Sequential habituation to space, object and stranger is differentially modulated by glutamatergic, cholinergic and dopaminergic transmission.

Novel object and social interaction tasks allow assessments of rodent cognition and social behavior. Here, we combined these tasks and defined unequivocal locations of interest. Our procedure, termed OF-NO-SI, comprised habituation to the open field (OF), novel object (NO) and social interaction (SI) stages. Habituation was measured within- and between-trials (10 minutes each, two per stage). Ambulation emerged as the appropriate proxy during the OF stage, but NO and SI trials were best quantified via direct exploration measures. We pharmacologically validated the paradigm using 5-month old C57BL/6J male mice, treated intraperitoneally with (1) 0.5 mg/kg scopolamine, (2) 0.05 mg/kg MK-801 and (3) 0.05 mg/kg SCH-23390 to block muscarinic (M1), NMDA, and D1 receptors, respectively, or (4) vehicle (distilled water). Activity and gross exploratory behavior were affected by all compounds cf. vehicle: scopolamine and MK-801 cohorts were hyperactive, while SCH-23390 caused hypo-locomotion throughout. Vehicle treated mice showed reliable habituation to all stages for time in interaction zone, directed exploration and number of visits. Exploration was severely impaired by scopolamine. MK-801 mostly affected within-session exploration but also increased exploration of the conspecific compared to the object. Interestingly, even though within-trial habituation was lacking in the SCH-23390 cohort, between-trial habituation was largely intact, despite reduced locomotion. Our data suggest that the OF-NO-SI task is a convenient and robust paradigm to measure habituation to different experimental settings and stimuli. It allows the dissociation of proxies related to activity and non-associative learning/memory, as revealed by distinct pharmacological treatment effects within- vs. between-trials.

Delirium screening in the intensive care unit using emerging QEEG techniques: A pilot study.

Delirium is an under-diagnosed yet frequently occurring clinical complication with potentially serious consequences for intensive care unit (ICU) patients. Diagnosis is currently reactive and based upon qualitative assessment of the patient's cognitive status by ICU staff. Here, we conducted a preliminary investigation into whether emerging quantitative electroencephalography (QEEG) analysis techniques can accurately discriminate between delirious and non-delirious patients in an ICU setting. Resting EEG recordings from 5 ICU patients in a state of delirium and 5 age matched control patients were analyzed using autoregressive spectral estimation for quantification of EEG power and renormalized partial directed coherence for analysis of directed functional connectivity. Delirious subjects exhibited pronounced EEG slowing as well as severe general loss of directed functional connectivity between recording sites. Distinction between groups based on these parameters was surprisingly clear given the low sample size employed. Furthermore, by targeting the electrode positions where effects were most apparent it was possible to clearly segregate patients using only 3 scalp electrodes. These findings indicate that quantitative diagnosis and monitoring of delirium is not only possible using emerging QEEG methods but is also accomplishable using very low-density electrode systems.

Knock-in of Mutated hTAU Causes Insulin Resistance, Inflammation and Proteostasis Disturbance in a Mouse Model of Frontotemporal Dementia.

Diabetes and obesity have been implicated as risk factors for dementia. However, metabolic mechanisms and associated signalling pathways have not been investigated in detail in frontotemporal dementia. We therefore here characterised physiological, behavioural and molecular phenotypes of 3- and 8-month-old male tau knock-in (PLB2TAU) vs wild-type (PLBWT) mice. Homecage analysis suggested intact habituation but a dramatic reduction in exploratory activity in PLB2TAU mice. Deficits in motor strength were also observed. At 3 months, PLB2TAU mice displayed normal glucose handling but developed hyperglycaemia at 8 months, suggesting a progressive diabetic phenotype. Brain, liver and muscle tissue analyses confirmed tissue-specific deregulation of metabolic and homeostatic pathways. In brain, increased levels of phosphorylated tau and inflammation were detected alongside reduced ER regulatory markers, overall suggesting a downregulation in essential cellular defence pathways. We suggest that subtle neuronal expression of mutated human tau is sufficient to disturb systems metabolism and protein handling. Whether respective dysfunctions in tauopathy patients are also a consequence of tau pathology remains to be confirmed, but could offer new avenues for therapeutic interventions.

Miniature Untethered EEG Recorder Improves Advanced Neuroscience Methodologies.

