Neural oscillations during cognitive processes in an <i>App</i> knock-in mouse model of Alzheimer's disease pathology

Multiple animal models have been created to gain insight into Alzheimer's disease (AD) pathology. Among the most commonly used models are transgenic mice overexpressing human amyloid precursor protein (APP) with mutations linked to familial AD, resulting in the formation of amyloid beta plaques, one of the pathological hallmarks observed in AD patients. However, recent evidence suggests that the overexpression of APP by itself can confound some of the reported observations. Therefore, we investigated in the present study the App(NL-G-F)model, an App knock-in (App-KI) mouse model that develops amyloidosis in the absence of APP-overexpression. Our findings at the behavioral, electrophysiological, and histopathological level confirmed an age-dependent increase in A beta 1-42 levels and plaque deposition in these mice in accordance with previous reports. This had apparently no consequences on cognitive performance in a visual discrimination (VD) task, which was largely unaffected in App(NL-G-F) mice at the ages tested. Additionally, we investigated neurophysiological functioning of several brain areas by phase-amplitude coupling (PAC) analysis, a measure associated with adequate cognitive functioning, during the VD task (starting at 4.5 months) and the exploration of home environment (at 5 and 8 months of age). While we did not detect age-dependent changes in PAC during home environment exploration for both the wild-type and the App(NL-G-F) mice, we did observe subtle changes in PAC in the wild-type mice that were not present in the App(NL-G-F) mice

What Electrophysiology Tells Us About Alzheimer’s Disease::A Window into the Synchronization and Connectivity of Brain Neurons

Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer’s disease (AD), despite a surge in recent validated evidence. This Position Paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.e., brain amyloidosis, tauopathy, and neurodegeneration) on neurophysiological mechanisms underpinning neural excitation/inhibition and neurotransmission as well as brain network dynamics, synchronization, and functional connectivity reflecting thalamocortical and cortico-cortical residual capacity. Converging evidence shows relationships between abnormalities in EEG/MEG markers and cognitive deficits in groups of AD patients at different disease stages. The supporting evidence for the application of electrophysiology in AD clinical research as well as drug discovery pathways warrants an international initiative to include the use of EEG/MEG biomarkers in the main multicentric projects planned in AD patients, to produce conclusive findings challenging the present regulatory requirements and guidelines for AD studies

Modulation of mGlu2 Receptors, but Not PDE10A Inhibition Normalizes Pharmacologically-Induced Deviance in Auditory Evoked Potentials and Oscillations in Conscious Rats.

Improvement of cognitive impairments represents a high medical need in the development of new antipsychotics. Aberrant EEG gamma oscillations and reductions in the P1/N1 complex peak amplitude of the auditory evoked potential (AEP) are neurophysiological biomarkers for schizophrenia that indicate disruption in sensory information processing. Inhibition of phosphodiesterase (i.e. PDE10A) and activation of metabotropic glutamate receptor (mGluR2) signaling are believed to provide antipsychotic efficacy in schizophrenia, but it is unclear whether this occurs with cognition-enhancing potential. The present study used the auditory paired click paradigm in passive awake Sprague Dawley rats to 1) model disruption of AEP waveforms and oscillations as observed in schizophrenia by peripheral administration of amphetamine and the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP); 2) confirm the potential of the antipsychotics risperidone and olanzapine to attenuate these disruptions; 3) evaluate the potential of mGluR2 agonist LY404039 and PDE10 inhibitor PQ-10 to improve AEP deficits in both the amphetamine and PCP models. PCP and amphetamine disrupted auditory information processing to the first click, associated with suppression of the P1/N1 complex peak amplitude, and increased cortical gamma oscillations. Risperidone and olanzapine normalized PCP and amphetamine-induced abnormalities in AEP waveforms and aberrant gamma/alpha oscillations, respectively. LY404039 increased P1/N1 complex peak amplitudes and potently attenuated the disruptive effects of both PCP and amphetamine on AEPs amplitudes and oscillations. However, PQ-10 failed to show such effect in either models. These outcomes indicate that modulation of the mGluR2 results in effective restoration of abnormalities in AEP components in two widely used animal models of psychosis, whereas PDE10A inhibition does not

Analysis of structural and proportional criteria of Romanesque and Pre-Romanesque rotundas.

