Chronic Glucocorticoid Effects in Prefrontal Cortex

描述(申请人提供)：慢性压力会导致认知障碍，并伴随神经化学和形态的改变。例如，应激和长期使用皮质酮都会导致海马神经元树突萎缩。前额叶皮质也是糖皮质激素的靶点，参与应激反应，表现出对应激反应的神经化学变化，并在经历应激诱导的改变的许多认知过程中发挥作用。因此，前额叶皮质的变化可能介导了一些应激和糖皮质激素诱导的认知障碍。为了确定糖皮质激素诱导的形态变化是否也发生在内侧前额叶皮质，我评估了长期给予皮质酮对该皮质边缘结构中树突形态的影响。在此之前，我证明了长期给予皮质酮导致大鼠前额叶内侧皮质II-III层锥体神经元顶端树突的显著重新分布：与对照组相比，胞体近端的树突状物质增加，而远端的树突状物质减少。这里提出的实验将为开始评估这种树突重组的功能意义和机制奠定必要的基础。为了确定改变内侧前额叶皮质锥体神经元结构所需的慢性轻度应激的最小持续时间，我将评估不同持续时间的慢性束缚应激对内侧前额叶皮质第II-III层锥体神经元树突分枝的影响。为了确定应激诱导的前额叶皮质变化是否由皮质酮介导，我将评估皮质酮阻滞剂的应用是否能阻止应激诱导的内侧前额叶皮质II-III层锥体神经元树突形态的变化。最后，为了确定压力是否会改变前额叶调节的行为，我将评估慢性束缚应激对消除恐惧条件反射的影响。

DESCRIPTION (provided by applicant): Chronic stress produces deficits in cognition accompanied by alterations in neural chemistry and morphology. For example, both stress and chronic administration of corticosterone produce dendritic atrophy in hippocampal neurons. Prefrontal cortex is also a target for glucocorticoids involved in the stress response shows neurochemical changes in response to stress and plays a role in many of the cognitive processes that undergo stress-induced alterations. Thus, changes in prefrontal cortex may mediate some stress- and glucocorticoid-induced cognitive deficits. To determine if glucocorticoid-induced morphological changes also occur in medial prefrontal cortex, I assessed the effects of chronic corticosterone administration on dendritic morphology in this corticolimbic structure. Previously, I demonstrated that chronic corticosterone administration resulted in a significant redistribution of apical dendrites of lamina II-III pyramidal neurons in medial prefrontal cortex of rats: amount of dendritic material proximal to the soma was increased, while distal dendritic material was decreased relative to controls. The experiments proposed here will lay the groundwork necessary to begin to assess the functional significance and mechanisms of this dendritic reorganization. To determine the minimum duration of chronic mild stress necessary to alter the structure of pyramidal neurons in medial prefrontal cortex, I will assess the effects of varying durations of chronic restraint stress on dendritic arborization of layer II-III pyramidal neurons in medial prefrontal cortex. To determine whether stress-induced changes in prefrontal cortex are mediated by corticosterone, I will assess whether administration of a corticosterone blocker prevents stress-induced changes in dendritic morphology of layer II-III pyramidal neurons in medial prefrontal cortex. Finally, to determine whether stress alters a prefrontally mediated behavior, I will assess the effect of chronic restraint stress on extinction of fear conditioning