Hippocampal Electrophysiology Research Articles

Targeting vulnerable microcircuits in the ventral hippocampus of male transgenic mice to rescue Alzheimer-like social memory loss

BackgroundEpisodic memory loss is a prominent clinical manifestation of Alzheimer’s disease (AD), which is closely related to tau pathology and hippocampal impairment. Due to the heterogeneity of brain neurons, the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear. Therefore, further investigation is necessary.MethodsWe investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis, social behavioural tests, hippocampal electrophysiology, immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine the effects of these agents on social memory in mice.ResultsThe results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, vCA1, especially its excitatory and parvalbumin (PV) neurons, were fully filled with mislocated and phosphorylated tau (p-Tau). This finding was not observed for dorsal hippocampal CA1 (dCA1). The overexpression of human tau (hTau) in excitatory and PV neurons mimicked AD-like tau accumulation, significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory. Notably, 1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB (TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory.ConclusionThis study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.

Early classification of Alzheimer's disease phenotype based on hippocampal electrophysiology in the TgF344-AD rat model

The hippocampus plays a vital role in navigation, learning, and memory, and is affected in Alzheimer's disease (AD). This study investigated the classification of AD-transgenic rats versus wild-type littermates using electrophysiological activity recorded from the hippocampus at an early, presymptomatic stage of the disease (6months old) in the TgF344-AD rat model. The recorded signals were filtered into low frequency (LFP) and high frequency (spiking activity) signals, and machine learning classifiers were employed to identify the rat genotype (TG vs. WT). By analyzing specific frequency bands in the low frequency signals and calculating distance metrics between spike trains in the high frequency signals, accurate classification was achieved. Gamma band power emerged as a valuable signal for classification, and combining information from both low and high frequency signals improved the accuracy further. These findings provide valuable insights into the early stage effects of AD on different regions of the hippocampus.

TREM2‐H157Y Increases Soluble TREM2 Production and Reduces Amyloid Pathology

AbstractBackgroundThe p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) has been reported to increase Alzheimer’s disease (AD) risk. This mutation in the extracellular domain of TREM2 localizes at the cleavage site and was shown to enhance shedding and impair phagocytosis in vitro by ectopic expression of TREM2‐H157Y in HEK293 cells. However, the physiological and AD‐related outcomes of TREM2 H157Y mutation in vivo remain unknown.MethodWe generated a novel Trem2 H157Y knock‐in mouse model through CRISPR‐Cas9 technology and investigated how Trem2 H157Y mutation impacts TREM2 proteolytic processing, synaptic function, and AD‐related amyloid pathology by conducting biochemical assays, immunofluorescent staining, hippocampal electrophysiology, and in vivo micro‐dialysis in awake, free‐moving animals.ResultConsistent with previous in vitro findings, TREM2‐H157Y increases the amount of soluble TREM2 (sTREM2) in the cortex and serum of mutant mice compared to the wild type controls. Interestingly, the Trem2 H157Y variant enhances synaptic plasticity without affecting microglial density and morphology. In the presence of amyloid pathology, TREM2‐H157Y surprisingly accelerates Aβ clearance and reduces amyloid burden and microgliosis.ConclusionTaken together, our findings support a beneficial effect of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD, we speculate TREM2‐H157Y might increase AD risk through an amyloid‐independent pathway, as such its effects on tauopathy and neurodegeneration merit further investigation.

Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology

BackgroundThe rare p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) was found to increase Alzheimer’s disease (AD) risk. This mutation is located at the cleavage site of TREM2 extracellular domain. Ectopic expression of TREM2-H157Y in HEK293 cells resulted in increased TREM2 shedding. However, the physiological outcomes of the TREM2 H157Y mutation remain unknown in the absence and presence of AD related pathologies.MethodsWe generated a novel Trem2 H157Y knock-in mouse model through CRISPR/Cas9 technology and investigated the effects of Trem2 H157Y on TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathologies by conducting biochemical assays, targeted mass spectrometry analysis of TREM2, hippocampal electrophysiology, immunofluorescent staining, in vivo micro-dialysis, and cortical bulk RNA sequencing.ResultsConsistent with previous in vitro findings, Trem2 H157Y increases TREM2 shedding with elevated soluble TREM2 levels in the brain and serum. Moreover, Trem2 H157Y enhances synaptic plasticity without affecting microglial density and morphology, or TREM2 signaling. In the presence of amyloid pathology, Trem2 H157Y accelerates amyloid-β (Aβ) clearance and reduces amyloid burden, dystrophic neurites, and gliosis in two independent founder lines. Targeted mass spectrometry analysis of TREM2 revealed higher ratios of soluble to full-length TREM2-H157Y compared to wild-type TREM2, indicating that the H157Y mutation promotes TREM2 shedding in the presence of Aβ. TREM2 signaling was further found reduced in Trem2 H157Y homozygous mice. Transcriptomic profiling revealed that Trem2 H157Y downregulates neuroinflammation-related genes and an immune module correlated with the amyloid pathology.ConclusionTaken together, our findings suggest beneficial effects of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD risk, we speculate TREM2 H157Y in humans might increase AD risk through an amyloid-independent pathway, such as its effects on tauopathy and neurodegeneration which merit further investigation.

Inhibition is a prevalent mode of activity in the neocortex around awake hippocampal ripples in mice.

Coordinated peri-ripple activity in the hippocampal-neocortical network is essential for mnemonic information processing in the brain. Hippocampal ripples likely serve different functions in sleep and awake states. Thus, the corresponding neocortical activity patterns may differ in important ways. We addressed this possibility by conducting voltage and glutamate wide-field imaging of the neocortex with concurrent hippocampal electrophysiology in awake mice. Contrary to our previously published sleep results, deactivation and activation were dominant in post-ripple neocortical voltage and glutamate activity, respectively, especially in the agranular retrosplenial cortex (aRSC). Additionally, the spiking activity of aRSC neurons, estimated by two-photon calcium imaging, revealed the existence of two subpopulations of excitatory neurons with opposite peri-ripple modulation patterns: one increases and the other decreases firing rate. These differences in peri-ripple spatiotemporal patterns of neocortical activity in sleep versus awake states might underlie the reported differences in the function of sleep versus awake ripples.

Combining Cortical Voltage Imaging and Hippocampal Electrophysiology for Investigating Global, Multi-Timescale Activity Interactions in the Brain.

A new generation of optogenetic tools for analyzing neural activity has been contributing to the elucidation of classical open questions in neuroscience. Specifically, voltage imaging technologies using enhanced genetically encoded voltage indicators have been increasingly used to observe the dynamics of large circuits at the mesoscale. Here, we describe how to combine cortical wide-field voltage imaging with hippocampal electrophysiology in awake, behaving mice. Furthermore, we highlight how this method can be useful for different possible investigations, using the characterization of hippocampal–neocortical interactions as a case study.

Spatial maps and oscillations in the healthy hippocampus of Octodon degus, a natural model of sporadic Alzheimer's disease.

The Octodon degus is a South American rodent that is receiving increased attention as a potential model of aging and sporadic late-onset Alzheimer’s disease (AD). Impairments in spatial memory tasks in Octodon degus have been reported in relation to either advanced AD-like disease or hippocampal lesion, opening the way to investigate how the function of hippocampal networks affects behavior across AD stages. However, no characterization of hippocampal electrophysiology exists in this species. Here we describe in young, healthy specimens the activity of neurons and local field potential rhythms during spatial navigation tasks with and without objects. Our findings show similarities between the Octodon degus and laboratory rodents. First, place cells with characteristics similar to those found in rats and mice exist in the CA1 subfield of the Octodon degus. Second, the introduction of objects elicits novelty-related exploration and an increase in activity of CA1 cells, with location specific and unspecific components. Third, oscillations of the local field potential are organized according to their spectral content into bands similar to those found in laboratory rodents. These results suggest a common framework of underlying mechanisms, opening the way to future studies of hippocampal dysfunction in this species associated to aging and disease.

The impact of short-term microbiota depletion on hippocampal electrophysiology in mice

The impact of short-term microbiota depletion on hippocampal electrophysiology in mice

Cortical low-frequency power correlates with behavioral impairment in animal model of focal limbic seizures.

