Identification of vagus nerve stimulation parameters affecting rat hippocampal electrophysiology without temperature effects

Background: Recent experiments in rats have demonstrated significant effects of VNS on hippocampal excitability but were partially attributed to hypothermia, induced by the applied VNS parameters. Objective: To allow meaningful preclinical research on the mechanisms of VNS and translation of rodent results to clinical VNS trials, we aimed to identify non-hypothermia inducing VNS parameters that significantly affect hippocampal excitability. Methods: VNS was administered in cycles of 30 s including either 0.1, 0.16, 0.25, 0.5, 1.5, 3 or 7 s of VNS ON time (biphasic pulses, 250ms/phase, 1 mA, 30 Hz) and the effect of different VNS ON times on brain temperature was evaluated. VNS paradigms with and without hypothermia were compared for their effects on hippocampal neurophysiology in freely moving rats. Results: Using VNS parameters with an ON time/OFF time of up to 0.5 s/30 s did not cause hypothermia, while clear hypothermia was detected with ON times of 1.5, 3 and 7 s/30 s. Relative to SHAM VNS, the normothermic 0.5 s VNS condition significantly decreased hippocampal EEG power and changed dentate gyrus evoked potentials with an increased field excitatory postsynaptic potential slope and a decreased population spike amplitude. Conclusion: VNS can be administered in freely moving rats without causing hypothermia, while profoundly affecting hippocampal neurophysiology suggestive of reduced excitability of hippocampal neurons despite increased synaptic transmission efficiency. (C) 2020 The Authors. Published by Elsevier Inc

Dynamics of sleep oscillations is coupled to brain temperature on multiple scales

Sleep spindle frequency positively, duration negatively correlates with brain temperature. Local heating of the thalamus produces similar effects in the heated area. Thalamic network model corroborates temperature dependence of sleep spindle frequency. Brain temperature shows spontaneous microfluctuations during both anesthesia and natural sleep. Larger fluctuations are associated with epochs of REM sleep. Smaller fluctuations correspond to the alteration of spindling and delta epochs of infra-slow oscillation.Every form of neural activity depends on temperature, yet its relationship to brain rhythms is poorly understood. In this work we examined how sleep spindles are influenced by changing brain temperatures and how brain temperature is influenced by sleep oscillations. We employed a novel thermoelectrode designed for measuring temperature while recording neural activity. We found that spindle frequency is positively correlated and duration negatively correlated with brain temperature. Local heating of the thalamus replicated the temperature dependence of spindle parameters in the heated area only, suggesting biophysical rather than global modulatory mechanisms, a finding also supported by a thalamic network model. Finally, we show that switches between oscillatory states also influence brain temperature on a shorter and smaller scale. Epochs of paradoxical sleep as well as the infra-slow oscillation were associated with brain temperature fluctuations below 0.2°C. Our results highlight that brain temperature is massively intertwined with sleep oscillations on various time scales

Cross-approximate entropy of cortical local field potentials quantifies effects of anesthesia - a pilot study in rats

<p>Abstract</p> <p>Background</p> <p>Anesthetics dose-dependently shift electroencephalographic (EEG) activity towards high-amplitude, slow rhythms, indicative of a synchronization of neuronal activity in thalamocortical networks. Additionally, they uncouple brain areas in higher (gamma) frequency ranges possibly underlying conscious perception. It is currently thought that both effects may impair brain function by impeding proper information exchange between cortical areas. But what happens at the local network level? Local networks with strong excitatory interconnections may be more resilient towards global changes in brain rhythms, but depend heavily on locally projecting, inhibitory interneurons. As anesthetics bias cortical networks towards inhibition, we hypothesized that they may cause excessive synchrony and compromise information processing already on a small spatial scale. Using a recently introduced measure of signal independence, cross-approximate entropy (XApEn), we investigated to what degree anesthetics synchronized local cortical network activity. We recorded local field potentials (LFP) from the somatosensory cortex of three rats chronically implanted with multielectrode arrays and compared activity patterns under control (awake state) with those at increasing concentrations of isoflurane, enflurane and halothane.</p> <p>Results</p> <p>Cortical LFP signals were more synchronous, as expressed by XApEn, in the presence of anesthetics. Specifically, XApEn was a monotonously declining function of anesthetic concentration. Isoflurane and enflurane were indistinguishable; at a concentration of 1 MAC (the minimum alveolar concentration required to suppress movement in response to noxious stimuli in 50% of subjects) both volatile agents reduced XApEn by about 70%, whereas halothane was less potent (50% reduction).</p> <p>Conclusions</p> <p>The results suggest that anesthetics strongly diminish the independence of operation of local cortical neuronal populations, and that the quantification of these effects in terms of XApEn has a similar discriminatory power as changes of spontaneous action potential rates. Thus, XApEn of field potentials recorded from local cortical networks provides valuable information on the anesthetic state of the brain.</p

