex. During proestrus, high anxiety females showed less anxiety-like behavior at 0.1 mg/kg while low anxiety females displayed less anxiety-like behavior at 0.1 and 1.0 doses, relative to males. Brain-derived neurotrophin protein was elevated in females in the medial prefrontal cortex and central amygdala while parvalbumin-immunoreactive cells were greater in males in the medial prefrontal cortex. Parvalbumin-positive cells in high anxiety females were higher in CA2 and dentate gyrus relative to males from the same line. In sum, when tested in proestrus, females showed greater anxiolytic effects of diazepam relative to males, and this correlated with increases in neurotrophin and parvalbumin neuron density in corticolimbic structures.

在人类及动物模型中，已有研究报道焦虑样行为及致焦虑刺激应答存在性别差异。本研究针对焦虑样行为与典型抗焦虑药物地西泮（diazepam）的应答效应展开探究，选用具有高、低焦虑样行为表型的成年Long Evans大鼠（Long Evans rats）第六代远交系群体，探究动情前期对基线状态及地西泮诱导行为的影响。我们设置0、0.1及1.0 mg/kg三种腹腔注射剂量的地西泮，通过高架十字迷宫（elevated plus maze）检测成年雌雄大鼠的致焦虑应答水平，并采用免疫组织化学法，检测了与焦虑/应激相关的前脑及边缘脑区中小白蛋白（parvalbumin）与脑源性神经营养因子（brain-derived neurotrophin）的蛋白表达水平。基线状态下，无论性别如何，不同焦虑表型大鼠间均存在显著差异：高焦虑表型大鼠在高架十字迷宫开放臂停留时间更短、开放臂进入次数更少。在动情前期，相较于同剂量下的雄性大鼠，高焦虑表型雌性大鼠在0.1 mg/kg剂量下表现出更弱的焦虑样行为，而低焦虑表型雌性大鼠在0.1及1.0 mg/kg剂量下均表现出更弱的焦虑样行为。雌性大鼠内侧前额叶皮层与中央杏仁核内的脑源性神经营养因子蛋白表达水平升高，而雄性大鼠内侧前额叶皮层内的小白蛋白免疫阳性细胞数量更多；相较于同表型的雄性大鼠，高焦虑表型雌性大鼠的海马CA2区与齿状回内的小白蛋白阳性细胞数量更多。综上，在动情前期进行检测时，相较于雄性大鼠，雌性大鼠对地西泮的抗焦虑应答效果更显著，这与皮层边缘结构内神经营养因子与小白蛋白阳性神经元密度的升高呈正相关。