Rodent electroencephalography (EEG) in preclinical research is frequently conducted in behaving animals. However, the difficulty inherent in identifying EEG epochs associated with a particular behavior or cue is a significant obstacle to more efficient analysis. In this paper we highlight a new solution, using infrared event stamping to accurately synchronize EEG, recorded from superficial sites above the hippocampus and prefrontal cortex, with video motion tracking data in a transgenic Alzheimer's disease (AD) mouse model. Epochs capturing specific behaviors were automatically identified and extracted prior to further analysis. This was achieved by the novel design of an ultra-miniature wearable EEG recorder, the NAT-1 device, and its in-situ IR recording module. The device is described in detail, and its contribution to enabling new neuroscience is demonstrated.

Of mice and motion: Behavioural-EEG phenotyping of Alzheimer's disease mouse models.

BACKGROUND: Rodent electroencephalography (EEG) in preclinical research is frequently conducted in behaving animals. EEG analysis is complicated by a number of confounds, particularly 1. The close relationship between EEG power and movement speed must be controlled for prior to further analysis. 2. The difficulty inherent in identifying EEG epochs associated with a particular behaviour. NEW METHOD: We utilized infra-red event stamping to accurately synchronize EEG recorded superficially above the hippocampus and prefrontal cortex with motion tracking data in a transgenic Alzheimer's disease (AD) mouse model (PLB1APP) and wild-type controls (PLBWT) performing a Y-maze spontaneous alternation task. Video tracking synchronized epochs capturing specific behaviours were automatically identified and extracted prior to auto-regressive spectral analysis. RESULTS: Despite comparable behavioural performance, PLB1APP mice demonstrated region and behavioural context specific deficits in regulation of Gamma power: In contrast to controls, hippocampal Gamma response to speed as well as prefrontal activity associated with correct vs. incorrect alternations was absent in PLB1APP mice. Regulation of hippocampal Gamma power in response to direction of movement did not differ. COMPARISON WITH EXISTING METHODS: This method allows for the first time to detect behaviour-specific differences in EEG response to speed that can be quantified and actively controlled for. Analysis across multiple parameters engaging different brain regions can now be used for detailed EEG profiling of brain-region specific functions. CONCLUSION: Combining infra-red event-stamping and auto-regressive modelling enables rapid, automated and sensitive phenotyping of AD mouse models. Subtle alterations in brain signalling can be detected prior to overt behavioural impairments.

Spatial learning and flexibility in 129S2/SvHsd and C57BL/6J mouse strains using different variants of the Barnes maze.

Behavioural flexibility is the ability to switch between tasks and strategies following a change in rules, and involves intact functioning of the medial prefrontal cortex. Impairments of behavioural flexibility have frequently been reported in patients with schizophrenia and rodents with disruption/dysfunction of the prefrontal cortex. The discovery of a mutation in the disrupted in schizophrenia 1 (DISC1) gene in the 129 mouse strain suggests that these mice may be exploited as a 'naturally occurring' model of schizophrenia. The aim of this present study was to assess cognition and behavioural flexibility of 129S2/SvHsd mice in comparison with C57BL/6J mice in the Barnes maze, using three different maze variations that consisted of either 8, 16 or 32 holes. Whereas C57BL/6J mice were able to perform both acquisition and reversal learning in all three mazes, 129S2/SvHsd mice displayed impairments dependent on the complexity of the test. Intact acquisition and reversal occurred in the 8-hole maze; intact acquisition, but impaired reversal, was evident in the 16-hole maze and impaired acquisition was evident in the most difficult 32-hole test. Furthermore, analysis of search strategies confirmed strain differences in the adoption of spatial searches across both acquisition and reversal trials. 129S2/SvHsd mice displayed fewer spatial-type trials than C57BL/6J mice and instead employed more random or serial/chaining search behaviours. The deficits observed in both cognition and behavioural flexibility support the notion of the 129 mouse strain as a potential model of schizophrenia.

Histological and Behavioral Phenotypes of a Novel Mutated APP Knock-In Mouse.

