NEURONAL REORGANIZATION IN ADULT HYPERTENSIVE RATS

鉴于许多关于阿尔茨海默病发病机制的研究 重点研究了发生在大脑边缘皮质的神经元丢失 病人，剩余神经元连接的重组 可能在这些患者的功能缺陷中起重要作用。 我们之前的研究表明，在老龄大鼠(超过24个月龄)中， 脾后颗粒皮质中的神经元改变其正常的、成熟的 构建和重塑它们的突触连接，可能是为了响应 突触活动减少。具体地说，A的顶端树枝状物 第二层神经元从第一层的外半部撤出，它们所在的位置 通常由丘脑前腹核的轴突支配。 这些树枝状晶随后在这一层(AN)的更深的一半内树枝状生长 丘脑前腹缺少丘脑神经支配的区域 细胞核和第II层细胞顶端树突的区域 通常不树枝)。此外，在老年大鼠中，顶端树突 第三层神经元延伸到第一层的外半部(它们 通常不占据)，并且看起来收缩丘脑的终末 这一区域的轴突。因此，在大脑皮层的这一区域，两边的神经元 第II层和第III层参与了老年大鼠的动态重组。 随后的研究表明，这些变化发生在 自发性高血压大鼠(SHR)，但年龄更早(12岁 几个月)；老鼠处于相对健康的年龄，可以 在行为测试中可靠运行。脾后重建术 12月龄自发性高血压大鼠大脑皮质明显减少 在学习和记忆方面。此外，最近的研究结果表明，年龄- 成熟期(12月龄)结构和功能的相关可塑性 甚至老年人(24个月以上)的自发性高血压病也会受到预防和/或 因慢性抗高血压治疗而显著延迟 血管紧张素转换酶抑制剂。因此，成熟的SHR提供了一种 模型，这将极大地促进对生物多样性的研究 活跃的边缘皮质神经元的结构和功能 重塑它们的结构和连接。第一个具体目标是 检验假设，局部乙酰胆碱释放减少 进入脾后皮质先于(并有助于)年龄相关的 大脑皮层神经元的重组。第二个具体目标是 测试大脑肾素-血管紧张素失衡的假设 系统改变脾后皮质的乙酰胆碱释放，从而 诱导树突和连接的结构重塑 成熟的自发性高血压。第三个具体目标将检验以下假设 替换脾后皮质的胆碱能神经将 延缓/阻止大鼠脾后皮质I层的重组 老化的粉碎机。第四个具体目标将检验这样一个假设： 丘脑前部至边缘的投射重组 皮质导致成熟自发性高血压大鼠的行为障碍。我们的将军 假设与年龄相关的脾后皮质重塑 成熟的自发性高血压是慢性突触减少的结果 激活第二层神经元的顶端树突，即使用 依赖可塑性。

Whereas many studies of the pathogenesis of Alzheimer's disease have focused on the neuronal losses that occur in the limbic cortex of these patients, the reorganization of the connections of the remaining neurons may play a significant role int he functional deficits of these patients. Our previous studies show that in aged rats (more than 24 months of age), neurons in the retrosplenial granular cortex alter their normal, mature structure and remodel their synaptic connections, likely in response to decreases in synaptic activity. Specifically,a the apical dendrites of layer II neurons withdraw from the outer half of layer I, where they are normally innervated by the axons of the anterior ventral thalamic nucleus. These dendrites subsequently arborize int he deeper half of this layer (an area that lacks thalamic innervation from the anterior ventral thalamic nucleus and an area in which t he apical dendrites of the layer II cells typically do not arborize). Further, in the aged rat, the apical dendrites of layer III neurons extend to the outer half of layer I (an area that they normally do not occupy) and appear to contract the terminals of thalamic axons in this region. Thus, in this area of the cortex the neurons in both layers II and III are engaged in dynamic reorganization in the aged rat. Subsequent studies have demonstrated that these changes occur in spontaneously hypertensive rats (SHR) but at a much earlier age (12 months); an age at which the rats are in relatively good health and can be run reliably in behavioral tests. The reorganization of the retrosplenial cortex ina the 12 month old SHR is correlated with a significant decrease in learning and memory. Further, recent findings demonstrate that the age- related plasticity of structure and function in the mature (12 months old) and even aged (more than 24 month old) SHR are prevented and/or significantly delayed by chronic antihypertensive therapy with an angiotensin converting enzyme inhibitor. Thus, the mature SHR offers an model that could significantly facilitate the study of the regulation of structure and function of limbic cortex neurons that are actively remodeling their structure and connections. The first specific aim will test the hypothesis that a local decrease in the release of acetylcholine into the retrosplenial cortex precedes (and contributes to) the age-related reorganization of neurons in this cortex. The second specific aim will test the hypothesis that an imbalance ina the brain renin-angiotensin system alters acetylcholine release in the retrosplenial cortex and thereby induces structural remodeling of the dendrites and connections in the mature SHR. The third specific aim will test the hypothesis that replacement of the cholinergic innervation of the retrosplenial cortex will delay/prevent the reorganization of layer I of the retrosplenial cortex in the aging shr. The fourth specific aim will test the hypothesis that the reorganization of the projection from the anterior thalamus to the limbic cortex leads to behavioral impairments int he mature SHR. Our general hypothesis is that the age-related remodeling of the retrosplenial cortex ina the mature SHR is the result of chronically decreased synaptic activation of the apical dendrites of the layer II neurons, i.e., use dependent plasticity.