Early brain activity : Translations between bedside and laboratory

Neural activity is both a driver of brain development and a readout of developmental processes. Changes in neuronal activity are therefore both the cause and consequence of neurodevelopmental compromises. Here, we review the assessment of neuronal activities in both preclinical models and clinical situations. We focus on issues that require urgent translational research, the challenges and bottlenecks preventing translation of biomedical research into new clinical diagnostics or treatments, and possibilities to overcome these barriers. The key questions are (i) what can be measured in clinical settings versus animal experiments, (ii) how do measurements relate to particular stages of development, and (iii) how can we balance practical and ethical realities with methodological compromises in measurements and treatments.Peer reviewe

Development and Localization of Spike-Wave Seizures in Animal Models

Animal models allow for detailed investigation of neuronal function, particularly invasive localization and developmental studies not possible in humans. This thesis will review the technical challenges of simultaneous EEG-fMRI, and epileptogenesis studies in animal models, including issues related to anesthesia, movement, signal artifact, physiology, electrode compatibility, data acquisition, and data analysis, and review recent findings from simultaneous EEG-fMRI studies in epilepsy and other fields. Original research will be presented on the localization of neuronal networks involved during spike-and-wave seizures in the WAG/Rij rat, a model of human absence epilepsy. Simultaneous EEG-fMRI at 9 Tesla, complimented by parallel electrophysiology, including Multiple Unit Activity (MUA), Local Field Potential (LFP), and Cerebral Blood Flow (CBF) measurements were employed to investigate the functioning of neuronal networks. This work indicates that while BOLD signal increases in the Somaotsensory Cortex and Thalamus during SWD are associated with MUA, LFP, and CBF increases, BOLD signal decreases in the Caudate are associated with CBF decreases and relatively larger increase in LFP and smaller increase in MUA. Complimenting the localization studies, original research will also be presented on the development of spike-and-wave epilepsy in the C3H/Hej mouse, a model which will allow for more advanced genetic and molecular investigation. This work shows seizure development progressing though immature, transitional, and mature stages

Aligning Acute and Chronic Functional Readouts and utilizing Zolpidem to improve Neurological Impairments after Cardiac Arrest

While cardiac arrest survival rates have improved alongside recent advances in modern resuscitation techniques and targeted temperature management, many survivors experience multiple ongoing symptoms after their hypoxic-ischemic brain injury (HIBI) including movement disorders, depression, and low cognitive arousal. Neurological assessments like the neurological deficit score (NDS), and physiological readouts from blood chemistry values are used to assess acute post-injury outcome, but little has been done to evaluate how these acute readouts distinguish heterogeneity within the injury population, or how they align with long term behavioral and neurological outcomes as a prognostic tool. Recent evidence also highlights zolpidem as an effective treatment for post-HIBI symptoms, but its clinical use has been met with mixed results. This study utilized a regression model and correlational analyses to evaluate associations among NDS, blood lactate, and blood acid base excess values as acute post-injury readouts, behavioral outcome, and dopamine neurotransmission outcomes obtained via fast scan cyclic voltammetry two weeks after a 5-min asphyxia cardiac arrest (ACA). A pilot study was also performed to evaluate the effects of chronic systemic zolpidem administration on improving behavioral outcomes and reversing striatal hyper-dopaminergia after ACA. NDS significantly aligned with survival probability after ACA. NDS and both blood chemistry readouts aligned with several behavioral and dopamine neurotransmission outcomes, and several dopaminergic and behavioral outcomes robustly correlated with one another. Additionally, chronic zolpidem reflexive and cognitive behavioral outcomes, as defined by the acoustic startle response and the sucrose preference test, respectively. This work highlights novel associations between post-HIBI behavioral and neurological outcomes as well as benefits of chronic zolpidem administration in ameliorating post-HIBI neurological sequelae. Future work should further characterize the effects of zolpidem administration after cardiac arrest and utilize molecular assays to identify protein expression changes that will unravel neurobiological mechanisms driving HIBI-induced functional impairments and highlight therapeutic targets to treat CA survivors