Impairment in consciousness is a debilitating symptom during and after seizures; however, its mechanism remains unclear. Limbic seizures have been shown to spread to arousal circuitry to result in a "network inhibition" phenomenon. However, prior animal model studies did not relate physiological network changes to behavioral responses during or following seizures. Focal onset limbic seizures were induced while rats were performing an operant conditioned behavioral task requiring response to an auditory stimulus to quantify how and when impairment of behavioral response occurs. Correct responses were rewarded with sucrose. Cortical and hippocampal electrophysiology measured by local field potential recordings was analyzed for changes in low- and high-frequency power in relation to behavioral responsiveness during seizures. As seen in patients with seizures, ictal (p<.0001) and postictal (p=.0015) responsiveness was variably impaired. Analysis of cortical and hippocampal electrophysiology revealed that ictal (p=.002) and postictal (p=.009) frontal cortical low-frequency 3-6-Hz power was associated with poor behavioral performance. In contrast, the hippocampus showed increased power over a wide frequency range during seizures, and suppression postictally, neither of which were related to behavioral impairment. These findings support prior human studies of temporal lobe epilepsy as well as anesthetized animal models suggesting that focal limbic seizures depress consciousness through remote network effects on the cortex, rather than through local hippocampal involvement. By identifying the cortical physiological changes associated with impaired arousal and responsiveness in focal seizures, these results may help guide future therapies to restore ictal and postictal consciousness, improving quality of life for people with epilepsy.

Postnatal Prebiotic Supplementation Has Long-Term Anxiolytic Effects, and Alters Hippocampal Network Activity, Developmental Metabolomics and Gut Microbiota in Male Rats

Feeding neonatal rats with a prebiotic (Bimuno galacto-oligosaccharides, B-GOS®), increased hippocampal NMDAR proteins. Here, we tested the effects of postnatal B-GOS® supplementation on anxious behavior, hippocampal electrophysiology, metabolomics, and faecal metagenomics in young, adolescent and adult rats. Postnatal, but not post-wean, B-GOS® administration reduced anxiety-like behaviour in adulthood, decreased the fast decay component of Τ (tau) of hippocampus CA1 NMDA currents and changed the age-specific modifications of the metabolomes of the brain, liver and intestines. Age, but not diet, affected the composition of the fecal microbiome overall on taxonomic genus level. However, B-GOS® supplementation reduced the abundance of Enterococcus and Dorea genera. In conclusion, the long-term anxiolytic effect of early-life B-GOS® intake, may be linked to altered hippocampal NMDA receptors kinetics. The prebiotic mediated changes in gut Enterococcus and Dorea and age-specific metabolic trajectories of central and peripheral tissues, may have contributed to the prolonged behavioural effect.

Sialylated human milk oligosaccharides program cognitive development through a non-genomic transmission mode

Breastmilk contains bioactive molecules essential for brain and cognitive development. While sialylated human milk oligosaccharides (HMOs) have been implicated in phenotypic programming, their selective role and underlying mechanisms remained elusive. Here, we investigated the long-term consequences of a selective lactational deprivation of a specific sialylated HMO in mice. We capitalized on a knock-out (KO) mouse model (B6.129-St6gal1tm2Jxm/J) lacking the gene responsible for the synthesis of sialyl(alpha2,6)lactose (6′SL), one of the two sources of sialic acid (Neu5Ac) to the lactating offspring. Neu5Ac is involved in the formation of brain structures sustaining cognition. To deprive lactating offspring of 6′SL, we cross-fostered newborn wild-type (WT) pups to KO dams, which provide 6′SL-deficient milk. To test whether lactational 6′SL deprivation affects cognitive capabilities in adulthood, we assessed attention, perseveration, and memory. To detail the associated endophenotypes, we investigated hippocampal electrophysiology, plasma metabolomics, and gut microbiota composition. To investigate the underlying molecular mechanisms, we assessed gene expression (at eye-opening and in adulthood) in two brain regions mediating executive functions and memory (hippocampus and prefrontal cortex, PFC). Compared to control mice, WT offspring deprived of 6′SL during lactation exhibited consistent alterations in all cognitive functions addressed, hippocampal electrophysiology, and in pathways regulating the serotonergic system (identified through gut microbiota and plasma metabolomics). These were associated with a site- (PFC) and time-specific (eye-opening) reduced expression of genes involved in central nervous system development. Our data suggest that 6′SL in maternal milk adjusts cognitive development through a short-term upregulation of genes modulating neuronal patterning in the PFC.

