Here, we aimed to determine the capacity of human short-term memory for allocentric spatial information in a real-world setting. Young adults were tested on their ability to learn, on a trial-unique basis, and remember over a 1-min interval the location(s) of 1, 3, 5, or 7 illuminating pads, among 23 pads distributed in a 4 m  4 m arena surrounded by curtains on three sides. Participants had to walk to and touch the pads with their foot to illuminate the goal locations. In contrast to the predictions from classical slot models of working memory capacity limited to a fixed number of items, i.e., Miller's magical number 7 or Cowan's magical number 4, we found that the number of visited locations to find the goals was consistently about 1.6 times the number of goals, whereas the number of correct choices before erring and the number of errorless trials varied with memory load even when memory load was below the hypothetical memory capacity. In contrast to resource models of visual working memory, we found no evidence that memory resources were evenly distributed among unlimited numbers of items to be remembered. Instead, we found that memory E-mail address: pamela.bantalavenex@unil.ch (P. Banta Lavenex).for even one individual location was imprecise, and that memory performance for one location could be used to predict memory performance for multiple locations. Our findings are consistent with a theoretical model suggesting that the precision of the memory for individual locations might determine the capacity of human shortterm memory for spatial information.

Peroxisome proliferator-activated receptors (PPARs) control the expression of genes involved in glucose homeostasis, lipid metabolism, inflammation, and cell differentiation. Here, we analyzed the effects of aleglitazar, a dual PPARα and PPARγ agonist with balanced affinity for either subtype, on subacute stroke outcome. Healthy young adult mice were subjected to transient 30 min middle cerebral artery occlusion (MCAo)/reperfusion. Daily treatment with aleglitazar was begun on the day of MCAo and continued until sacrifice. Blood glucose measurements and lipid profile did not differ between mice receiving aleglitazar and mice receiving vehicle after MCAo. Aleglitazar reduced the size of the ischemic lesion as assessed using NeuN immunohistochemistry on day 7. Sensorimotor performance on the rotarod was impaired during the first week after MCAo, an effect that was significantly attenuated by treatment with aleglitazar. Smaller lesion volume in mice treated with aleglitazar was accompanied by a decrease in mRNA transcription of IL-1β , Vcam-1 , and Icam-1 , suggesting that reduced proinflammatory signaling and reduced vascular inflammation in the ischemic hemisphere contribute to the beneficial effects of aleglitazar during the first week after stroke. Further experiments in primary murine microglia confirmed that aleglitazar reduces key aspects of microglia activation including NO production, release of proinflammatory cytokines, migration, and phagocytosis. In aggregate, a brief course of PPARα/γ agonist aleglitazar initiated post-event affords stroke protection and functional recovery in a model of mild brain ischemia. Our data underscores the theme of delayed injury processes such as neuroinflammation as promising therapeutic targets in stroke. Key messages PPARα/γ agonist aleglitazar improves stroke outcome after transient brain ischemia. Aleglitazar attenuates inflammatory responses in post-ischemic brain. Aleglitazar reduces microglia migration, phagocytosis, and release of cytokines. Beneficial effects of aleglitazar independent of glucose regulation. Aleglitazar provides extended window of opportunity for stroke treatment.

Microglia senescence may promote neuropsychiatric disease. This prompted us to examine the relationship between microglia activation states and telomere biology. A panel of candidate genes associated with telomere maintenance, mitochondrial biogenesis, and cell-cycle regulation were investigated in M1- and M2-polarized microglia in vitro as well as in MACS-purified CD11b+ microglia/brain macrophages from models of stroke, Alzheimer’s disease, and chronic stress. M1 polarization, ischemia, and Alzheimer pathology elicited a strikingly similar transcriptomic profile with, in particular, reduced expression of murine Tert. Our results link classical microglia activation with repression of telomere-associated genes, suggesting a new mechanism underlying microglia dysfunction.

Vascular mechanisms underlying the adverse effects that depression and stress-related mental disorders have on stroke outcome are only partially understood. Identifying the transcriptomic signature of chronic stress in endothelium harvested from the ischemic brain is an important step towards elucidating the biological processes involved. Here, we subjected male 129S6/ SvEv mice to a 28-day model of chronic stress. The ischemic lesion was quantified after 30 min filamentous middle cerebral artery occlusion (MCAo) and 48 h reperfusion by T2-weighted MRI. RNA sequencing was used to profile transcriptomic changes in cerebrovascular endothelial cells (ECs) from the infarct. Mice subjected to the stress procedure displayed reduced weight gain, increased adrenal gland weight, and increased hypothalamic FKBP5 mRNA and protein expression. Chronic stress conferred increased lesion volume upon MCAo. Stress-exposed mice showed a higher number of differentially expressed genes between ECs isolated from the ipsilateral and contralateral hemisphere than control mice. The genes in question are enriched for roles in biological processes closely linked to endothelial proliferation and neoangiogenesis. MicroRNA-34a was associated with nine of the top 10 biological process Gene Ontology terms selectively enriched in ECs from stressed mice. Moreover, expression of mature miR-34a-5p and miR-34a-3p in ischemic brain tissue was positively related to infarct size and negatively related to sirtuin 1 (Sirt1) mRNA transcription. In conclusion, this study represents the first EC-specific transcriptomic analysis of chronic stress in brain ischemia. The stress signature uncovered relates to worse stroke outcome and is directly relevant to endothelial mechanisms in the pathogenesis of stroke.