Towner Trevor T, Applegate Devon T, Varlinskaya Elena I, Werner David F
Neurobiology of Adolescent Drinking in Adulthood Consortium, Center for Development and Behavioral Neuroscience, Department of Psychology, Binghamton University, Binghamton, NY, United States.
Front Pharmacol. 2022 Mar 23;13:841657. doi: 10.3389/fphar.2022.841657. eCollection 2022.
Adolescence is a sensitive developmental period during which alcohol use is often initiated and consumed in high quantities, often at binge or even high-intensity drinking levels. Our lab has repeatedly found that adolescent intermittent ethanol (AIE) exposure in rats results in long-lasting social impairments, specifically in males, however our knowledge of the neuronal underpinnings to this sex-specific effect of AIE is limited. The present study was designed to test whether social anxiety-like alterations in AIE-exposed males would be accompanied by alterations of neuronal activation across brain regions associated with social behavior, with AIE females demonstrating no social impairments and alterations in neuronal activation. Adolescent male and female cFos-LacZ transgenic rats on a Sprague-Dawley background were exposed to ethanol (4 g/kg, 25% v/v) or water intragastric gavage every other day during postnatal days (P) 25-45 for a total of 11 exposures ( = 13 per group). Social behavior of adult rats was assessed on P70 using a modified social interaction test, and neuronal activation in brain regions implicated in social responding was assessed β-galactosidase (β-gal) expression. We found that AIE exposure in males resulted in a significantly lower social preference coefficient relative to water-exposed controls, with no effect evident in females. Exposure-specific relationships between social behavior and neuronal activation were identified, with AIE eliminating correlations found in water controls related to social interaction, and eliciting negative correlations mainly in limbic regions in a sex-specific manner. AIE exposure in the absence of social testing was also found to differentially affect neural activity in the orbitofrontal cortex and central amygdala in males and females. These data suggest that AIE produces sex-specific social impairments that are potentially driven by differential neuronal activation states in regions important for social behavior, including the medial prefrontal and orbitofrontal cortices, nucleus accumbens, lateral septum, and central amygdala. Future studies should be focused on identification of specific neuronal phenotypes activated by interaction with a social partner in AIE-exposed subjects and their control counterparts.
青春期是一个敏感的发育阶段，在此期间，饮酒行为往往开始出现且饮酒量很大，常常达到暴饮甚至高强度饮酒的水平。我们实验室多次发现，大鼠青春期间歇性乙醇（AIE）暴露会导致长期的社交障碍，尤其是在雄性大鼠中，然而，我们对AIE这种性别特异性效应的神经学基础的了解有限。本研究旨在测试AIE暴露雄性大鼠的社交焦虑样改变是否会伴随着与社交行为相关的脑区神经元激活的改变，而AIE暴露的雌性大鼠未表现出社交障碍和神经元激活的改变。在出生后第25至45天，对斯普拉格-道利背景的青春期雄性和雌性cFos-LacZ转基因大鼠每隔一天进行乙醇（4 g/kg，25% v/v）或水的灌胃，共进行11次暴露（每组 = 13只）。在出生后第70天，使用改良的社交互动测试评估成年大鼠的社交行为，并通过β-半乳糖苷酶（β-gal）表达评估参与社交反应的脑区的神经元激活情况。我们发现，与水暴露对照组相比，AIE暴露的雄性大鼠的社交偏好系数显著降低，而雌性大鼠未出现明显影响。确定了社交行为与神经元激活之间的暴露特异性关系，AIE消除了水对照组中与社交互动相关的相关性，并主要以性别特异性方式在边缘区域引发负相关。还发现，在没有社交测试的情况下，AIE暴露对雄性和雌性大鼠眶额皮质和中央杏仁核的神经活动有不同影响。这些数据表明，AIE会产生性别特异性的社交障碍，这可能是由社交行为重要区域（包括内侧前额叶和眶额皮质、伏隔核、外侧隔核和中央杏仁核）中不同的神经元激活状态驱动的。未来的研究应集中于确定AIE暴露的实验对象及其对照对象中与社交伙伴互动激活的特定神经元表型。
