Hydroxycarboxylic Acid Receptor 1 and Neuroprotection in a Mouse Model of Cerebral Ischemia-Reperfusion.

Lactate is an intriguing molecule with emerging physiological roles in the brain. It has beneficial effects in animal models of acute brain injuries and traumatic brain injury or subarachnoid hemorrhage patients. However, the mechanism by which lactate provides protection is unclear. While there is evidence of a metabolic effect of lactate providing energy to deprived neurons, it can also activate the hydroxycarboxylic acid receptor 1 (HCAR1), a Gi-coupled protein receptor that modulates neuronal firing rates. After cerebral hypoxia-ischemia, endogenously produced brain lactate is largely increased, and the exogenous administration of more lactate can decrease lesion size and ameliorate the neurological outcome. To test whether HCAR1 plays a role in lactate-induced neuroprotection, we injected the agonists 3-chloro-5-hydroxybenzoic acid and 3,5-dihydroxybenzoic acid into mice subjected to 30-min middle cerebral artery occlusion. The in vivo administration of HCAR1 agonists at reperfusion did not appear to exert any relevant protective effect as seen with lactate administration. Our results suggest that the protective effects of lactate after hypoxia-ischemia come rather from the metabolic effects of lactate than its signaling through HCAR1.

Caveolin-1 Regulates Perivascular Aquaporin-4 Expression After Cerebral Ischemia.

Edema is a hallmark of many brain disorders including stroke. During vasogenic edema, blood-brain barrier (BBB) permeability increases, contributing to the entry of plasma proteins followed by water. Caveolae and caveolin-1 (Cav-1) are involved in these BBB permeability changes. The expression of the aquaporin-4 (AQP4) water channel relates to brain swelling, however, its regulation is poorly understood. Here we tested whether Cav-1 regulates AQP4 expression in the perivascular region after brain ischemia in mice. We showed that Cav-1 knockout mice had enhanced hemispheric swelling and decreased perivascular AQP4 expression in perilesional and contralateral cortical regions compared to wild-type. Glial fibrillary acidic protein-positive astrocytes displayed less branching and ramification in Cav-1 knockout mice compared to wild-type animals. There was a positive correlation between the area of perivascular AQP4-immunolabelling and branch length of Glial fibrillary acidic protein-positive astrocytes in wild-type mice, not seen in Cav-1 knockout mice. In summary, we show for the first time that loss of Cav-1 results in decreased AQP4 expression and impaired perivascular AQP4 covering after cerebral ischemia associated with altered reactive astrocyte morphology and enhanced brain swelling. Therapeutic approaches targeting Cav-1 may provide new opportunities for improving stroke outcome. SIGNIFICANCE STATEMENT: Severe brain edema worsens outcome in stroke patients. Available treatments for stroke-related edema are not efficient and molecular and cellular mechanisms are poorly understood. Cellular water channels, aquaporins (AQPs), are mainly expressed in astrocytes in the brain and play a key role in water movements and cerebral edema, while endothelial caveolins have been suggested to play a role in vasogenic edema. Here we used an integrative approach to study possible interaction between AQP4 and caveolin-1 (Cav-1) after stroke. Absence of Cav-1 was associated with perivascular changes in AQP4 expression and enhanced brain swelling at 3 days after cerebral ischemia. The present work indicates a direct or indirect effect of Cav-1 on perivascular AQP4, which may lead to novel edema therapy.

Involvement of caveolin-1 in neurovascular unit remodeling after stroke: Effects on neovascularization and astrogliosis.

Complex cellular and molecular events occur in the neurovascular unit after stroke, such as blood-brain barrier (BBB) dysfunction and inflammation that contribute to neuronal death, neurological deterioration and mortality. Caveolin-1 (Cav-1) has distinct physiological functions such as caveolae formation associated with endocytosis and transcytosis as well as in signaling pathways. Cav-1 has been proposed to be involved in BBB dysfunction after brain injury; however, its precise role is poorly understood. The goal of this study was to characterize the expression and effect of Cav-1 deletion on outcome in the first week in a transient Middle Cerebral Artery Occlusion stroke model. We found increased Cav-1 expression in new blood vessels in the lesion and in reactive astrocytes in the peri-lesion areas. In Cav-1 KO mice, the lesion volume was larger and the behavioral outcome worse than in WT mice. Cav-1 KO mice exhibited reduced neovascularization and modified astrogliosis, without formation of a proper glial scar around the lesion at three days post injury, coinciding with aggravated outcomes. Altogether, these results point towards a potential protective role of endogenous Cav-1 in the first days after ischemia by promoting neovascularization, astrogliosis and scar formation.

