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In response to sensory stimulation, the cortex exhibits an early transient response followed by a late and slower activation pattern. Recent studies suggest that the early component represents features of the stimulus while the late component is associated with stimulus perception. Although very informative, these studies only focus on the amplitude of the evoked responses to study its relationship with sensory perception. In this work we expand upon the study of how patterns of evoked and spontaneous activity are modified by experience at mesoscale level using voltage and extracellular glutamate transient recordings over widespread regions of mice dorsal neocortex. We find that repeated tactile or auditory stimulation selectively modifies the spatiotemporal patterns of cortical activity, mainly of the late evoked response in anesthetized mice injected with amphetamine and also in awake mice. This modification lasted up to 60 minutes and results not only in an increase in amplitude of the late response after repeated stimulation, but also in an increase in the similarity between the spatiotemporal patterns of the late and the early evoked response patterns in anesthetized mice. This similarity increase occurs only for the evoked responses of the sensory modality that received the repeated stimulation. Thus, this selective long-lasting spatiotemporal modification of the cortical activity patterns might provide evidence that evoked responses are a cortex-wide phenomenon. This work opens new questions about how perception-related cortical activity changes with sensory experience across the cortex.

SummaryHippocampus-neocortex interactions during sleep are critical for memory processes: hippocampally-initiated replay contributes to memory consolidation in the neocortex and hippocampal sharp wave/ripples are linked to generalized increases in neocortical cell activity and DOWN-UP state transitions. Yet, the spatial and temporal patterns of this exchange are unknown. With voltage imaging, electrocorticography, and laminarly-resolved hippocampal potentials, we characterized cortico-hippocampal interactions during anesthesia and NREM sleep. We observed neocortical activation transients spanning multiple spatial scales hinting at a quasi-critical regime. Transients were organized in a small number of functional networks matching known anatomical connectivity. A network overlapping with the default mode network and centered on retrosplenial cortex was the most associated with the hippocampus. Interestingly, hippocampal slow gamma was the oscillation that best correlated with this neocortical network, outpacing ripples. In fact, neocortical activity predicted hippocampal slow gamma and followed ripples, suggesting that consolidation processes rely on bi-directional exchanges between hippocampus and neocortex.

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.

Episodic memory depends on the association of diverse attribute representations that are distributed across the neocortex, and evidence suggests that these attributes are linked, at least initially, by the hippocampus, which orchestrates retrieval and the offline replay of experience during memory consolidation. The dynamics that characterize this hippocampal-cortical dialogue, however, are only partly understood. Although it was originally proposed that replay is initiated in CA3, with the spontaneous emission of sharp-wave ripple (SWR) bursts, increasing evidence suggests that cortex may seed the process with partial information, leading to pattern completion in CA3 and subsequent global reactivation of the episode. A recent study has shown that the secondary motor cortex (M2), among other areas, carries two distinct types of representations: place cell-like activity, which relies on an intact hippocampus for its development, and responses tied to visuo-tactile cues — the ‘attributes’ of the experience, which do not require the hippocampus. Using two-photon Ca2+imaging, while simultaneously acquiring LFP from the ipsilateral CA1, we assessed the interactions among cortical retrieval of visuo-tactile attributes of previous experiences in a virtual environment, hippocampal SWR, and the cortical reinstatement of the spatial aspects of the same experiences. During rest after the experience, two types of reactivation events occurred, which separately conveyed information about spatial trajectories and visuo-tactile attributes. Reactivation of attribute information preceded that of trajectories in relation to hippocampal SWRs. Furthermore, paired reactivations of cue and trajectory information supported similar features of previous experiences. These results are consistent with the hypothesis that cortical retrieval of non-spatial attributes of recent experience seeds hippocampal reactivation of associated spatial sequences, which is followed by retrieval of episodic memory traces.

