Sex Differences in Cognitive Impairment Induced by Cerebral Microhemorrhage

Abstract

It has been suggested that cerebral microhemorrhages (CMHs) could be involved in cognitive decline. However, little is known about the sex-dependency of this effect. Using a multimodal approach combining behavioral tests, in vivo imaging, biochemistry, and molecular biology, we studied the cortical and hippocampal impact of a CMH in male and female mice (C57BL/6J) 6 weeks post-induction using a collagenase-induced model. Our work shows for the first time that a single cortical CMH exerts sex-specific effects on cognition. It notably induced visuospatial memory impairment in males only. This sex difference might be explained by cortical changes secondary to the lesion. In fact, the CMH induced an upregulation of ERα mRNA only in the female cortex. Besides, in male mice, we observed an impairment of pathways associated to neuronal, glial, or vascular functions: decrease in the P-GSK3β/GSK3β ratio, in BDNF and VEGF levels, and in microvascular water mobility. The CMH also exerted spatial remote effects in the hippocampus by increasing the number of astrocytes in both sexes, increasing the mean area occupied by each astrocyte in males, and decreasing hippocampal BDNF in females suggesting a cortical-hippocampal network impairment. This work demonstrates that a CMH could directly affect cognition in a sex-specific manner and highlights the need to study both sexes in preclinical models.

Keywords: Cerebral microhemorrhage; Cognitive impairment; Estrogen receptors; Neuronal network; Preclinical model; Sex effect.