Examining the effects of a sub-chronic exposure to phencyclidine: An analysis of functional network connectivity, behavior, and mRNA expression

Glutamate is the primary excitatory neurotransmitter in the central nervous system and plays a vital role in the pathology of various disease states. Thus, the manipulation and examination of glutamate has been and continues to be pivotal in experimental research. For example, a chronic administration of phencyclidine (PCP), a non-competitive glutamatergic N-methyl-D-Aspartate (NMDA) receptor antagonist, generates behavioral and neurobiological changes that mimic symptoms and microlevel changes found in psychiatric disease states, such as schizophrenia [30]. Prior research has established that PCP induces cognitive deficits, impedes spatial learning and memory performance, and alters mRNA expression of γ-aminobutyric acid (GABA)ergic markers parvalbumin, GAD67, calbindin, and tyrosine kinase ErbB4 in addition to glutamate NMDA receptor subunits GluN2A and GluN2B in ways that are comparable to findings in the schizophrenia population [10, 11, 18, 48]. Recently, a growing interest in observing functional network connectivity (FNC) has lead to innovative ways of examining both normal systems and disease states. FNC imaging has successfully identified similar networks in both humans and rats [29] which has motivated translational research. Yet, little research has examined the effects of PCP on FNC in an animal system. In the current study, we characterized how a sub-chronic administration of PCP can manipulate FNC and how those changes relate to observed behavioral and mRNA expression outcomes. Adult male hooded Long Evan rats (N=40) were pre-trained in the hidden platform Morris water task (MWT) prior to beginning their sub-chronic treatment. Rats received 14 intraperitoneal (i.p.) injections of either PCP (2.58 mg/kg/injection) or 0.9% saline solution (1 mL/kg) over a period of 26 days. Seventy-two hours after the final injection all animals were anesthetized with isoflurane and imaged in a 4.7 T Bruker Biospin MRI Scanner. Fast spin-echo anatomical scans, resting state functional magnetic resonance imaging (fMRI) scans with echo-planar imaging (EPI) acquisition sequences, and arterial spin labeling (ASL) scans were acquired during the one-hour imaging session. On day 36, 10 days following the final injection, a subset of animals (PCP treated n=10, saline treated n=10) were rescanned to examine the effects of a one week washout period. Following the final scan all animals were retested in the MWT. The animals were initially tested in 8 retraining trials. After a break of least an hour in their home cage, the animals were given a short retraining session consisting of 4 trials followed by 8 trials of reversal where the hidden platform was shifted 180o from the trained location in order to examine behavioral flexibility. Upon completion of behavioral testing, the animals were sacrificed and tissue was collected and stored at -80 degrees C for GABA and NMDA receptor mRNA expression analysis. Group differences in the individual components were assessed through comparisons of FNC (inter-component correlations) and spectral power comparisons. Group independent component analyses (ICA) were conducted through the implementation of the Group ICA of fMRI Toolbox (GIFT). Additionally, select brain regions of interest, including the medial frontal cortex and ventral frontal cortex, were assessed for mRNA expression. Real-time polymerase chain reaction (RT-PCR) was used to assess mRNA expression of the GABAergic markers parvalbumin, calbindin, ErbB4, and GAD67, as well as NMDA receptor subunits GluN2A and GluN2B. The expression of these receptors within the frontal cortex were compared to expression levels within the parietal cortex, which was used as a control region. These analyses were used to observe the neurobiological effects of a sub-chronic exposure to PCP. MWT data was analyzed to determine the effects of the treatments and to characterize learning and memory performance changes following a low dose sub-chronic administration of PCP. Finally, these behavioral data also allowed for the examination of behavioral differences between groups based on temporal proximity to cessation of PCP treatment. The PCP exposed animals displayed persistent connectivity changes and alterations in mRNA expression of parvalbumin, calbindin, and GAD67