Background. Alzheimer’s disease (AD) is characterized by the prion-like propagation of amyloid-β (Aβ). However, the role of Ab in cognitive impairment is still unclear. Methods. Two-month-old AppNL-G-F were intracerebrally seeded with three conformationally distinct Aβ seeds. The mice were trained in a multi-model paradigm using multiple behavioural tests. Immunohistochemical techniques were used to assess Ab deposition, microgliosis, and cholinergic tone. Results. Seeding accelerated AD pathology throughout the brain in a region-dependent manner. Microgliosis was elevated in the substantia nigra reticular area. The cholinergic tone was found to be significantly reduced in the medial septal band. No impairment in learning and memory was found. Conclusion. These results suggest seeding accelerates microglial and Ab plaque progression in a regional distinct manner with the seed having no unique effect on behaviour or histological markers.

Alzheimer’s disease (AD) is characterized neuropathologically by amyloid-β (Aβ) plaques and neurofibrillary tangles. Vascular pathology caused by chronic cerebral hypoperfusion (HP) is hypothesised to exacerbate AD pathology and has emerged as an increasing cause of age-related cognitive impairment. In this study we examined the effects of gradual cerebral HP on cognitive dysfunction, Aβ pathology, microgliosis, and cortical network dynamics in C57BL/6J mice and a single App knock-in mouse model of AD (AppNL-G-F). We performed unilateral common carotid artery gradual occlusion (UCAgO) in two-month-old mice using an ameroid constrictor. At 4 months of age, animals were tested in a behavioral battery consisting of tests of spatial learning and memory (Morris water task), recognition memory (novel object recognition task), and motor coordination (balance beam). Following behavioural testing,in vivomesoscale wide-field voltage imaging was done to assess cortical functional connectivity and sensory-evoked cortical activity, and brains were harvested for pathology characterization using immunohistochemistry. We found that UCAgO reduced cerebral blood flow (CBF) in the occluded hemisphere (OH), however, subtle behavioural deficits were observed due to HP. A dissociative effect of HP was observed in resting-state functional connectivity analysis, where HP led to hyper-connectivity in C57 mice and hypo-connectivity in App mice. Interestingly, sensory stimulation of limbs contralateral to OH revealed hyper-cortical activations in the non-occluded hemisphere of C57 HP mice, however, hypo-cortical activations were observed in App HP mice. Furthermore, we found that the UCAgO increased cortical and hippocampal microgliosis in both hemispheres of C57 and App mice, a bilateral increase in Aβ deposition was only observed in App mice. These results suggest that gradual cerebral HP leads to cortical network alterations in AD, which is partly mediated via activation of microglia.

Alzheimer's disease (AD) is characterized by the prion-like propagation of amyloid-β (Aβ). However, the role of Aβ in cognitive impairment is still unclear. To determine the causal role of Aβ in AD, we intracerebrally seeded the entorhinal cortex of a 2-month-old AppNL−G−F mouse model with an Aβ peptide derived from patients who died from rapidly progressing AD. When the mice were 3 months of age or 1 month following seeding, spatial learning and memory were tested using the Morris water task. Immunohistochemical labeling showed seeding with the Aβ was found accelerate Aβ plaque deposition and microgliosis in the AppNL−G−F mice, but this was dependent on the presence of the knocked-in genes. However, we found no correlation between pathology and spatial performance. The results of the present study show the seeding effects in the AppNL−G−F knock-in model, and how these are dependent on the presence of a humanized App gene. But these pathological changes were not initially causal in memory impairment.

The functional organization of sensory cortices is modulated by both extrinsic events and intrinsic states. The present study aimed to assess the mouse auditory cortex (AC) responses under varying conditions of stimulus complexity and brain state. Using wide-field calcium imaging, our results suggest a complete outline of topographic maps of frequency and FM rate as well as highly responsive regions to mouse ultrasonic vocalizations (USVs) in both awake and anesthetized states. Three new regions responsive to high-frequency tones and four new gradients responsive to frequency modulations (FMs) were identified. These maps are highly replicable across weeks and between animals. In awake versus anesthetized states, cortical responsiveness to pure tones was stronger, and regions that preferentially responded to slow rate FMs were smaller. In both states, fast FM regions showed the greatest contribution to the processing of USVs. Finally, our modeling of how best tone frequency or FM rate changes as a function of distance along a topographic gradient resulted in a sigmoid function. Together, our findings provide a better understanding of mouse AC functional organization and how this organization is modulated by changes in stimulus complexity and brain state. The function of newly identified regions in higher-order auditory/vocal processing and animal behavior should be considered in future research.

