Cortical Aging, Estrogen and Behavior

描述（由申请人提供）：本提案的重点是衰老对内侧前额叶皮层和相关行为的影响，重点是雌性大鼠和雌激素和黄体酮在认知衰老中的作用。该提案探讨了内侧前额叶皮层是与衰老相关的认知能力下降以及雌激素和孕激素对这种下降的作用的重要部位之一的假设。这里将讨论三个问题。其中一个是关于内侧前额叶皮层在与年龄相关的认知能力下降中的作用。由于许多老年雄性认知行为任务（如水迷宫、桡臂迷宫）依赖于海马，因此对大鼠海马体的研究得到了相当大的重视。内侧前额叶皮层也参与这些任务，尽管有大脑皮层衰老的神经解剖学证据，但尚未得到广泛研究。第二个主题是雌性大鼠衰老的表征。直到最近，关于衰老的行为和神经影响的文献一直强调雄性大鼠。许多与认知相关的神经区域的性别差异已经被记录在案，这表明男性和女性进入衰老阶段时，神经系统的二态性可能会影响衰老过程本身。第三个问题涉及激素替代疗法的疗效，包括替代模式（慢性激素与循环激素）对神经和行为衰老的影响。去卵巢老龄大鼠可作为慢性和强直HRT治疗神经和行为衰老的模型。最近来自妇女健康倡议的结果使得这里提出的研究具有很大的临床意义。随着女性人口的老龄化，激素替代疗法已经变得非常普遍。了解雌激素和黄体酮对衰老过程的影响以及这些激素的影响如何被不同的替代方案所改变是至关重要的。临床重要性的另一个重要方面是卵巢类固醇对内侧前额叶皮层的作用，因为这个区域的人类类似物被认为与精神分裂症有关。在精神分裂症发病的年龄和严重程度上存在性别差异，并且随着更年期症状加重，这可能表明雌激素和黄体酮对该区域具有保护作用。最后，人类的核磁共振成像显示，随着年龄的增长，许多神经区域的体积发生了变化。探索这些变化的细胞基础在人类身上是不可行的，但衰老的大鼠可以作为人类衰老背后的细胞变化类型的模型。

DESCRIPTION (provided by applicant): This proposal is focused on the effects of aging in the medial prefrontal cortex and associated behavior, with an emphasis on female rats and the role of estrogen and progesterone in cognitive aging. The proposal explores the hypothesis that the medial prefrontal cortex is one of the important sites for the cognitive decline associated with aging and for the actions of estrogen and progesterone on that decline. There are three issues that will be addressed here. One concerns the role of the medial prefrontal cortex in age-related cognitive decline. There has been considerable emphasis on the hippocampus in the rat because many of the cognitive behavioral tasks that show deficits in aged males are hippocampal dependent (eg, water maze, radial arm maze). The medial prefrontal cortex also is engaged in these tasks and is not as extensively studied, although there is neuro-anatomical evidence of aging in the cerebral cortex. The second topic is the characterization of aging in female rats. The literature on behavioral and neural effects of aging has, until recently, emphasized male rats. The many sex differences that have been documented in neural areas associated with cognition indicate that males and females enter the aging life phase with dimorphic nervous systems that may affect the aging process itself. The third issue concerns the efficacy of hormone replacement therapy including the mode of replacement (chronic vs cyclic hormones) on neural and behavioral aging. Ovariectomized, aged rats can provide a model for both chronic and tonic HRT on neural and behavioral aging. The recent results from the Women's Health Initiative make the studies proposed here of great clinical relevance. Hormone replacement therapy has become very common as the female population ages. It is essential to understand the effects of estrogen and progesterone on the aging process and how the effects of these hormones may be altered by different regimens of replacement. Another important aspect of clinical importance is the actions of ovarian steroids on the medial prefrontal cortex because the human analogue of this region is thought to be involved in schizophrenia. There are sex differences in the age and severity of onset of schizophrenia, and symptoms become exacerbated with menopause, which may indicate a protective role of estrogen and possibly progesterone for this region. Lastly, MRI in humans indicates changes in the volume of may neural areas with age. Exploring the cellular basis for these changes is not feasible in humans, but the aging rat can serve as a model for the types of cellular changes that underlie human aging.