The effects of social environment on AD-related pathology in hAPP-J20 mice and tau-P301L mice

In humans, social factors (e.g., loneliness) have been linked to the risk of developing Alzheimer's Disease (AD). To date, AD pathology is primarily characterized by amyloid-β plaques and tau tangles. We aimed to assess the effect of single- and group-housing on AD-related pathology in a mouse model for amyloid pathology (J20, and WT controls) and a mouse model for tau pathology (P301L) with and without seeding of synthetic human tau fragments (K18). Female mice were either single housed (SH) or group housed (GH) from the age of 6-7 weeks onwards. In 12-week-old P301L mice, tau pathology was induced through seeding by injecting K18 into the dorsal hippocampus (P301L K18), while control mice received a PBS injection (P301L PBS). P301L mice were sacrificed at 4 months of age and J20 mice at 10 months of age. In all mice brain pathology was histologically assessed by examining microglia, the CA1 pyramidal cell layer and specific AD pathology: analysis of plaques in J20 mice and tau hyperphosphorylation in P301L mice. Contrary to our expectation, SH-J20 mice interestingly displayed fewer plaques in the hippocampus compared to GH-J20 mice. However, housing did not affect tau hyperphosphorylation at Ser202/Thr205 of P301L mice, nor neuronal cell death in the CA1 region in any of the mice. The number of microglia was increased by the J20 genotype, and their activation (based on cell body to cell size ratio) in the CA1 was affected by genotype and housing condition (interaction effect). Single housing of P301L mice was linked to the development of stereotypic behavior (i.e. somersaulting and circling behavior). In P301L K18 mice, an increased number of microglia were observed, among which were rod microglia. Taken together, our findings point to a significant effect of social housing conditions on amyloid plaques and microglia in J20 mice and on the development of stereotypic behavior in P301L mice, indicating that the social environment can modulate AD-related pathology. </p

Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-a]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2

We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-c]pyridines with mGlu(2) positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters k(on), k(off) and residence time (RT) were determined. The PAMs showed various kinetic profiles; k(on) values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant k(on) was linearly correlated to affinity. Evaluation of a short, medium, and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep-wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu(2) PAMs with high values for k(on) but not necessarily optimized RT, which is key to predicting optimal efficacy in vivo

International Federation of Clinical Neurophysiology (IFCN) – EEG research workgroup: Recommendations on frequency and topographic analysis of resting state EEG rhythms. Part 1: Applications in clinical research studies

In 1999, the International Federation of Clinical Neurophysiology (IFCN) published “IFCN Guidelines for topographic and frequency analysis of EEGs and EPs” (Nuwer et al., 1999). Here a Workgroup of IFCN experts presents unanimous recommendations on the following procedures relevant for the topographic and frequency analysis of resting state EEGs (rsEEGs) in clinical research defined as neurophysiological experimental studies carried out in neurological and psychiatric patients: (1) recording of rsEEGs (environmental conditions and instructions to participants; montage of the EEG electrodes; recording settings); (2) digital storage of rsEEG and control data; (3) computerized visualization of rsEEGs and control data (identification of artifacts and neuropathological rsEEG waveforms); (4) extraction of “synchronization” features based on frequency analysis (band-pass filtering and computation of rsEEG amplitude/power density spectrum); (5) extraction of “connectivity” features based on frequency analysis (linear and nonlinear measures); (6) extraction of “topographic” features (topographic mapping; cortical source mapping; estimation of scalp current density and dura surface potential; cortical connectivity mapping), and (7) statistical analysis and neurophysiological interpretation of those rsEEG features. As core outcomes, the IFCN Workgroup endorsed the use of the most promising “synchronization” and “connectivity” features for clinical research, carefully considering the limitations discussed in this paper. The Workgroup also encourages more experimental (i.e. simulation studies) and clinical research within international initiatives (i.e., shared software platforms and databases) facing the open controversies about electrode montages and linear vs. nonlinear and electrode vs. source levels of those analyses

Cholinergic Mechanisms of Target Oddball Stimuli Detection: The Late “P300-Like” Event-Related Potential in Rats

Event-related potentials (ERPs) and oscillations (EROs) provide powerful tools for studying the brain’s synaptic function underlying information processing. The P300 component of ERPs indexing attention and working memory shows abnormal amplitude and latency in neurological and psychiatric diseases that are sensitive to pharmacological agents. In the active auditory oddball discriminant paradigm, behavior and auditory-evoked potentials (AEPs) were simultaneously recorded in awake rats to investigate whether P300-like potentials generated in rats responding to rare target oddball tones are sensitive to subcutaneous modulation of the cholinergic tone by donepezil (1 mg/kg) and scopolamine (0.64 mg/kg). After operant training, rats consistently discriminate rare target auditory stimuli from frequent irrelevant nontarget auditory stimuli by a higher level of correct lever presses (i.e., accuracy) in target trials associated with a food reward. Donepezil attenuated the disruptive effect of scopolamine on the level of accuracy and premature responses in target trials. Larger P300-like peaks with early and late components were revealed in correct rare target stimuli trials as compared to frequent tones. Donepezil enhanced the peak amplitude of the P300-like component to target stimuli and evoked slow theta and gamma oscillations, whereas scopolamine altered the amplitude of the P300-like component and EROs to target stimuli. Pretreatment with donepezil attenuated effects of scopolamine on the peak amplitude of the P300-like component and on EROs. This study provides evidence that AEP P300-like responses can be elicited by rats engaged in attentive and memory processing of target stimuli and outline the relevance of the cholinergic system in stimulus discrimination processing. The findings highlight the sensitivity of this translational index for investigating brain circuits and/or novel pharmacological agents, which modulate cholinergic transmission associated with increased allocation of attentional resources

Recognition memory in rats-I. Concepts and classification

Recognition is the process by which a subject is aware that a stimulus has been previously experienced. It requires that the characteristics of events are perceived, discriminated, identified and then compared (matched) against a memory of the characteristics of previously experienced events. Understanding recognition memory, its underlying neuronal mechanisms, its dysfunction and alleviation of the latter by putative cognition enhancing drugs is a major research target and has triggered a wealth of animal studies. One of the most widely used animals for this purpose is the rat, and it is the rat's recognition memory which is the focus of this review. In this first part, concepts of recognition memory, stages of mnemonic processing and paradigms for the measurement of the rat's recognition memory will be discussed. In two subsequent articles (parts II and III) we will focus on the neuronal mechanisms underlying recognition memory in rats. Three major points arise from the comparison of paradigms that have in the past been used to assess recognition memory in rats. First, it should be realized that some tasks which, at face value, can all be considered to measure recognition memory in rats, may not assess recognition memory at all but may, for example, be based on recall rather than recognition. Second, it is evident that different types of recognition memory can be distinguished and that tasks differ in the type of recognition memory taxed. Some paradigms, for example, measure familiarity, whereas others assess recency. Furthermore, paradigms differ as to whether spatial stimuli or items are employed. Third, different processes, ranging from stimulus–response learning to the formation of concepts, may be involved to varying extent in different tasks. These are important considerations and question the predictive validity of the results obtained from studies examining, for example, the effects of putative cognition enhancing drugs