The past decade marked the beginning of the use of resting-state functional connectivity (RSFC) imaging in bilingualism studies. This paper intends to review the latest evidence of changes in RSFC in language and cognitive control networks in bilinguals during adulthood, aging, and early Alzheimer's disease, which can add to our understanding of brain functional reshaping in the context of second language (L2) acquisition. Because of high variability in bilingual experience, recent studies mostly focus on the role of the main aspects of bilingual experience (age of acquisition (AoA), language proficiency, and language usage) on intrinsic functional connectivity (FC). Existing evidence accounts for stronger FC in simultaneous rather than sequential bilinguals in language and control networks, and the modulation of the AoA impact by language proficiency and usage. Studies on older bilingual adults show stronger FC in language and frontoparietal networks and preserved FC in posterior brain regions, which can protect the brain against cognitive decline and neurodegenerative processes. Altered RSFC in language and control networks subsequent to L2 training programs also is associated with improved global cognition in older adults. This review ends with a brief discussion of potential confounding factors in bilingualism research and conclusions and suggestions for future research.

This study investigated the dynamics of recruitment of cells in the CA1 region of the hippocampus in response to sensory stimuli presented during immobility, movement, and their transitions. Two-photon calcium imaging of somal activity in CA1 neuron populations was done in head fixed mice. Sensory stimuli, either a light flash or an air stream, were delivered to the mice when at rest, when moving spontaneously, and while they were induced to run a fixed distance on the conveyor belt. Overall, 99% of 2083 identified cells (from 5 mice) were active across one or more of 20 sensorimotor events. A larger proportion of cells were active during locomotion. Nevertheless, for any given sensorimotor event, only about 17% of cells were active. When considering pairs of sensorimotor event types, the active cell population consisted of conjunctive (C ∈ A and B) cells, active across both events, and complementary (C ∈ A not B or C ∈ B not A) cells that were active only during individual events. Whereas conjunctive cells characterised stable representations of repeated sensorimotor events, complementary cells characterised recruitment of new cells for encoding novel sensorimotor events. The moment-to-moment recruitment of conjunctive and complementary cells across changing sensorimotor events signifies the involvement of the hippocampus in functional networks integrating sensory information with ongoing movement. This role of the hippocampus is well suited for movement guidance that secondarily might include spatial behavior, episodic learning and memory, context representation, and scene construction.

There has been considerable research showing populations of neurons encoding for different aspects of space in the brain. Recently, several studies using two-photon calcium imaging and virtual navigation have identified “spatially” modulated neurons in the posterior cortex. We enquire here whether the presence of such spatial representations may be a cortex-wide phenomenon and, if so, whether these representations can be organized in the absence of the hippocampus. To this end, we imaged the dorsal cortex of mice running on a treadmill populated with tactile cues. A high percentage (40–80%) of the detected neurons exhibited sparse, spatially localized activity, with activity fields uniformly localized over the track. The development of this location specificity was impaired by hippocampal damage. Thus, there is a substantial population of neurons distributed widely over the cortex that collectively form a continuous representation of the explored environment, and hippocampal outflow is necessary to organize this phenomenon.SIGNIFICANCE STATEMENTIncreasing evidence points to the role of the neocortex in encoding spatial information. Whether this feature is linked to hippocampal functions is largely unknown. Here, we systematically surveyed multiple regions in the dorsal cortex of the same animal for the presence of signals encoding for spatial position. We described populations of cortical neurons expressing sequential patterns of activity localized in space in primary, secondary, and associational areas. Furthermore, we showed that the formation of these spatial representations was impacted by hippocampal lesion. Our results indicate that hippocampal inputs are necessary to maintain a precise cortical representation of space.

