Spatial-Temporal Analysis of Neural Desynchronization in Sleeplike States Reveals Critical Dynamics.

Sleep is characterized by nonrapid eye movement sleep, originating from widespread neuronal synchrony, and rapid eye movement sleep, with neuronal desynchronization akin to waking behavior. While these were thought to be global brain states, recent research suggests otherwise. Using time-frequency analysis of mesoscopic voltage-sensitive dye recordings of mice in a urethane-anesthetized model of sleep, we find transient neural desynchronization occurring heterogeneously across the cortex within a background of synchronized neural activity, in a manner reminiscent of a critical spreading process and indicative of an "edge-of-synchronization" phase transition.

Hippocampal ripples coincide with "up-state" and spindles in retrosplenial cortex.

During NREM sleep, hippocampal sharp-wave ripple (SWR) events are thought to stabilize memory traces for long-term storage in downstream neocortical structures. Within the neocortex, a set of distributed networks organized around retrosplenial cortex (RS-network) interact preferentially with the hippocampus purportedly to consolidate those traces. Transient bouts of slow oscillations and sleep spindles in this RS-network are often observed around SWRs, suggesting that these two activities are related and that their interplay possibly contributes to memory consolidation. To investigate how SWRs interact with the RS-network and spindles, we combined cortical wide-field voltage imaging, Electrocorticography, and hippocampal LFP recordings in anesthetized and sleeping mice. Here, we show that, during SWR, "up-states" and spindles reliably co-occur in a cortical subnetwork centered around the retrosplenial cortex. Furthermore, retrosplenial transient activations and spindles predict slow gamma oscillations in CA1 during SWRs. Together, our results suggest that retrosplenial-hippocampal interaction may be a critical pathway of information exchange between the cortex and hippocampus.

A systematic review of altered resting-state networks in early deafness and implications for cochlear implantation outcomes.

Auditory deprivation following congenital/pre-lingual deafness (C/PD) can drastically affect brain development and its functional organisation. This systematic review intends to extend current knowledge of the impact of C/PD and deafness duration on brain resting-state networks (RSNs), review changes in RSNs and spoken language outcomes post-cochlear implant (CI) and draw conclusions for future research. The systematic literature search followed the PRISMA guideline. Two independent reviewers searched four electronic databases using combined keywords: 'auditory deprivation', 'congenital/prelingual deafness', 'resting-state functional connectivity' (RSFC), 'resting-state fMRI' and 'cochlear implant'. Seventeen studies (16 cross-sectional and one longitudinal) met the inclusion criteria. Using the Crowe Critical Appraisal Tool, the publications' quality was rated between 65.0% and 92.5% (mean: 84.10%), ≥80% in 13 out of 17 studies. A few studies were deficient in sampling and/or ethical considerations. According to the findings, early auditory deprivation results in enhanced RSFC between the auditory network and brain networks involved in non-verbal communication, and high levels of spontaneous neural activity in the auditory cortex before CI are evidence of occupied auditory cortical areas with other sensory modalities (cross-modal plasticity) and sub-optimal CI outcomes. Overall, current evidence supports the idea that moreover intramodal and cross-modal plasticity, the entire brain adaptation following auditory deprivation contributes to spoken language development and compensatory behaviours.

Correction: Data-driven analyses of motor impairments in animal models of neurological disorders.

[This corrects the article DOI: 10.1371/journal.pbio.3000516.].

The Nonclassic Psychedelic Ibogaine Disrupts Cognitive Maps.

Background: The ability of psychedelic compounds to profoundly alter mental function has been long known, but the underlying changes in cellular-level information encoding remain poorly understood. Methods: We used two-photon microscopy to record from the retrosplenial cortex in head-fixed mice running on a treadmill before and after injection of the nonclassic psychedelic ibogaine (40 mg/kg intraperitoneally). Results: We found that the cognitive map, formed by the representation of position encoded by ensembles of individual neurons in the retrosplenial cortex, was destabilized by ibogaine when mice had to infer position between tactile landmarks. This corresponded with increased neural activity rates, loss of correlation structure, and increased responses to cues. Ibogaine had surprisingly little effect on the size-frequency distribution of network activity events, suggesting that signal propagation within the retrosplenial cortex was largely unaffected. Conclusions: Taken together, these data support proposals that compounds with psychedelic properties disrupt representations that are important for constraining neocortical activity, thereby increasing the entropy of neural signaling. Furthermore, the loss of expected position encoding between landmarks recapitulated effects of hippocampal impairment, suggesting that disruption of cognitive maps or other hippocampal processing may be a contributing mechanism of discoordinated neocortical activity in psychedelic states.

Repeated multi-domain cognitive training prevents cognitive decline, anxiety and amyloid pathology found in a mouse model of Alzheimer disease.

