A place for place cells in post-stroke cognitive impairment.

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Published in final edited form as: Trends Neurosci. 2025 May 20;48(6):391–392. doi: 10.1016/j.tins.2025.05.001 A place for place cells in post-stroke cognitive impairment Abbie C Chapman 1 Author information Article notes Copyright and License information 1 Department of Psychology, Binghamton University – SUNY, Binghamton, NY 13902 ✉ Correspondence: [ achapman@binghamton.edu ] (Abbie Chapman) Issue date 2025 Jun. PMC Copyright notice PMCID: PMC12158631  NIHMSID: NIHMS2080081  PMID: 40399215 The publisher's version of this article is available at Trends Neurosci Abstract In a recent study, Heiser et al. showed that hippocampal place cell stability and spatial encoding were disrupted in mice after brain-wide microstrokes. These findings suggest hippocampal neurons are particularly vulnerable to dysfunction after stroke, even in the absence of local lesions, and the potential to improve place cell stability and rescue post-stroke memory function. Keywords: neuroplasticity, memory, ischemic stroke, hippocampus In 2021, it was estimated that over 55 million people world-wide were living with dementia, which is projected to reach 78 million by 2030 and exceed 135 million in 2050 [ 1 ]. Vascular contributions to cognitive impairment and dementia are the second leading cause of age-related cognitive decline after Alzheimer’s disease. Cognitive impairment developing after stroke is the most common form of vascular cognitive impairment that contributes to decreased quality of life of stroke survivors and their loved ones [ 2 ]. Post-stroke cognitive impairment describes a spectrum of cognitive impairments, ranging from mild to its most severe form, post-stroke dementia, and is increasing in prevalence due to an aging population and thanks to decreased stroke-related mortality [ 2 , 3 ]. This occurs in up to 80% of stroke survivors and involves multiple cognitive domains, including memory [ 4 , 5 ]. While post-stroke cognitive impairment can often be explained by the location of the infarction, that is generally not the case with post-stroke memory loss. In fact, ischemic stroke in brain regions most-directly involved in memory (e.g., the medial temporal lobe and hippocampus) is rare, yet post-stroke cognitive impairment is frequently associated with hippocampal neurodegeneration and decreased hippocampal functionality as assessed using fMRI [ 6 – 8 ]. The hippocampus is a deep, bilateral brain region central to learning and memory and is one of the most susceptible brain regions to injury, including from hypoxia/ischemia. How hippocampal neuronal and network functions are impacted by ischemic stroke, and how they change over time after stroke remains unclear. Addressing these questions is an important goal, given this brain region’s central roles in learning and memory and high susceptibility to injury. Progress in this research area is being made, as evidenced by a recent article by Heiser et al. [ 9 ] investigating the impact of wide-spread microstrokes on hippocampal neuronal function and post-stroke memory decline in mice. The authors used an innovative approach to determine the impact of multiple microstrokes distributed throughout the brain at the individual neuronal level (e.g., hippocampal place cells that are active when an animal is in a specific location) as well as at the network level in the CA1 region of the hippocampus [ 9 ]. Using chronic two-photon calcium imaging in mice, they simultaneously assessed place cell activity while the animals were navigating through a virtual reality corridor prior to and after microstrokes were induced via unilateral internal carotid artery microsphere infusion. The majority of microspheres and lesions were in the neocortex (~ 40%) and to a lesser extent in the hippocampus (~ 14 %). Prior to stroke, mice were trained to use visual cues to identify reward zones within the virtual corridor. This learned ability was disrupted after microstrokes which correlated with the amount of microspheres in the brain, particularly in the early post-stroke period (within seven days). Of note, three days after microstrokes were induced, all post-stroke mice had impaired performance in the spatial navigation task compared to their pre-stroke level. Importantly, mice with microstrokes did not display task-relevant motor impairment and there was no correlation between microspheres/lesions in the visual cortex and task performance, suggesting impaired spatial navigation was not due to stroke-induced changes in mobility or vision, but rather due to the resulting ischemic injury [ 9 ]. Functional remapping of hippocampal networks is highly dynamic, and as mice learned the navigation task, the corresponding hippocampal neuronal network consolidated as place cells stabilized. By assessing neuronal activity over time, Heiser and colleagues [ 9 ] assigned distinct functions to individual neurons within the hippocampal network. In fact, in healthy (pre-stroke) mice, place cell population encoding could accurately predict the location of the mouse in the corridor. This place cell stability and place field encoding was impaired in the early phase after stroke, as stable place cells retained their function significantly less often than in sham controls, and no longer accurately predicted location. In sham, but not post-stroke mice, continued functional consolidation and refinement of the spatial neuronal network occurred over time, where unstable place cells