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.

Sleep consists of two basic stages: non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. NREM sleep is characterized by slow high-amplitude cortical EEG signals, while REM sleep is characterized desynchronized cortical rhythms. While, until recently, it has been widely believed that cortical activity during REM sleep is globally desynchronized, recent electrophysiological studies showed slow waves (SW) in some cortical areas during REM sleep. Electrophysiological techniques, however, have been unable to resolve the regional structure of these activities, due to relatively sparse sampling. We mapped functional gradients in cortical activity during REM sleep using mesoscale imaging in mice, and observed local SW patterns occurring mainly in somatomotor and auditory cortical regions, with minimum presence within the default mode network. The role of the cholinergic system in local desynchronization during REM sleep was also explored by calcium imaging of cholinergic terminal activity within the mouse cortex. Terminal activity was weaker in regions exhibiting SW activity more frequently during REM sleep. We also analyzed Allen Mouse Brain Connectivity dataset and found that these regions have weaker cholinergic projections from the basal forebrain.

Alzheimer Disease (AD) is associated with cerebral plaques and tangles, reduced synapse number, and shrinkage in several brain areas and these morphological effects are associated with the onset of compromised cognitive, motor, and anxiety-like behaviours. The focus of this study was to examine the effect of neonatal tactile stimulation on AD-like behavioural and neurological symptoms on APP NL-G-F/NL-G-F mice, a mouse model of AD. Our findings indicate that neonatal tactile stimulation improves cognition, motor skills, and anxiety-like symptoms in both gestationally stressed and non-stressed adult APP mice and that these alterations are associated with reduced Aβ plaque formation. Thus, tactile stimulation appears to be a promising non-invasive preventative strategy for slowing the onset of dementia in aging animals.

Alzheimer’s Disease (AD) is one of the largest health crises in the world. There are, however, limited but expensive pharmaceutical interventions to treat AD and most of the treatment options are not for cure or prevention, but to slow down the progression of the disease. The aim of this study was to examine the effect of tactile stimulation on AD-like symptoms and pathology in APP NL-G-F/NL-G-F mice, a mouse model of AD. The results show that tactile stimulation improves the AD-like symptoms on tests of cognition, motor, and anxiety-like behaviours and these improvements are associated with reduced AD pathology in APP mice.

A network of cholinergic neurons in the basal forebrain innerve the forebrain and are proposed to contribute to a variety of functions including attention, and cortical plasticity. This study examined the contribution of the nucleus basalis cholinergic projection to the sensorimotor cortex on recovery on a skilled reach-to-eat task following photothrombotic stroke in the forelimb region of the somatosensory cortex. Mice were trained to perform a single-pellet skilled reaching task and their pre and poststroke performance, from Day 4 to Day 28 poststroke, was assessed frame-by-frame by video analysis with end point, movement and sensorimotor integration measures. Somatosensory forelimb lesions produced impairments in endpoint and movement component measures of reaching and increased the incidence of fictive eating, a sensory impairment in mistaking a missed reach for a successful reach. Upregulated acetylcholine (ACh) release, as measured by local field potential recording, elicited via optogenetic stimulation of the nucleus basalis improved recovery of reaching and improved movement scores but did not affect a sensorimotor integration impairment poststroke. The results show that the mouse cortical forelimb somatosensory region contributes to forelimb motor behavior and suggest that ACh upregulation could serve as an adjunct to behavioral therapy for the acute treatment of stroke.