Irradiation of the head reduces adult hippocampal neurogenesis and impairs spatial memory, but leaves overall health intact in rats.

Treatment of brain cancer, glioma, can cause cognitive impairment as a side-effect, possibly because it disrupts the integrity of the hippocampus, a structure vital for normal memory. Radiotherapy is commonly used to treat glioma, but the effects of irradiation on the brain are still poorly understood, and other biological effects have not been extensively studied. Here, we exposed healthy adult male rats to moderate-dose irradiation of the head. We found no effect of irradiation on systemic inflammation, weight gain or gut microbiota diversity, although it increased the abundance of Bacteroidaceae family, namely Bacteroides genus in the gut microbiota. Irradiation had no effect on long-term potentiation in the CA3-CA1 synapse or endogenous hippocampal electrophysiology, but it did reduce adult hippocampal neurogenesis and impaired short-term spatial recognition memory. However, no overall cognitive impairment was observed. To summarize, our results suggest that in adult male rats head irradiation does not compromise health or cognition overall even though the number of new, adult-born hippocampal neurons is decreased. Thus, the sole effects of head irradiation on the body, brain and cognition might be less harmful than previously thought, and the cognitive decline experienced by cancer patients might originate from physiological and mental effects of the disease itself. Therefore, to increase the translational value of animal studies, the effects of irradiation should be studied together with cancer, in older animals, using varying irradiation protocols and doses.

Glycogen synthase kinase-3 inhibition rescues sex-dependent contextual fear memory deficit in human immunodeficiency virus-1 transgenic mice.

A significant number of HIV-1 patients on antiretroviral therapy develop HIV-associated neurocognitive disorders (HAND). Evidence indicate that biological sex may regulate HAND pathogenesis, but the mechanisms remain unknown. We investigated synaptic mechanisms associated with sex differences in HAND, using the HIV-1-transgenic 26 (Tg26) mouse model. Contextual- and cue-dependent memories of male and female Tg26 mice and littermate wild type mice were assessed in a fear conditioning paradigm. Hippocampal electrophysiology, immunohistochemistry, western blot, qRT-PCR and ELISA techniques were used to investigate cellular, synaptic and molecular impairments. Cue-dependent memory was unaltered in male and female Tg26 mice, when compared to wild type mice. Male, but not female, Tg26 mice showed deficits in contextual fear memory. Consistently, only male Tg26 mice showed depressed hippocampal basal synaptic transmission and impaired LTP induction in area CA1. These deficits in male Tg26 mice were independent of hippocampal neuronal loss and microglial activation but were associated with increased HIV-1 long terminal repeat mRNA expression, reduced hippocampal synapsin-1 protein, reduced BDNF mRNA and protein, reduced AMPA glutamate receptor (GluA1) phosphorylation levels and increased glycogen synthase kinase 3 (GSK3) activity. Importantly, selective GSK3 inhibition using 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione increased levels of synapsin-1, BDNF and phosphorylated-GluA1 proteins, restored hippocampal basal synaptic transmission and LTP, and improved contextual fear memory in male Tg26 mice. Sex-dependent impairments in contextual fear memory and synaptic plasticity in Tg26 mice are associated with increased GSK3 activity. This implicates GSK3 inhibition as a potential therapeutic strategy to improve cognition in HIV-1 patients.

Transplanted Wharton’s jelly mesenchymal stem cells improve memory and brain hippocampal electrophysiology in rat model of Parkinson’s disease

BackgroundExperimental findings have shown that stem cell transplantation is a therapeutic procedure for Parkinson’s disease (PD). In this study, effects of human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs), alone and combined with l-dopa, were examined for repairing memory impairment in a rat model of PD. MethodsFifty adult male Wistar rats were randomly divided into five groups: 1) sham, 2) PD, 3) PD + C, 4) PD + C+D, and 5) PD + D. PD was induced by 6-OHDA injection (16 μg/2 μl) into medial forebrain bundle (MFB) and was confirmed 14 days later by contralateral rotation using apomorphine injection. The rats received hWJ-MSCs (1 × 106 cells, i.v.) twice on the 14th and 28th days post PD induction. Treated PD rats received hWJ-MSCs alone or combined with l-Dopa and Carbidopa (10/30 mg/kg, i.p.). Four months later, memory, hippocampal long-term potentiation (hLTP), histological changes, and the levels of BDNF and NGF in striatum were evaluated. ResultsPD caused both cell loss with small dark stained nuclei in granular zone as well as significant decrement of BDNF and NGF (P < 0.001) in striatum. These pathological alterations were associated with memory and hLTP deficits (P < 0.001 respectively). Treating PD rats with hWJ-MSCs, alone (P < 0.05 and P < 0.001) and combined with l-Dopa (P < 0.001), significantly restored the levels of both of the neurotrophins followed by improving cognition and hLTP (P < 0.001). ConclusionCurrent findings showed that chronic treatment of PD rats with hWJ-MSCs, alone and in combination with l-Dopa, could restore memory and hLTP by reconstructing dopaminergic neurons and elevating the BDNF and NGF factors.

