Differential Effects of Murine Stroke Models on Dopaminergic Neurons, Glial Responses, and Neurobehavioral Outcomes

Abstract

Stroke is a leading cause of disability worldwide, often resulting in persistent motor, cognitive, and emotional impairments. While the hippocampus and amygdala play critical roles in post-stroke behavioral changes, specific neuronal alterations and prolonged glial responses within these regions across different stroke types remain unclear. This study investigates the behavioral, neuronal, and glial effects of subarachnoid hemorrhage (SAH), transient middle cerebral artery occlusion (tMCAO), and photothrombotic stimulation (PTS) in mice. SAH and tMCAO models exhibited significant motor deficits, spatial and recognition memory impairments, and increased anxiety- and depressive-like behaviors, whereas the PTS model showed similar motor and cognitive impairments but lacked affective (anxiety- and depressive-like) behavioral changes. Immunohistochemical analysis revealed increased overlap of tyrosine hydroxylase (TH, a dopaminergic marker) process with NeuN (a neuronal marker) in the dentate gyrus (DG) of SAH and tMCAO mice, highlighting region-specific vulnerability to ischemic damage in the hippocampus. In the amygdala, elevated overlap of TH+ process with NeuN in SAH and tMCAO mice suggests enhanced dopaminergic involvement in emotional dysregulation. In contrast, the PTS model did not exhibit any changes in overlap of TH+ process with NeuN in either the hippocampus or amygdala, consistent with the absence of affective behavioral deficits. Additionally, SAH and tMCAO models exhibited persistent astrocytic and microglial activation in the amygdala, characterized by increased intensity and density without significant morphological changes, indicative of a chronic inflammatory response. The PTS model also showed increased microglial intensity and density without overt morphological changes, suggesting a more moderate, possibly subclinical inflammatory response. These findings highlight the differential effects of stroke models on behavior, neuronal populations, and glial responses in limbic regions. The pronounced dopaminergic and glial alterations in SAH and tMCAO may underlie post-stroke emotional and cognitive disturbances.