This review examines the adverse impacts of different noise exposure paradigms on the neuroendocrine system, hippocampal and neocortical structures, cognitive performances, and the development of Alzheimer's disease (AD)-like neuropathological changes in the brain of laboratory animals. Studies were reviewed in three periods during the lifespan including: adult animals exposed to noise, female rodents exposed to noise during gestation, and offspring exposed to noise during the prenatal period. Findings imply that chronic noise exposure dysregulates the neuroendocrine system leading to hyperactivation of the sympathetic divisions of the autonomic nervous system (i.e., the hypothalamic-pituitary-adrenal (HPA)-axis), and increases stress hormones that affect brain and behaviour. Enduring dysregulation of the HPA-axis was the most discussed mechanism for the harmful effect of noise during the lifespan. Studies also suggest a causative association of noise with diverse indicators of the AD-like neuropathology in rodents and a hypersusceptibility in females. The results indicate the importance of future neuroimaging studies to quantify the potential contribution of noise in predisposing cognitive decline and preclinical signs of dementia in humans.

PD is a progressive and complex neurological disorder with heterogeneous symptomatology. PD is characterized by classical motor features of parkinsonism and nonmotor symptoms and involves extensive regions of the nervous system, various neurotransmitters, and protein aggregates. Extensive evidence supports auditory dysfunction as an additional nonmotor feature of PD. Studies indicate a broad range of auditory impairments in PD, from the peripheral hearing system to the auditory brainstem and cortical areas. For instance, research demonstrates a higher occurrence of hearing loss in early-onset PD and evidence of abnormal auditory evoked potentials, event-related potentials, and habituation to novel stimuli. Electrophysiological data, such as auditory P3a, also is suggested as a sensitive measure of illness duration and severity. Improvement in auditory responses following dopaminergic therapies also indicates the presence of similar neurotransmitters (i.e., glutamate and dopamine) in the auditory system and basal ganglia. Nonetheless, hearing impairments in PD have received little attention in clinical practice so far. This review summarizes evidence of peripheral and central auditory impairments in PD and provides conclusions and directions for future empirical and clinical research. © 2020 International Parkinson and Movement Disorder Society.

Whereas chronic noise exposure (CNE) is a known risk factor for tinnitus, little is known about how a history of CNE impacts tinnitus characteristics and its comorbid symptoms.Seventy-five participants with chronic tinnitus (59m/16f, 22-78 years, 48 with sensory-neural hearing loss, and 27 with a normal audiogram) including 43 individuals with (Tin-CNE group) and 32 without (Tin group) a history of long-term occupational noise exposure were studied. Tinnitus characteristics were rated by a visual analog scale, and tinnitus comorbid symptoms were scored using self-assessment questionnaires.The Tin-CNE group showed reduced uncomfortable loudness level (ULL), sound tolerance, and quality of life (QoL), and increased tinnitus loudness, tinnitus handicap, anxiety, depression, insomnia severity, and tinnitus annoyance scores compared to the Tin group. Higher tinnitus loudness and a lower anxiety score were observed in participants with hearing loss relative to those without. Using a stepwise regression model also showed that tinnitus-related characteristics, hyperacusis, and tinnitus comorbid symptoms enhance one another.The findings were in support of accumulative evidence indicating the adverse auditory and non-auditory effects of CNE, including exacerbated sound intolerance and tinnitus-related psychiatric symptoms. The results also showed that tinnitus alone can affect mental health regardless of hearing loss.

Prenatal stress (PS) can impact fetal brain structure and function and contribute to higher vulnerability to neurodevelopmental and neuropsychiatric disorders. To understand how PS alters evoked and spontaneous neocortical activity and intrinsic brain functional connectivity, mesoscale voltage imaging was performed in adult C57BL/6NJ mice that had been exposed to auditory stress on gestational days 12-16, the age at which neocortex is developing. PS mice had a four-fold higher basal corticosterone level and reduced amplitude of cortical sensory-evoked responses to visual, auditory, whisker, forelimb, and hindlimb stimuli. Relative to control animals, PS led to a general reduction of resting-state functional connectivity, as well as reduced inter-modular connectivity, enhanced intra-modular connectivity, and altered frequency of auditory and forelimb spontaneous sensory motifs. These resting-state changes resulted in a cortical connectivity pattern featuring disjoint but tight modules and a decline in network efficiency. The findings demonstrate that cortical connectivity is sensitive to PS and exposed offspring may be at risk for adult stress-related neuropsychiatric disorders.

Huntington disease (HD), a hereditary neurodegenerative disorder, manifests as progressively impaired movement and cognition. Although early abnormalities of neuronal activity in striatum are well established in HD models, there are fewer in vivo studies of the cortex. Here, we record local field potentials (LFPs) in YAC128 HD model mice versus wild-type mice. In multiple cortical areas, limb sensory stimulation evokes a greater change in LFP power in YAC128 mice. Mesoscopic imaging using voltage-sensitive dyes reveal more extensive spread of evoked sensory signals across the cortical surface in YAC128 mice. YAC128 layer 2/3 sensory cortical neurons ex vivo show increased excitatory events, which could contribute to enhanced sensory responses in vivo. Cortical LFP responses to limb stimulation, visual and auditory input are also significantly increased in zQ175 HD mice. Results presented here extend knowledge of HD beyond ex vivo studies of individual neurons to the intact cortical network.

The new next-generation sequencing platforms by Oxford Nanopore Technologies for direct RNA sequencing (direct RNA-seq) allow for an in-depth and comprehensive study of the epitranscriptome by enabling direct base calling of RNA modifications. Non-coding RNAs constitute the most frequently documented targets for RNA modifications. However, the current standard direct RNA-seq approach is unable to detect many of these RNAs. Here we present NERD-seq, a sequencing approach which enables the detection of multiple classes of non-coding RNAs excluded by the current standard approach. Using total RNA from a tissue with high known transcriptional and non-coding RNA activity in mouse, the brain hippocampus, we show that, in addition to detecting polyadenylated coding and non-coding transcripts as the standard approach does, NERD-seq is able to significantly expand the representation for other classes of RNAs such as snoRNAs, snRNAs, scRNAs, srpRNAs, tRNAs, rRFs and non-coding RNAs originating from LINE L1 elements. Thus, NERD-seq presents a new comprehensive direct RNA-seq approach for the study of epitranscriptomes in brain tissues and beyond.

Documenting a mouse's "real world" behavior in the "small world" of a laboratory cage with continuous video recordings offers insights into phenotypical expression of mouse genotypes, development and aging, and neurological disease. Nevertheless, there are challenges in the design of a small world, the behavior selected for analysis, and the form of the analysis used. Here we offer insights into small world analyses by describing how acute behavioral procedures can guide continuous behavioral methodology. We show how algorithms can identify behavioral acts including walking and rearing, circadian patterns of action including sleep duration and waking activity, and the organization of patterns of movement into home base activity and excursions, and how they are altered with aging. We additionally describe how specific tests can be incorporated within a mouse's living arrangement. We emphasize how machine learning can condense and organize continuous activity that extends over extended periods of time.

The prepulse inhibition (PPI) of the acoustic startle reflex (ASR), as an index of sensorimotor gating, is one of the most extensively used paradigms in the field of neuropsychiatric disorders. Few studies have examined how prenatal stress (PS) regulates the sensorimotor gating during the lifespan and how PS modifies the development of amyloid-beta (Aβ) pathology in brain areas underlying the PPI formation. We followed alternations in corticosterone levels, learning and memory, and the PPI of the ASR measures in APPNL-G-F/NL-G-F offspring of dams exposed to gestational noise stress. In-depth quantifications of the Aβ plaque accumulation were also performed at 6 months. The results indicated an age-dependent deterioration of sensorimotor gating, long-lasting PS-induced abnormalities in PPI magnitudes, as well as deficits in spatial memory. The PS also resulted in a higher Aβ aggregation predominantly in brain areas associated with the PPI modulation network. The findings suggest the contribution of a PS-induced hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in regulating the PPI modulation substrates leading to the abnormal development of the neural protection system in response to disruptive stimuli. The long-lasting HPA axis dysregulation appears to be the major underlying mechanism in precipitating the Aβ deposition, especially in brain areas contributed to the PPI modulation network.

Saito et al developed a novel amyloid precursor protein (APP) knock-in mouse model (APPNL-G-F) for Alzheimer's disease (AD) to overcome the problem of overexpression of APP in available transgenic mouse models. However, this new mouse model for AD is not fully characterized age-dependently with respect to behavioral and biochemical changes. Therefore, in the present study, we performed an age-dependent behavioral and biochemical characterization of this newly developed mouse model. Here, we used 3-, 6-, 9-, and 12-month-old APPNL-G-F and C57BL/6J mice. We used a separate cohort of animals at each age point. Morris water maze, object recognition, and fear-conditioning tests were used for the assessment of learning and memory functions and open-field test to measure the general locomotor activity of mice. After each testing point, we perfused the mice and collected the brain for immunostaining. We performed the immunostaining for amyloid burden (4G8), glial fibrillary acidic protein, choline acetyltransferase, and tyrosine hydroxylase. The results of the present study indicate that APPNL-G-F mice showed age-dependent memory impairments with maximum impairment at the age of 12 months. These mice showed memory impairment in Morris water maze and fear conditioning tests when they were 6 months old, whereas, in object recognition test, memory deficit was found in 9-month-old mice. APPNL-G-F mice age dependently showed an increase in amyloid load in different brain regions. However, no amyloid pathology was found in 3-month-old APPNL-G-F mice. Choline acetyltransferase neurons in medial septum-diagonal band complex and tyrosine hydroxylase neurons in locus coeruleus were decreased significantly in APPNL-G-F mice. This mouse model also indicated an age-dependent increase in glial fibrillary acidic protein load. It can be concluded from the results that the APPNL-G-F mouse model may be used to explore the Aβ hypothesis, molecular, and cellular mechanisms involved in AD pathology and to screen the therapeutic potential compounds for the treatment of AD.

Most studies investigating hippocampal-dependent learning and memory in mouse models of disease use the standard version of the Morris water task (MWT), in which a place is learned over several days. While useful in determining if there are learning and memory deficits, often it is not clear if memory acquisition, consolidation, or retrieval is affected. For rats, we developed a variant of the task in which we added a single-massed training session to a new location after the standard distributed version of the MWT. Using this version of the task, competition between these two spatial representations can then be assessed in a probe trial. We have found in rat models of Alzheimer's disease that this paradigm can detect subtle impairments that are often missed in the standard version of the MWT. To the best of our knowledge, MWT paradigm with a single-massed training session have never been used for mice. We sought to validate this paradigm for the use of assessing mouse models of disease. In the first two experiments, control mice did not have a preference for the new platform location, but instead with extensive training in the massed session displayed a preference for both the old and new locations. In the third experiment, a novel mouse model of Alzheimer's disease was impaired in the standard version of the MWT, but not in the massed training phase of this paradigm. Importantly, these data demonstrate that our paradigm is more informative in characterizing spatial learning and memory in mouse models of disease. © 2018 Wiley Periodicals, Inc.