Functionally distinct high and low theta oscillations in the human hippocampus

Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4–10 Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in theta’s function. To characterize human hippocampal theta, we examine the properties of theta oscillations throughout the anterior–posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observe hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displays oscillations at ~8-Hz and the precise frequency of these oscillations correlates with the speed of movement, implicating these signals in spatial navigation. We also observe slower ~3 Hz oscillations, but these signals are more prevalent in the anterior hippocampus and their frequency does not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high- and low-frequency theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes.

Effect of sevoflurane inhalation on electrophysiology and ultrastructure of hippocampus in neonatal rats

ObjectiveThe hippocampal neuron electrophysiology and structure might be the basis of postoperative cognitive function‐related diseases after anesthesia. Here, we examined whether sevoflurane inhalation affected the electrophysiological and ultrastructural morphology of the hippocampal neurons.MethodsThe rats were randomly divided into the air/oxygen and Sevoflurane group (SEV group). The air/oxygen group inhaled carrier gas (1 L/min O2 + 1 L/min air) for 2 hours; The SEV group inhaled 3.4% sevoflurane &amp; carrier gas for 2 hours. After that, the hippocampal electrophysiology signals were observed 1 week after anesthesia. Then, Transmission Electron Microscope was used to observe the neuron cell morphology, structures, and related synaptic morphology in hippocampi.ResultsCompared with the air/oxygen group, the numbers of spontaneous discharge and the values of maximum current significantly decreased in the SEV group, and the neuron cytoplasm edema and organelles also were damaged.ConclusionThe results showed that sevoflurane could weaken the electrophysiological signals of hippocampal neurons and damage the ultrastructure of neurons.

Hypothermia Masks Most of the Effects of Rapid Cycling VNS on Rat Hippocampal Electrophysiology.

AIM. Vagus nerve stimulation (VNS) modulates hippocampal dentate gyrus (DG) electrophysiology and induces hypothermia in freely moving rats. This study evaluated whether hippocampal (CA1) electrophysiology is similarly modulated and to what extent this is associated with VNS-induced hypothermia. METHODS. Six freely moving rats received a first 4h session of rapid cycling VNS (7s on/18s off), while CA1 evoked potentials, EEG and core temperature were recorded. In a second 4h session, external heating was applied during the 3rd and 4thh of VNS counteracting VNS-induced hypothermia. RESULTS. VNS decreased the slope of the field excitatory postsynaptic potential (fEPSP), increased the population spike (PS) amplitude and latency, decreased theta (4-12Hz) and gamma (30-100Hz) band power and theta peak frequency. Normalizing body temperature during VNS through external heating abolished the effects completely for fEPSP slope, PS latency and gamma band power, partially for theta band power and theta peak frequency and inverted the effect on PS amplitude. CONCLUSIONS. Rapid cycle VNS modulates CA1 electrophysiology similarly to DG, suggesting a wide-spread VNS-induced effect on hippocampal electrophysiology. Normalizing core temperature elucidated that VNS-induced hypothermia directly influences several electrophysiological parameters but also masks a VNS-inducedreduction in neuronal excitability.

Acute slice preparation for electrophysiology increases spine numbers equivalently in the male and female juvenile hippocampus: a DiI labeling study.