Gene mutations within amyloid precursor protein (APP or AßPP) and/or presenilin 1 (PS1) genes are determinants of familial Alzheimer's disease (fAD) and remain fundamental for experimental models. Here, we generated a neuronal knock-in mouse (PLB2APP) with mutated human APPSwe/Lon and investigated histopathology and behavioral phenotypes. Additionally, PLB2APP mice were cross-bred with a presenilin (PS1A246E) line to assess the impact of this gene combination. Immunohistochemistry determined amyloid-ß (Aß) pathology, astrogliosis (via GFAP labelling), and neuronal densities in hippocampal and cortical brain regions. One-year old PLB2APP mice showed higher levels of intracellular Aß in CA1, dentate gyrus, and cortical regions compared to PLBWT controls. Co-expression of PS1 reduced hippocampal but elevated cortical Aß build-up. Amyloid plaques were sparse in aged PLB2APP mice, and co-expression of PS1 promoted plaque formation. Heightened GFAP expression followed the region-specific pattern of Aß in PLB2APP and PLB2APP/PS1 mice. Behaviorally, habituation to a novel environment was delayed in 6-month-old PLB2APP mice, and overall home-cage activity was reduced in both lines at 6 and 12 months, particularly during the dark phase. Spatial learning in the water maze was impaired in PLB2APP mice independent of PS1 expression and associated with reduced spatial navigation strategies. Memory retrieval was compromised in PLB2APP mice only. Our data demonstrate that low expression of APP is sufficient to drive histopathological and cognitive changes in mice without overexpression or excessive plaque deposition. AD-like phenotypes were altered by co-expression of PS1, including a shift from hippocampal to cortical Aß pathology, alongside reduced deficits in spatial learning.

Detection of time-, frequency- and direction-resolved communication within brain networks.

Electroencephalography (EEG) records fast-changing neuronal signalling and communication and thus can offer a deep understanding of cognitive processes. However, traditional data analyses which employ the Fast-Fourier Transform (FFT) have been of limited use as they do not allow time- and frequency-resolved tracking of brain activity and detection of directional connectivity. Here, we applied advanced qEEG tools using autoregressive (AR) modelling, alongside traditional approaches, to murine data sets from common research scenarios: (a) the effect of age on resting EEG; (b) drug actions on non-rapid eye movement (NREM) sleep EEG (pharmaco-EEG); and (c) dynamic EEG profiles during correct vs incorrect spontaneous alternation responses in the Y-maze. AR analyses of short data strips reliably detected age- and drug-induced spectral EEG changes, while renormalized partial directed coherence (rPDC) reported direction- and time-resolved connectivity dynamics in mice. Our approach allows for the first time inference of behaviour- and stage-dependent data in a time- and frequency-resolved manner, and offers insights into brain networks that underlie working memory processing beyond what can be achieved with traditional methods.

Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility.

Dysfunction of parvalbumin (PV)-positive GABAergic interneurons (PVIs) within the prefrontal cortex (PFC) has been implicated in schizophrenia pathology. It is however unclear, how impaired signaling of these neurons may contribute to PFC dysfunction. To identify how PVIs contribute to PFC-dependent behaviors we inactivated PVIs in the PFC in mice using region- and cell-type-selective expression of tetanus toxin light chain (TeLC) and compared the functional consequences of this manipulation with non-cell-type-selective perturbations of the same circuitry. By sampling for behavioral alterations that map onto distinct symptom categories in schizophrenia, we show that dysfunction of PVI signaling in the PFC specifically produces deficits in the cognitive domain, but does not give rise to PFC-dependent correlates of negative or positive symptoms. Our results suggest that distinct aspects of the complex symptomatology of PFC dysfunction in schizophrenia can be attributed to specific prefrontal circuit elements.

Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes.

Key neuropathological hallmarks of Alzheimer's disease (AD) are elevated levels of amyloid ß-peptide (Aß) species generated via amyloid precursor protein (APP) endoproteolysis and cleavage by the rate-limiting ß-site enzyme 1 (BACE1). Because rodents do not develop amyloid pathologies, we here investigated whether AD-like endophenotypes can be created in mice by expression of human bace1. To avoid pitfalls of existing models, we introduced hbace1 via knock-in under the control of the CaMKII α promoter into the safe HPRT locus. We report amyloidogenic processing of murine APP in the hBACE1 mice (termed PLB4), resulting in the formation of toxic APP metabolites that accumulate intra- and extraneuronally in hippocampus and cortex. Pronounced accumulation of Aß*56 and Aß hexamers in the absence of plaque deposition was detected in brain tissue from symptomatic PLB4 mice. Heightened levels of inflammation (gliosis) also appeared in several AD-related brain regions (dentate gyrus, hippocampal area CA1, piriform and parietal cortices) at 6 and 12 months of age. Behaviorally, deficits in habituation to a novel environment and semantic-like memory (social transmission of food preference) were detected from 3 to 4 months of age. Impairments in spatial learning strategies in long-term reference (water maze) and working memory (Y-maze) tasks presented at 6 months, and were distinct from reductions in locomotor activity and anxiety. Overall, our data indicate for the first time that targeted, subtle forebrain-specific expression through single gene knock-in of hBACE1 is sufficient to generate AD-relevant cognitive impairments amid corresponding histopathologies, confirming human BACE as the key parameter in amyloid pathogenesis.