L-Lactate Treatment at 24 h and 48 h after Acute Experimental Stroke Is Neuroprotective via Activation of the L-Lactate Receptor HCA1.

Stroke is the main cause for acquired disabilities. Pharmaceutical or mechanical removal of the thrombus is the cornerstone of stroke treatment but can only be administered to a subset of patients and within a narrow time window. Novel treatment options are therefore required. Here we induced stroke by permanent occlusion of the distal medial cerebral artery of wild-type mice and knockout mice for the lactate receptor hydroxycarboxylic acid receptor 1 (HCA1). At 24 h and 48 h after stroke induction, we injected L-lactate intraperitoneal. The resulting atrophy was measured in Nissl-stained brain sections, and capillary density and neurogenesis were measured after immunolabeling and confocal imaging. In wild-type mice, L-lactate treatment resulted in an HCA1-dependent reduction in the lesion volume accompanied by enhanced angiogenesis. In HCA1 knockout mice, on the other hand, there was no increase in angiogenesis and no reduction in lesion volume in response to L-lactate treatment. Nevertheless, the lesion volumes in HCA1 knockout mice-regardless of L-lactate treatment-were smaller than in control mice, indicating a multifactorial role of HCA1 in stroke. Our findings suggest that L-lactate administered 24 h and 48 h after stroke is protective in stroke. This represents a time window where no effective treatment options are currently available.

The Lactate Receptor HCA1 Is Present in the Choroid Plexus, the Tela Choroidea, and the Neuroepithelial Lining of the Dorsal Part of the Third Ventricle.

The volume, composition, and movement of the cerebrospinal fluid (CSF) are important for brain physiology, pathology, and diagnostics. Nevertheless, few studies have focused on the main structure that produces CSF, the choroid plexus (CP). Due to the presence of monocarboxylate transporters (MCTs) in the CP, changes in blood and brain lactate levels are reflected in the CSF. A lactate receptor, the hydroxycarboxylic acid receptor 1 (HCA1), is present in the brain, but whether it is located in the CP or in other periventricular structures has not been studied. Here, we investigated the distribution of HCA1 in the cerebral ventricular system using monomeric red fluorescent protein (mRFP)-HCA1 reporter mice. The reporter signal was only detected in the dorsal part of the third ventricle, where strong mRFP-HCA1 labeling was present in cells of the CP, the tela choroidea, and the neuroepithelial ventricular lining. Co-labeling experiments identified these cells as fibroblasts (in the CP, the tela choroidea, and the ventricle lining) and ependymal cells (in the tela choroidea and the ventricle lining). Our data suggest that the HCA1-containing fibroblasts and ependymal cells have the ability to respond to alterations in CSF lactate in body-brain signaling, but also as a sign of neuropathology (e.g., stroke and Alzheimer's disease biomarker).

Non-ictal, interictal and ictal déjà vu: a systematic review and meta-analysis.

Background: Déjà vu, French for "already seen," is a phenomenon most people will experience at least once in their lifetime. Emerging evidence suggests that déjà vu occurs in healthy individuals (as "non-ictal déjà vu") and in epilepsy patients during seizures (as "ictal déjà vu") and between seizures (as "interictal déjà vu"). Although the ILAE has recognized déjà vu as a feature of epileptic seizures, it is notably absent from the ICD-11. A lack of evidence-based research may account for this omission. To our knowledge, this study represents the first systematic review and meta-analysis on déjà vu experiences. Through detailed examinations of non-ictal, interictal and ictal déjà vu, we seek to highlight possible clinical implications. Rethinking the status quo of ictal déjà vu could potentially lead to earlier interventions and improve outcomes for epilepsy patients. Methods: This study was registered in PROSPERO (ID: CRD42023394239) on 5 February 2023. Systematic searches were conducted across four databases: EMBASE, MEDLINE, PsycINFO, and PubMed, from inception to 1 February 2023, limited to English language and human participants. Studies were included/excluded based on predefined criteria. Data was extracted according to the PICO framework and synthesized through a thematic approach. Meta-analyses were performed to estimate prevalence's of the phenomena. Study quality, heterogeneity, and publication bias were assessed. Results: Database searching identified 1,677 records, of which 46 studies were included. Meta-analyses of prevalence showed that non-ictal déjà vu was experienced by 0.74 (95% CI [0.67, 0.79], p < 0.001) of healthy individuals, whereas interictal déjà vu was experienced by 0.62 (95% CI [0.48, 0.75], p = 0.099) and ictal déjà vu by 0.22 (95% CI [0.15, 0.32], p = 0.001) of epilepsy patients. Examinations of phenomenological (sex, age, frequency, duration, emotional valence, and dissociative symptoms) and neuroscientific (brain structures and functions) data revealed significant variations between non-ictal, interictal and ictal déjà vu on several domains. Conclusion: This systematic review and meta-analysis do not support the notion that non-ictal, interictal and ictal déjà vu are homogenous experiences. Instead, it provides insight into ictal déjà vu as a symptom of epilepsy that should be considered included in future revisions of the ICD-11. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=394239, CRD42023394239.

L-lactate induces neurogenesis in the mouse ventricular-subventricular zone via the lactate receptor HCA1.

AIM: Adult neurogenesis occurs in two major niches in the brain: the subgranular zone of the hippocampal formation and the ventricular-subventricular zone. Neurogenesis in both niches is reduced in ageing and neurological disease involving dementia. Exercise can rescue memory by enhancing hippocampal neurogenesis, but whether exercise affects adult neurogenesis in the ventricular-subventricular zone remains unresolved. Previously, we reported that exercise induces angiogenesis through activation of the lactate receptor HCA1. The aim of the present study is to investigate HCA1 -dependent effects on neurogenesis in the two main neurogenic niches. METHODS: Wild-type and HCA1 knock-out mice received high intensity interval exercise, subcutaneous injections of L-lactate, or saline injections, five days per week for seven weeks. Well-established markers for proliferating cells (Ki-67) and immature neurons (doublecortin), were used to investigate neurogenesis in the subgranular zone and the ventricular-subventricular zone. RESULTS: We demonstrated that neurogenesis in the ventricular-subventricular zone is enhanced by HCA1 activation: Treatment with exercise or lactate resulted in increased neurogenesis in wild-type, but not in HCA1 knock-out mice. In the subgranular zone, neurogenesis was induced by exercise in both genotypes, but unaffected by lactate treatment. CONCLUSION: Our study demonstrates that neurogenesis in the two main neurogenic niches in the brain is regulated differently: Neurogenesis in both niches was induced by exercise, but only in the ventricular-subventricular zone was neurogenesis induced by lactate through HCA1 activation. This opens for a role of HCA1 in the physiological control of neurogenesis, and potentially in counteracting age-related cognitive decline.

Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1.

Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor.