Type-2 Diabetes Alters Hippocampal Neural Oscillations and Disrupts Synchrony between the Hippocampus and Cortex.

Type 2 diabetes mellitus (T2DM) increases the risk of neurological diseases, yet how brain oscillations change as age and T2DM interact is not well characterized. To delineate the age and diabetic effect on neurophysiology, we recorded local field potentials with multichannel electrodes spanning the somatosensory cortex and hippocampus (HPC) under urethane anesthesia in diabetic and normoglycemic control mice, at 200 and 400 days of age. We analyzed the signal power of brain oscillations, brain state, sharp wave associate ripples (SPW-Rs), and functional connectivity between the cortex and HPC. We found that while both age and T2DM were correlated with a breakdown in long-range functional connectivity and reduced neurogenesis in the dentate gyrus and subventricular zone, T2DM further slowed brain oscillations and reduced theta-gamma coupling. Age and T2DM also prolonged the duration of SPW-Rs and increased gamma power during SPW-R phase. Our results have identified potential electrophysiological substrates of hippocampal changes associated with T2DM and age. The perturbed brain oscillation features and diminished neurogenesis may underlie T2DM-accelerated cognitive impairment.

Type-2 diabetes alters hippocampal neural oscillations and disrupts synchrony between hippocampus and cortex.

Type 2 diabetes mellitus (T2DM) increases the risk of neurological diseases, yet how brain oscillations change as age and T2DM interact is not well characterized. To delineate the age and diabetic effect on neurophysiology, we recorded local field potentials with multichannel electrodes spanning the somatosensory cortex and hippocampus (HPC) under urethane anesthesia in diabetic and normoglycemic control mice, at 200 and 400 days of age. We analyzed the signal power of brain oscillations, brain state, sharp wave associate ripples (SPW-Rs), and functional connectivity between the cortex and HPC. We found that while both age and T2DM were correlated with a breakdown in long-range functional connectivity and reduced neurogenesis in the dentate gyrus and subventricular zone, T2DM further slowed brain oscillations and reduced theta-gamma coupling. Age and T2DM also prolonged the duration of SPW-Rs and increased gamma power during SPW-R phase. Our results have identified potential electrophysiological substrates of hippocampal changes associated with T2DM and age. The perturbed brain oscillation features and diminished neurogenesis may underlie T2DM-accelerated cognitive impairment.

Connectome-based prediction of functional impairment in experimental stroke models.

Experimental rat models of stroke and hemorrhage are important tools to investigate cerebrovascular disease pathophysiology mechanisms, yet how significant patterns of functional impairment induced in various models of stroke are related to changes in connectivity at the level of neuronal populations and mesoscopic parcellations of rat brains remain unresolved. To address this gap in knowledge, we employed two middle cerebral artery occlusion models and one intracerebral hemorrhage model with variant extent and location of neuronal dysfunction. Motor and spatial memory function was assessed and the level of hippocampal activation via Fos immunohistochemistry. Contribution of connectivity change to functional impairment was analyzed for connection similarities, graph distances and spatial distances as well as the importance of regions in terms of network architecture based on the neuroVIISAS rat connectome. We found that functional impairment correlated with not only the extent but also the locations of the injury among the models. In addition, via coactivation analysis in dynamic rat brain models, we found that lesioned regions led to stronger coactivations with motor function and spatial learning regions than with other unaffected regions of the connectome. Dynamic modeling with the weighted bilateral connectome detected changes in signal propagation in the remote hippocampus in all 3 stroke types, predicting the extent of hippocampal hypoactivation and impairment in spatial learning and memory function. Our study provides a comprehensive analytical framework in predictive identification of remote regions not directly altered by stroke events and their functional implication.

Pathological changes of brain oscillations following ischemic stroke.

Brain oscillations recorded in the extracellular space are among the most important aspects of neurophysiology data reflecting the activity and function of neurons in a population or a network. The signal strength and patterns of brain oscillations can be powerful biomarkers used for disease detection and prediction of the recovery of function. Electrophysiological signals can also serve as an index for many cutting-edge technologies aiming to interface between the nervous system and neuroprosthetic devices and to monitor the efficacy of boosting neural activity. In this review, we provided an overview of the basic knowledge regarding local field potential, electro- or magneto- encephalography signals, and their biological relevance, followed by a summary of the findings reported in various clinical and experimental stroke studies. We reviewed evidence of stroke-induced changes in hippocampal oscillations and disruption of communication between brain networks as potential mechanisms underlying post-stroke cognitive dysfunction. We also discussed the promise of brain stimulation in promoting post stroke functional recovery via restoring neural activity and enhancing brain plasticity.

Local field potentials identify features of cortico-hippocampal communication impacted by stroke and environmental enrichment therapy.

