Hormonal Regulation of Sex Differences in Stress Effects in Prefrontal Cortex

描述（由申请人提供）：压力会破坏认知和情绪行为，并可能引发或加剧许多心理障碍。性是影响许多压力相关疾病的重要变量。因此，了解这种性别差异的基础是制定适当干预压力相关疾病的重要目标。应激对海马、杏仁核和前额皮质等皮质边缘结构的形态有深远的影响。越来越多的研究表明，性别差异在许多行为、神经化学和形态学上对压力的反应。我们最近的研究表明，慢性应激使雄性大鼠前额叶内侧皮层锥体神经元顶端树突分支的数量和长度减少，而雌性大鼠则相反，使顶端树突长度增加。我们进一步证明雌二醇介导了这种应激诱导的雌性树突肥大：植入雌二醇的假手术和去卵巢的雌性都表现出应激诱导的顶端树突物质增加，而不替换雌二醇的卵巢切除术则可以防止应激诱导的树突物质增加。有趣的是，虽然没有雌二醇替代的卵巢切除术可以防止应激性肥大，但它并没有产生男性应激效应。这表明性腺激素可能允许应力诱导的结构可塑性，但通过不同的激素或不同的激素机制在男性和女性中产生不同的作用。为了更充分地表征应激对mPFC影响的潜在性别差异，我们将评估应激和非应激雄性大鼠与雌性大鼠在执行情绪调节任务时边缘下皮层的单位活动和边缘下皮层锥体细胞的树突形态。为了确定性腺激素是否允许慢性应激对雄性边缘下皮层神经元结构和功能的影响，我们将评估在情绪调节任务中表现的前额叶皮层的单位活动和边缘下皮层锥体细胞的树突形态，在阉割和植入无激素、睾酮、二氢睾酮或雌二醇的应激和非应激大鼠中。为了确定雄激素管理是否会对雌性边缘下皮层神经元的形态和生理产生雄性模式的慢性应激影响，我们将评估在情绪调节任务中表现的前额叶皮层的单位活动和雌性边缘下皮层锥体细胞的树突形态，这些大鼠分别接受了卵巢切除术和无激素、睾酮、二氢睾酮或雌二醇的植入。所提出的研究结果将有助于我们理解前额叶压力效应中性别差异的机制。

DESCRIPTION (provided by applicant): Stress can disrupt cognitive and emotional behavior and can precipitate or exacerbate many psychological disorders. Sex is an important variable influencing many stress-related disorders. Thus, understanding the basis of this sex difference is an important goal in developing appropriate interventions for stress-related disorders. Stress has profound effects on the morphology of corticolimbic structures including the hippocampus, amygdala, and prefrontal cortex. A growing body of work has documented sex differences in many behavioral, neurochemical, and morphological responses to stress. We have recently shown that chronic stress decreases the number and length of apical dendritic branches of pyramidal neurons in medial prefrontal cortex of male rats, but has the opposite effect in females, increasing apical dendritic length. We have further demonstrated that estradiol mediates this stress-induced dendritic hypertrophy in females: Both sham-operated and ovariectomized females with estradiol implants show stress-induced increases in apical dendritic material, whereas ovariectomy without estradiol replacement prevents the stress-induced increase. Interestingly, while ovariectomy without estradiol replacement prevented the stress-induced hypertrophy, it did not produce the male pattern of stress effects. This suggests that gonadal hormones may be permissive of stress-induced structural plasticity, but produce different effects in males and females, through either different hormones or different hormonal mechanisms. To more fully characterize potential sex differences in stress effects in mPFC, we will assess unit activity in the infralimbic cortex during performance on an emotion regulation task and dendritic morphology of pyramidal cells in the infralimbic cortex in stressed and unstressed male versus female rats. To determine whether gonadal hormones are permissive of the effects of chronic stress on structure and function of neurons in infralimbic cortex of males, we will assess unit activity in prefrontal cortex during performance on an emotion regulation task and dendritic morphology of pyramidal cells in infralimbic cortex in stressed and unstressed rats that have undergone castration and implantation of either no hormone, testosterone, dihydrotestosterone, or estradiol. To determine whether androgen administration can produce a male pattern of chronic stress effects on morphology and physiology of neurons in infralimbic cortex of females, we will assess unit activity in prefrontal cortex during performance on an emotion regulation task and dendritic morphology of pyramidal cells in infralimbic cortex in female stressed and unstressed rats that have undergone ovariectomy and implantation of either no hormone, testosterone, dihydrotestosterone, or estradiol. Results of the proposed studies will contribute to our understanding of the mechanisms underlying the sex difference seen in prefrontal stress effects. PUBLIC HEALTH RELEVANCE: This research will contribute to our understanding of the neurobiological mechanisms underlying sex differences in the influence of stress on emotional processing and negatively motivated behaviors. It will also aid in our understanding of how stress differentially influences mental illnesses such as posttraumatic stress disorder, depression, or schizophrenia in men and women.