Topic of this dissertation thesis follows previous dissertations dealing with reconstructions of historical buildings that were successfully defended at Institute of Building Structures, Faculty of Civil Engineering, Brno University of Technology. The thesis deals with Romanesque and Pre-Romanesque round churches, called rotundas, that were built between 9th and 13th century in the historical territory of Great Moravia. Churches of similar shape can be also found in surrounding countries, but only scarcely. By the time of origin these rotundas were among the oldest masonry buildings built within borders of contemporary Czech Republic. Later some rotundas were destroyed and are known only thanks to the archaeological findings or written records. Some are still waiting to be discovered. Surviving rotundas are the oldest masonry buildings in Czech Republic, therefore it can be said that they belong to the most valuable historical buildings in the country. Preserved rotundas were often modified or rebuild in some way. Thanks to their age, origins of many of these buildings are shrouded in a mystery, which is one of the reasons why they attract attention of many researchers – archaeologists, historians and art historians. Many questions arise from their research. These questions have interdisciplinary character and finding the answers requires cooperation of specialists in different fields. One of these fields is building engineering. This dissertation thesis deals with proportional and structural analysis of Pre-Romanesque and Romanesque rotundas. For the proportional analysis author focused on verifying of some of the hypotheses of other researchers connected to the Romanesque rotundas. These include hypothesis dealing with use of historical units for the design of rotundas, hypothetical use of proportional canon, or some universal sets of proportional ratios of vertical and horizontal dimensions. The proportional analysis also helped with verification of some hypoth

Effects of acute administration of olanzapine (2.5 mg/kg), amphetamine (0.64 mg/kg) or in combination on A/ Grand average evoked potentials derived from the frontal right hemisphere, B/ peak amplitude of the P1, N1, and P2 components (expressed in μV), C/ Mean S2/S1 ratio represent the gating index, D/ Average time frequency response in alpha EEG oscillations from the right frontal cortex in awake motionless state during the period of 40–60 min following the combined pharmacological treatment.

<p>Data are presented as mean ± S.E.M. of (n) animals for each condition (vehicle (7), olanzapine (7), amphetamine (7) and alanzapine + amphetamine (7)). 4 animals with baseline S2/S1 ratio higher than 5 across different conditions were discarded from the analysis. Olanzapine restored amphetamine-induced deficits in P1 and N1 gating responses and changes in low alpha oscillations. * indicates significant difference from vehicle (p < 0.05).</p

mGlu2 Receptor Agonism, but Not Positive Allosteric Modulation, Elicits Rapid Tolerance towards Their Primary Efficacy on Sleep Measures in Rats.

G-protein-coupled receptor (GPCR) agonists are known to induce both cellular adaptations resulting in tolerance to therapeutic effects and withdrawal symptoms upon treatment discontinuation. Glutamate neurotransmission is an integral part of sleep-wake mechanisms, which processes have translational relevance for central activity and target engagement. Here, we investigated the efficacy and tolerance potential of the metabotropic glutamate receptors (mGluR2/3) agonist LY354740 versus mGluR2 positive allosteric modulator (PAM) JNJ-42153605 on sleep-wake organisation in rats. In vitro, the selectivity and potency of JNJ-42153605 were characterized. In vivo, effects on sleep measures were investigated in rats after once daily oral repeated treatment for 7 days, withdrawal and consecutive re-administration of LY354740 (1-10 mg/kg) and JNJ-42153605 (3-30 mg/kg). JNJ-42153605 showed high affinity, potency and selectivity at mGluR2. Binding site analyses and knowledge-based docking confirmed the specificity of JNJ-42153605 at the mGluR2 allosteric binding site. Acute LY354740 and JNJ-42153605 dose-dependently decreased rapid eye movement (REM) sleep time and prolonged its onset latency. Sub chronic effects of LY354740 on REM sleep measures disappeared from day 3 onwards, whereas those of JNJ-42153605 were maintained after repeated exposure. LY354740 attenuated REM sleep homeostatic recovery, while this was preserved after JNJ-42153605 administration. JNJ-42153605 enhanced sleep continuity and efficiency, suggesting its potential as an add-on medication for impaired sleep quality during early stages of treatment. Abrupt cessation of JNJ-42153605 did not induce withdrawal phenomena and sleep disturbances, while the initial drug effect was fully reinstated after re-administration. Collectively, long-term treatment with JNJ-42153605 did not induce tolerance phenomena to its primary functional effects on sleep measures, nor adverse effects at withdrawal, while it promoted homeostatic recovery sleep. From the translational perspective, the present rodent findings suggest that mGluR2 positive allosteric modulation has therapeutic potential based on its superior long term efficacy over agonists in psychiatric disorders, particularly of those commonly occurring with REM sleep overdrive

Bar graphs depicting peak amplitude of the P1, N1, and P2 components (expressed in μV) and S2/S1 ratios of frontal auditory potentials after acute administration of A/ PQ-10 and B/ LY404039 compared to vehicle values.

<p>Data are presented as mean ± S.E.M. of (n) animals for each condition: PQ10 (vehicle (7), 0.3 (7), 1 (8) and 3mg/kg (8)), and LY404039 (vehicle (6), 1 (7), 3 (7) and 10 mg/kg (8)). Animals with baseline S2/S1 ratio higher than 5 across different conditions were discarded from the analysis (2 and 3 animals in PQ-10 and LY404039 experiments, respectively). There was a significant reduction of peak amplitude and S2/S1 ratios for P1 at the highest dose of both drugs (* p<0.05).</p