Imaging fast neural traffic at fascicular level with electrical impedance tomography: proof of principle in rat sciatic nerve.

OBJECTIVE: Understanding the coding of neural activity in nerve fascicles is a high priority in computational neuroscience, electroceutical autonomic nerve stimulation and functional electrical stimulation for treatment of paraplegia. Unfortunately, it has been little studied as no technique has yet been available to permit imaging of neuronal depolarization within fascicles in peripheral nerve. APPROACH: We report a novel method for achieving this, using a flexible cylindrical multi-electrode cuff placed around nerve and the new medical imaging technique of fast neural electrical impedance tomography (EIT). In the rat sciatic nerve, it was possible to distinguish separate fascicles activated in response to direct electrical stimulation of the posterior tibial and common peroneal nerves. MAIN RESULTS: Reconstructed EIT images of fascicular activation corresponded with high spatial accuracy to the appropriate fascicles apparent in histology, as well as the inverse source analysis (ISA) of compound action potentials (CAP). With this method, a temporal resolution of 0.3 ms and spatial resolution of less than 100 µm was achieved. SIGNIFICANCE: The method presented here is a potential solution for imaging activity within peripheral nerves with high spatial accuracy. It also provides a basis for imaging and selective neuromodulation to be incorporated in a single implantable non-penetrating peri-neural device.

Alpha reactivity to complex sounds differs during REM sleep and wakefulness.

We aimed at better understanding the brain mechanisms involved in the processing of alerting meaningful sounds during sleep, investigating alpha activity. During EEG acquisition, subjects were presented with a passive auditory oddball paradigm including rare complex sounds called Novels (the own first name - OWN, and an unfamiliar first name - OTHER) while they were watching a silent movie in the evening or sleeping at night. During the experimental night, the subjects' quality of sleep was generally preserved. During wakefulness, the decrease in alpha power (8-12 Hz) induced by Novels was significantly larger for OWN than for OTHER at parietal electrodes, between 600 and 900 ms after stimulus onset. Conversely, during REM sleep, Novels induced an increase in alpha power (from 0 to 1200 ms at all electrodes), significantly larger for OWN than for OTHER at several parietal electrodes between 700 and 1200 ms after stimulus onset. These results show that complex sounds have a different effect on the alpha power during wakefulness (decrease) and during REM sleep (increase) and that OWN induce a specific effect in these two states. The increased alpha power induced by Novels during REM sleep may 1) correspond to a short and transient increase in arousal; in this case, our study provides an objective measure of the greater arousing power of OWN over OTHER, 2) indicate a cortical inhibition associated with sleep protection. These results suggest that alpha modulation could participate in the selection of stimuli to be further processed during sleep.

Alpha reactivity to first names differs in subjects with high and low dream recall frequency.

Studies in cognitive psychology showed that personality (openness to experience, thin boundaries, absorption), creativity, nocturnal awakenings, and attitude toward dreams are significantly related to dream recall frequency (DRF). These results suggest the possibility of neurophysiological trait differences between subjects with high and low DRF. To test this hypothesis we compared sleep characteristics and alpha reactivity to sounds in subjects with high and low DRF using polysomnographic recordings and electroencephalography (EEG). We acquired EEG from 21 channels in 36 healthy subjects while they were presented with a passive auditory oddball paradigm (frequent standard tones, rare deviant tones and very rare first names) during wakefulness and sleep (intensity, 50 dB above the subject's hearing level). Subjects were selected as High-recallers (HR, DRF = 4.42 ± 0.25 SEM, dream recalls per week) and Low-recallers (LR, DRF = 0.25 ± 0.02) using a questionnaire and an interview on sleep and dream habits. Despite the disturbing setup, the subjects' quality of sleep was generally preserved. First names induced a more sustained decrease in alpha activity in HR than in LR at Pz (1000-1200 ms) during wakefulness, but no group difference was found in REM sleep. The current dominant hypothesis proposes that alpha rhythms would be involved in the active inhibition of the brain regions not involved in the ongoing brain operation. According to this hypothesis, a more sustained alpha decrease in HR would reflect a longer release of inhibition, suggesting a deeper processing of complex sounds than in LR during wakefulness. A possibility to explain the absence of group difference during sleep is that increase in alpha power in HR may have resulted in awakenings. Our results support this hypothesis since HR experienced more intra sleep wakefulness than LR (30 ± 4 vs. 14 ± 4 min). As a whole our results support the hypothesis of neurophysiological trait differences in high and low-recallers.