Hormonal Regulation of Sex Differences in Stress Effects in Prefrontal Cortex

描述（由申请人提供）：压力会扰乱认知和情感行为，并可能引发或加剧许多心理障碍。性别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一个重要的目标，在制定适当的干预措施，与压力有关的疾病。压力对皮质边缘结构的形态学有深远的影响，包括海马体、杏仁核和前额皮质。越来越多的研究表明，在对压力的行为、神经化学和形态反应方面，性别存在差异。我们最近发现，慢性应激减少了雄性大鼠内侧前额叶皮层锥体神经元的顶端树突分支的数量和长度，但在雌性大鼠中具有相反的效果，增加了顶端树突长度。我们已经进一步证明，雌二醇介导这种压力诱导的树突状细胞肥大的女性：假手术和卵巢切除的女性雌二醇植入物显示压力诱导的增加顶端树突状材料，而卵巢切除术没有雌二醇替代防止压力诱导的增加。有趣的是，虽然没有雌二醇替代卵巢切除术防止了应激诱导的肥大，但它并没有产生男性模式的应激效应。这表明，性腺激素可能是允许的压力诱导的结构可塑性，但产生不同的影响，在男性和女性，通过不同的激素或不同的激素机制。为了更充分地表征潜在的性别差异，在mPFC的压力影响，我们将评估单位活动在边缘下皮层的情绪调节任务和树突状形态的锥体细胞在边缘下皮层在应激和非应激的雄性与雌性大鼠的表现。为了确定是否性腺激素是允许的慢性应激对男性边缘下皮层的神经元的结构和功能的影响，我们将评估单位活动在前额叶皮层的情绪调节任务和树突状形态的锥体细胞在边缘下皮层的应激和非应激大鼠进行了阉割和植入无激素，睾酮，双氢睾酮，或雌二醇的性能。为了确定雄激素给药是否能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效应，我们将评估雌性应激和非应激大鼠在执行情绪调节任务期间前额皮质的单位活动和边缘下皮层锥体细胞的树突形态，所述大鼠经历了卵巢切除术和植入无激素、睾酮、双氢睾酮或雌二醇。建议的研究结果将有助于我们了解的机制，性别差异的前额叶压力的影响。 公共卫生相关性：本研究将有助于我们理解压力对情绪加工和负性动机行为影响的性别差异的神经生物学机制。它还将有助于我们理解压力如何不同地影响精神疾病，如创伤后应激障碍，抑郁症或精神分裂症在男性和女性中。

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.