Objectives:Extensive studies indicate that severe acute respiratory syndrome coronavirus (SARS-CoV-2) involves human sensory systems. A lack of discussion, however, exists given the auditory–vestibular system involvement in CoV disease 2019 (COVID-19). The present systematic review and meta-analysis were performed to determine the event rate (ER) of hearing loss, tinnitus, and dizziness caused by SARS-CoV-2.Methods:Databases (PubMed, ScienceDirect, Wiley) and World Health Organization updates were searched using combined keywords: ‘COVID-19,’ ‘SARS-CoV-2,’ ‘pandemic,’ ‘auditory dysfunction,’ ‘hearing loss,’ ‘tinnitus,’ ‘vestibular dysfunction,’ ‘dizziness,’ ‘vertigo,’ and ‘otologic symptoms.’Results:Twelve papers met the eligibility criteria and were included in the study. These papers were single group prospective, cross-sectional, or retrospective studies on otolaryngologic, neurologic, or general clinical symptoms of COVID-19 and had used subjective assessments for data collection (case histories/medical records). The results of the meta-analysis demonstrate that the ER of hearing loss (3.1%, CIs: 0.01–0.09), tinnitus (4.5%, CIs: 0.012–0.153), and dizziness (12.2%, CIs: 0.070–0.204) is statistically significant in patients with COVID-19 (Z ≤ −4.469, p ≤ 0.001).Conclusions:COVID-19 can cause hearing loss, tinnitus, and dizziness. These findings, however, should be interpreted with caution given insufficient evidence and heterogeneity among studies. Well-designed studies and follow-up assessments on otologic symptoms of SARS-CoV-2 using standard objective tests are recommended.

Despite significant steps in our understanding of Alzheimer's disease (AD), many of the molecular processes underlying its pathogenesis remain largely unknown. Here, we focus on the role of non-coding RNAs produced by small interspersed nuclear elements (SINEs). RNAs from SINE B2 repeats in mouse and SINE Alu repeats in humans, long regarded as "junk" DNA, control gene expression by binding RNA polymerase II and suppressing transcription. They also possess self-cleaving activity that is accelerated through their interaction with certain proteins disabling this suppression. Here, we show that similar to mouse SINE RNAs, human Alu RNAs, are processed, and the processing rate is increased in brains of AD patients. This increased processing correlates with the activation of genes up-regulated in AD patients, while increased intact Alu RNA levels correlate with down-regulated gene expression in AD. In vitro assays show that processing of Alu RNAs is accelerated by HSF1. Overall, our data show that RNAs from SINE elements in the human brain show a similar pattern of deregulation during amyloid beta pathology as in mouse.

The functional importance of many non-coding RNAs (ncRNAs) generated by repetitive elements and their connection with pathologic processes remains elusive. B2 RNAs, a class of ncRNAs of the B2 family of SINE repeats, mediate through their processing the transcriptional activation of various genes in response to stress. Here, we show that this response is dysfunctional during amyloid beta toxicity and pathology in the mouse hippocampus due to increased levels of B2 RNA processing, leading to constitutively elevated B2 RNA target gene expression and high Trp53 levels. Evidence indicates that Hsf1, a master regulator of stress response, mediates B2 RNA processing in hippocampal cells and is activated during amyloid toxicity, accelerating the processing of SINE RNAs and gene hyper-activation. Our study reveals that in mouse, SINE RNAs constitute a novel pathway deregulated in amyloid beta pathology, with potential implications for similar cases in the human brain, such as Alzheimer’s disease (AD).

Prenatal stress (PS) can impact fetal brain structure and function and lead to higher vulnerability to neurodevelopmental and neuropsychiatric disorders. To understand how PS alters evoked and spontaneous cortical activity and intrinsic brain functional connectivity, mesoscale voltage imaging was performed in adult C57BL/6NJ mice who were exposed to an auditory stress paradigm on gestational days 12-16. PS mice demonstrated a four-fold higher basal corticosterone level, reduced amplitude of all cortical sensory-evoked responses (visual, auditory, whisker, forelimb, and hindlimb), decreased overall resting-state functional connectivity, declined network efficiency, reduced inter-module connectivity, enhanced intra-module connectivity, and altered frequency of auditory and forelimb spontaneous sensory motifs relative to control animals. In fact, for PS, the resting-state functional connectivity changes drastically towards an overall less connected structure that consists of largely disjoint but tight modules, leading to a declined network efficiency. The changes in structure also indicate that the posterior secondary motor, primary barrel, and secondary hindlimb cortices are cortical areas with higher susceptibility to dysfunction. Our findings highlight the PS modulation of brain functional connectivity that can pose offspring at risk for stress-related neuropsychiatric disorders.