Hippocampal slices are widely used for in vitro electrophysiological experiments to study underlying mechanisms for synaptic transmission and plasticity, and there is a growing appreciation for sex differences in synaptic plasticity. To date, several studies have shown that the process of making slices from male animals can induce synaptogenesis in cornu ammonis area 1 (CA1) pyramidal cells, but there is a paucity of data for females and other brain regions. In the current study we use microcrystals of the lipophilic carbocyanine dye DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) to stain individual neurons in the CA1 and dentate gyrus (DG) hippocampal subfields of postnatal day 21 male and female rats. We show that the preparation of sections for electrophysiology produces significant increases in spines in sections obtained from females, similar to that observed in males. We also show that the procedures used for in vitro electrophysiology also result in significant spine increases in the DG and CA1 subfields. These results demonstrate the utility of this refined DiI procedure for staining neuronal dendrites and spines. They also show, for the first time, that in vitro electrophysiology slice preparations enhance spine numbers on hippocampal cells equivalently in both juvenile females and males.NEW & NOTEWORTHY This study introduces a new DiI technique that elucidates differences in spine numbers in juvenile female and male hippocampus, and shows that slice preparations for hippocampal electrophysiology in vitro may mask these differences.

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Models of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIα promoter), human mutated Tau (hTauP301L+R406W) knock-in mouse was generated out of the previously characterised PLB1Triple mouse, and named PLB2Tau. After confirmation of an additional hTau species (~60kDa) in forebrain samples, we identified age-dependent progressive Tau phosphorylation which coincided with the emergence of FTD relevant behavioural traits. In line with the non-cognitive symptomatology of FTD, PLB2Tau mice demonstrated early emerging (~6months) phenotypes of heightened anxiety in the elevated plus maze, depressive/apathetic behaviour in a sucrose preference test and generally reduced exploratory activity in the absence of motor impairments. Investigations of cognitive performance indicated prominent dysfunctions in semantic memory, as assessed by social transmission of food preference, and in behavioural flexibility during spatial reversal learning in a home cage corner-learning task. Spatial learning was only mildly affected and task-specific, with impairments at 12months of age in the corner learning but not in the water maze task. Electroencephalographic (EEG) investigations indicated a vigilance-stage specific loss of alpha power during wakefulness at both parietal and prefrontal recording sites, and site-specific EEG changes during non-rapid eye movement sleep (prefrontal) and rapid eye movement sleep (parietal). Further investigation of hippocampal electrophysiology conducted in slice preparations indicated a modest reduction in efficacy of synaptic transmission in the absence of altered synaptic plasticity.Together, our data demonstrate that the transgenic PLB2Tau mouse model presents with a striking behavioural and physiological face validity relevant for FTD, driven by the low level expression of mutant FTD hTau.

Hippocampal Sharp-Wave Ripples Influence Selective Activation of the Default Mode Network

SummaryThe default mode network (DMN) is a commonly observed resting-state network (RSN) that includes medial temporal, parietal, and prefrontal regions involved in episodic memory [1, 2, 3]. The behavioral relevance of endogenous DMN activity remains elusive, despite an emerging literature correlating resting fMRI fluctuations with memory performance [4, 5]—particularly in DMN regions [6, 7, 8]. Mechanistic support for the DMN’s role in memory consolidation might come from investigation of large deflections (sharp-waves) in the hippocampal local field potential that co-occur with high-frequency (>80 Hz) oscillations called ripples—both during sleep [9, 10] and awake deliberative periods [11, 12, 13]. Ripples are ideally suited for memory consolidation [14, 15], since the reactivation of hippocampal place cell ensembles occurs during ripples [16, 17, 18, 19]. Moreover, the number of ripples after learning predicts subsequent memory performance in rodents [20, 21, 22] and humans [23], whereas electrical stimulation of the hippocampus after learning interferes with memory consolidation [24, 25, 26]. A recent study in macaques showed diffuse fMRI neocortical activation and subcortical deactivation specifically after ripples [27]. Yet it is unclear whether ripples and other hippocampal neural events influence endogenous fluctuations in specific RSNs—like the DMN—unitarily. Here, we examine fMRI datasets from anesthetized monkeys with simultaneous hippocampal electrophysiology recordings, where we observe a dramatic increase in the DMN fMRI signal following ripples, but not following other hippocampal electrophysiological events. Crucially, we find increases in ongoing DMN activity after ripples, but not in other RSNs. Our results relate endogenous DMN fluctuations to hippocampal ripples, thereby linking network-level resting fMRI fluctuations with behaviorally relevant circuit-level neural dynamics.