often transitioned to stable place cells. These findings suggest spatial coding was impaired several days after widespread microstrokes. As mentioned above, place cell instability was observed in the early phase after stroke, including three days after microstroke induction when all post-stroke mice demonstrated cognitive impairment. Interestingly, a subset of post-stroke mice demonstrated recovery of cognitive function 10 days after stroke, whereas others showed no notable recovery and had chronic cognitive deficit into the late phase after stroke (28 days). Interestingly, mice with chronic spatial memory impairments had larger lesions and lost a significant portion of hippocampal place cells after microstrokes that persistently impaired spatial encoding and network stability compared to post-stroke mice with cognitive recovery. By contrast, mice with cognitive recovery had transiently reduced stable place cells that increased to the level of sham controls in the late phase after stroke and were again able to accurately predict corridor location and reward zones and demonstrated improved neuronal network function and stability [ 9 ]. These findings indicate that place cells and spatial encoding are particularly vulnerable to dysfunction several days after microstrokes, and that there is potential to improve place cell stability and rescue post-stroke spatial memory dysfunction. While several preclinical studies have determined impaired hippocampal neuroplasticity occurs after a transient large artery occlusion using ex vivo hippocampal slice electrophysiology (e.g. [ 10 ]), the study by Heiser et al. [ 9 ] is among the first to examine changes in individual neuronal coding in vivo after brain-wide microstrokes. The longitudinal experimental design allowed assessment of place cell function prior to and after stroke, including the detailed trajectories of place cell stability as it relates to spatial encoding, network and place field dynamics, and post-stroke spatial memory dysfunction. The role of place cells in cognitive recovery/no-recovery subsets of post-stroke mice suggests that place cell stability and spatial encoding may represent therapeutic targets to prevent or slow memory decline after stroke. The findings by Heiser et al. also underscore the susceptibility of the hippocampus to injury after ischemic stroke even in the absence of focal ischemic damage, given that robust spatial memory impairment was observed in all post-stroke mice when only a small portion of microstrokes occurred in the hippocampus itself. The findings by Heiser et al. [ 9 ] of the direct involvement of place cells in memory dysfunction after brain-wide microstrokes advance our understanding of underlying mechanisms of post-stroke cognitive impairment. Further, these findings suggest there may be an acute period of time during which hippocampal neuroplasticity can be targeted to stabilize place cells and restore spatial encoding and memory function after ischemic stroke. Acknowledgments This work was supported by the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke and the National Institute on Aging 1R01 NS127284. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Declaration of interests The author declares no competing interests. References 1. World Health Organization (2021). Global status report on the public health response to dementia. Geneva: World Health Organization [ Google Scholar ] 2. Iadecola C et al. (2019) Vascular Cognitive Impairment and Dementia: JACC Scientific Expert Panel. Journal of the American College of Cardiology 73, 3326–3344. 10.1016/j.jacc.2019.04.034 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 3. El Husseini N et al. (2023) Cognitive Impairment After Ischemic and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association/American Stroke Association. Stroke 54, e272–e291. 10.1161/STR.0000000000000430 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 4. Jokinen H et al. (2015) Post-stroke cognitive impairment is common even after successful clinical recovery. Eur J Neurol 22, 1288–1294. 10.1111/ene.12743 [ DOI ] [ PubMed ] [ Google Scholar ] 5. Middleton LE et al. (2014) Frequency of domain-specific cognitive impairment in sub-acute and chronic stroke. NeuroRehabilitation 34, 305–312. 10.3233/NRE-131030 [ DOI ] [ PubMed ] [ Google Scholar ] 6. Snaphaan L et al. (2009) Reduced medial temporal lobe functionality in stroke patients: a functional magnetic resonance imaging study. Brain 132, 1882–1888. 10.1093/brain/awp133 [ DOI ] [ PubMed ] [ Google Scholar ] 7. Gemmell E et al. (2014) Neuron volumes in hippocampal subfields in delayed poststroke and aging-related dementias. J Neuropathol Exp Neurol 73, 305–311. 10.1097/NEN.0000000000000054 [ DOI ] [ PubMed ] [ Google Scholar ] 8. Akinyemi RO et al. (2017) Hippocampal Neurodegenerative Pathology in Post-stroke Dementia Compared to Other Dementias and Aging Controls. 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J Cereb Blood Flow Metab, 271678X17750761. 10.1177/0271678X17750761 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] ACTIONS View on publisher site PDF (40.2 KB) Cite Collections Permalink RESOURCES Similar articles Cited by other articles Links to NCBI Databases Follow NCBI NCBI on X (formerly known as Twitter) NCBI on Facebook NCBI on LinkedIn NCBI on GitHub NCBI RSS feed Connect with NLM NLM on X (formerly known as Twitter) NLM on Facebook NLM on YouTube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov Back to Top

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