Vascular disease plays an important role in all kinds of cognitive impairment and dementia. Diabetes increases the risk of vascular disease and dementia. However, it is not clear how existing vascular disease in the brain accelerates the development of small vessel disease and promotes cognitive dysfunction in diabetes. We used microemboli (ME) injection model in the current study to test the hypothesis that cerebrovascular dysfunction in diabetes facilitates entrapment of ME leading to inflammation and cognitive decline. We investigated cognitive function, axonal/white matter (WM) changes, neurovascular coupling, and microglial activation in control and diabetic male and female Wistar rats subjected to sham or low/high dose ME injection. Diabetic male animals had cognitive deficits, WM demyelination and greater microglial activation than the control animals even at baseline. Functional hyperemia gradually declined in diabetic male animals after ME injection. Both low and high ME injection worsened WM damage and increased microglial activation in diabetic male and female animals. Low ME did not cause cognitive decline in controls, while promoting learning/memory deficits in diabetic female rats and no further decline in diabetic male animals. High ME led to cognitive decline in control male rats and exacerbated the deficits in diabetic cohort. These results suggest that the existing cerebrovascular dysfunction in diabetes may facilitate ME-mediated demyelination leading to cognitive decline. It is important to integrate comorbidities/sex as a biological variable into experimental models for the development of preventive or therapeutic targets.

血管疾病在各种认知障碍和痴呆中起着重要作用。糖尿病会增加血管疾病和痴呆的风险。然而，目前尚不清楚大脑中现有的血管疾病如何加速小血管疾病的发展并促进糖尿病患者的认知功能障碍。我们在当前的研究中使用微栓子 (ME) 注射模型来检验糖尿病脑血管功能障碍促进 ME 被困导致炎症和认知能力下降的假设。我们研究了接受假手术或低/高剂量 ME 注射的对照和糖尿病雄性和雌性 Wistar 大鼠的认知功能、轴突/白质 (WM) 变化、神经血管耦合和小胶质细胞激活。糖尿病雄性动物有认知缺陷，WM 脱髓鞘和比对照动物更大的小胶质细胞活化，即使在基线时也是如此。注射 ME 后，糖尿病雄性动物的功能性充血逐渐减少。在糖尿病雄性和雌性动物中，低和高 ME 注射均能造成 WM 损伤并增加小胶质细胞活化。低 ME 不会导致对照组的认知能力下降，同时会促进糖尿病雌性大鼠的学习/记忆缺陷，并且不会导致糖尿病雄性动物的进一步下降。高 ME 导致对照雄性大鼠的认知能力下降，并加剧了糖尿病队列的缺陷。这些结果表明，糖尿病中现有的脑血管功能障碍可能会促进 ME 介导的脱髓鞘，导致认知能力下降。