Objective. Cognitive and memory impairments are common sequelae after stroke, yet how middle cerebral artery (MCA) stroke chronically affects the neural activity of the hippocampus, a brain region critical for memory but remote from the stroke epicenter, is poorly understood. Environmental enrichment (EE) improves cognition following stroke; however, the electrophysiology that underlies this behavioral intervention is still elusive.Approach.We recorded extracellular local field potentials simultaneously from sensorimotor cortex and hippocampus in rats during urethane anesthesia following MCA occlusion and subsequent EE treatment.Main results.We found that MCA stroke significantly impacted the electrophysiology in the hippocampus, in particular it disrupted characteristics of sharp-wave associated ripples (SPW-Rs) altered brain state, and disrupted phase amplitude coupling (PAC) within the hippocampus and between the cortex and hippocampus. Importantly, we show that EE mitigates stroke-induced changes to SPW-R characteristics but does not restore hippocampal brain state or PAC.Significance.These results begin to uncover the complex interaction between cognitive deficit following stroke and EE treatment, providing a testbed to assess different strategies for therapeutics following stroke.

The effect of type 2 diabetes on CD36 expression and the uptake of oxLDL: Diabetes affects CD36 and oxLDL uptake.

We investigated whether type 2 diabetes mellitus (T2DM), a risk factor of stroke, affects the level of scavenger receptor CD36 and the uptake of its ligand, oxidized LDL (oxLDL); and whether pioglitazone, a drug that enhances CD36, promotes oxLDL uptake. Compared to normoglycemic db/+ mice, adult db/db mice showed a pronounced reduction in surface CD36 expression on myeloid cells from the blood, brain, and bone marrow as detected by flow cytometry, which correlated with elevated plasma soluble-CD36 as determined by ELISA. Increased CD36 expression was found in brain macrophages and microglia of both genotypes 7 days after ischemic stroke. In juvenile db/db mice, prior to obesity and hyperglycemia, only a mild reduction of surface CD36 was found in blood neutrophils, while all other myeloid cells showed no difference relative to the db/+ strain. In vivo, oral pioglitazone treatment for four weeks increased CD36 levels on myeloid cells in db/db mice. In vitro, uptake of oxLDL by bone marrow derived macrophages (BMDMs) of db/db mice was reduced relative to db/+ mice in normal glucose medium. OxLDL uptake inversely correlated with glucose levels in the medium in db/+ BMDMs. Furthermore, pioglitazone restored oxLDL uptake by BMDMs from db/db mice cultured in high glucose. Our data suggest that T2DM is associated with reduced CD36 on adult myeloid cells, and pioglitazone enhances CD36 expression in db/db cells. T2DM or high glucose reduces oxLDL uptake while pioglitazone enhances oxLDL uptake. Our findings provide new insight into the mechanism by which pioglitazone may be beneficial in the treatment of insulin resistance.

Experimental cortical stroke induces aberrant increase of sharp-wave-associated ripples in the hippocampus and disrupts cortico-hippocampal communication.

The functional consequences of ischemic stroke in the remote brain regions are not well characterized. The current study sought to determine changes in hippocampal oscillatory activity that may underlie the cognitive impairment observed following distal middle cerebral artery occlusion (dMCAO) without causing hippocampal structural damage. Local field potentials were recorded from the dorsal hippocampus and cortex in urethane-anesthetized rats with multichannel silicon probes during dMCAO and reperfusion, or mild ischemia induced by bilateral common carotid artery occlusion (CCAO). Bilateral change of brain state was evidenced by reduced theta/delta amplitude ratio and shortened high theta duration following acute dMCAO but not CCAO. An aberrant increase in the occurrence of sharp-wave-associated ripples (150-250 Hz), crucial for memory consolidation, was only detected after dMCAO reperfusion, coinciding with an increased occurrence of high-frequency discharges (250-450 Hz). dMCAO also significantly affected the modulation of gamma amplitude in the cortex coupled to hippocampal theta phase, although both hippocampal theta and gamma power were temporarily decreased during dMCAO. Our results suggest that MCAO may disrupt the balance between excitatory and inhibitory circuits in the hippocampus and alter the function of cortico-hippocampal network, providing a novel insight in how cortical stroke affects function in remote brain regions.

Perturbation of Brain Oscillations after Ischemic Stroke: A Potential Biomarker for Post-Stroke Function and Therapy.

Brain waves resonate from the generators of electrical current and propagate across brain regions with oscillation frequencies ranging from 0.05 to 500 Hz. The commonly observed oscillatory waves recorded by an electroencephalogram (EEG) in normal adult humans can be grouped into five main categories according to the frequency and amplitude, namely δ (1-4 Hz, 20-200 µV), θ (4-8 Hz, 10 µV), α (8-12 Hz, 20-200 µV), ß (12-30 Hz, 5-10 µV), and γ (30-80 Hz, low amplitude). Emerging evidence from experimental and human studies suggests that groups of function and behavior seem to be specifically associated with the presence of each oscillation band, although the complex relationship between oscillation frequency and function, as well as the interaction between brain oscillations, are far from clear. Changes of brain oscillation patterns have long been implicated in the diseases of the central nervous system including ischemic stroke, in which the reduction of cerebral blood flow as well as the progression of tissue damage have direct spatiotemporal effects on the power of several oscillatory bands and their interactions. This review summarizes the current knowledge in behavior and function associated with each brain oscillation, and also in the specific changes in brain electrical activities that correspond to the molecular events and functional alterations observed after experimental and human stroke. We provide the basis of the generations of brain oscillations and potential cellular and molecular mechanisms underlying stroke-induced perturbation. We will also discuss the implications of using brain oscillation patterns as biomarkers for the prediction of stroke outcome and therapeutic efficacy.