Stansbury, S. M. | Search bioRxiv

bioRxiv2025

Effects of Global Ripk2 Genetic Deficiency in Aged Mice following Experimental Ischemic Stroke

Besides the loss of blood and oxygen reaching the ischemic tissue, many secondary effects of ischemic stroke can cause additional tissue death, including inflammation, oxidative stress, and proteomic disturbances. Receptor-interacting serine/threonine kinase 2 (RIPK2) is an important mediator in the post-stroke inflammatory cascade that responds to signals and molecular patterns released by dead or dying cells in the ischemic area. We hypothesize that RIPK2 signaling worsens injury and neurological recovery post-stroke and that global deletion of Ripk2 will be protective following ischemic stroke in aged mice. Aged (18-24 months) male mice were subjected to permanent middle cerebral artery occlusion (pMCAO). Vertical grid, weight grip, and open field were conducted at baseline and on days 1, 2, 3, 8, 15, and 22 post-stroke. Cognitive tests (novel object recognition and Y-maze) were performed at baseline and day 28 post-stroke. Infarct size was measured using cresyl violet staining, and reactive gliosis was measured using Iba1 and GFAP staining at day 28 post-stroke. Global deletion of Ripk2 (Ripk2-/-) in aged mice resulted in smaller infarct volume and improved performance on vertical grid and weight grip tests compared to aged wildtype (WT) mice. Additionally, aged Ripk2-/- mice had less Iba1 staining in the ipsilateral cortex than the aged WT control mice. This study further elucidates the role of RIPK2 signaling in the ischemic cascade and expands our knowledge of RIPK2 in stroke to aged mice. These results support the hypothesis that RIPK2 signaling worsens injury post-stroke and may be an attractive candidate for therapeutic intervention.

neuroscience↗

bioRxiv2023

Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward

Neuronal primary cilia are being recognized for their role in mediating signaling associated with a variety of neurobehaviors, including responses to drugs of abuse. Primary cilia are microtubule-based organelles that project from the surface of nearly all mammalian cells, including neurons. They function as signaling hubs and are enriched with a diverse array of GPCRs, including several known to be associated with motivation and drug-related behaviors; however, our understanding of how cilia regulate neuronal function and behavior is still limited. The objective of the current study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to cocaine. To test the consequences of cilia loss on cocaine-induced locomotion and reward-related behavior, we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in male and female mice. Cilia ablation on either population of neurons failed to significantly alter acute locomotor responses to cocaine at a range of doses. With repeated administration, mice lacking cilia on GAD2-GABAergic neurons exhibited greater locomotor sensitization to cocaine compared to wild-type littermates, whereas mice lacking cilia on dopaminergic neurons exhibited reduced locomotor sensitization to cocaine at 10 & 30mg/kg. Mice lacking cilia on GAD2-GABAergic neurons showed no difference in cocaine conditioned place preference (CPP), whereas mice lacking cilia on dopaminergic neurons exhibited reduced CPP compared to wild-type littermates. Combined with previous findings using amphetamine, our results show that behavioral effects of cilia ablation are cell-and drug type-specific, and that neuronal cilia contribute to modulation of both the locomotor-inducing and rewarding properties of cocaine.

neuroscience↗