Education, occupation, and an active lifestyle, comprising enhanced social, physical, and mental components are associated with improved cognitive functions in aged people and may delay the progression of various neurodegenerative diseases including Alzheimer's disease. To investigate this protective effect, 3-month-old APPNL-G-F/NL-G-F mice were exposed to repeated single- or multi-domain cognitive training. Cognitive training was given at the age of 3, 6, & 9 months. Single-domain cognitive training was limited to a spatial navigation task. Multi-domain cognitive training consisted of a spatial navigation task, object recognition, and fear conditioning. At the age of 12 months, behavioral tests were completed for all groups. Then, mice were sacrificed, and their brains were assessed for pathology. APPNL-G-F/NL-G-F mice given multi-domain cognitive training compared to APPNL-G-F/NL-G-F control group showed an improvement in cognitive functions, reductions in amyloid load and microgliosis, and a preservation of cholinergic function. Additionally, multi-domain cognitive training improved anxiety in APPNL-G-F/NL-G-F mice as evidenced by measuring thigmotaxis behavior in the Morris water maze. There were mild reductions in microgliosis in the brain of APPNL-G-F/NL-G-F mice with single-domain cognitive training. These findings provide causal evidence for the potential of certain forms of cognitive training to mitigate the cognitive deficits in Alzheimer disease.

Cortical reactivation of spatial and non-spatial features coordinates with hippocampus to form a memory dialogue.

Episodic memories comprise diverse attributes of experience distributed across neocortical areas. The hippocampus is integral to rapidly binding these diffuse representations, as they occur, to be later reinstated. However, the nature of the information exchanged during this hippocampal-cortical dialogue remains poorly understood. A recent study has shown that the secondary motor cortex carries two types of representations: place cell-like activity, which were impaired by hippocampal lesions, and responses tied to visuo-tactile cues, which became more pronounced following hippocampal lesions. Using two-photon Ca2+ imaging to record neuronal activities in the secondary motor cortex of male Thy1-GCaMP6s mice, we assessed the cortical retrieval of spatial and non-spatial attributes from previous explorations in a virtual environment. We show that, following navigation, spontaneous resting state reactivations convey varying degrees of spatial (trajectory sequences) and non-spatial (visuo-tactile attributes) information, while reactivations of non-spatial attributes tend to precede reactivations of spatial representations surrounding hippocampal sharp-wave ripples.

Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer's disease mutations.

Disinhibition during early stages of Alzheimer's disease is postulated to cause network dysfunction and hyperexcitability leading to cognitive deficits. However, the underlying molecular mechanism remains unknown. Here we show that, in mouse lines carrying Alzheimer's disease-related mutations, a loss of neuronal membrane potassium-chloride cotransporter KCC2, responsible for maintaining the robustness of GABAA-mediated inhibition, occurs pre-symptomatically in the hippocampus and prefrontal cortex. KCC2 downregulation was inversely correlated with the age-dependent increase in amyloid-ß 42 (Aß42). Acute administration of Aß42 caused a downregulation of membrane KCC2. Loss of KCC2 resulted in impaired chloride homeostasis. Preventing the decrease in KCC2 using long term treatment with CLP290 protected against deterioration of learning and cortical hyperactivity. In addition, restoring KCC2, using short term CLP290 treatment, following the transporter reduction effectively reversed spatial memory deficits and social dysfunction, linking chloride dysregulation with Alzheimer's disease-related cognitive decline. These results reveal KCC2 hypofunction as a viable target for treatment of Alzheimer's disease-related cognitive decline; they confirm target engagement, where the therapeutic intervention takes place, and its effectiveness.

Early tactile stimulation influences the development of Alzheimer's disease in gestationally stressed APP NL-G-F adult offspring NL-G-F/NL-G-F mice.

Alzheimer's 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 appearance of both anatomical and behavioural symptoms is worsened by stress. 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, who have been gestationally stressed. 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 Aß plaque formation. Thus, tactile stimulation appears to be a promising non-invasive preventative strategy for slowing the onset of dementia in aging animals.

Weak-hyperactive hippocampal CA1 neurons in the prodromal stage of Alzheimer's disease in hybrid AppNL-G-F/NL-G-F × Thy1-GCaMP6s+/- mice suggest disrupted plasticity.

This study investigated the impact of familial Alzheimer's disease (AD)-linked amyloid precursor protein (App) mutations on hippocampal CA1 neuronal activity and function at an early disease stage in AppNL-G-F/NL-G-F × Thy1-GCaMP6s+/- (A-TG) mice using calcium imaging. Longitudinal assessment of spatial behavior at 12 and 18 months of age identified an early disease stage at 12 months when there was significant amyloid beta pathology with mild behavioral deficits. Hippocampal CA1 neuronal activity and event-related encoding of distance and time were therefore assessed at 12 months of age in several configurations of an air-induced running task to assess the dynamics of cellular activity. Neurons in A-TG mice displayed diminished (weaker) and more frequent (hyperactive) neuronal firing that was more pronounced during movement compared to immobility. Responsive neurons showed configuration-specific deficits in distance and time encoding with impairment in adapting their responses to changing configurations. These results suggest that at an early stage of AD in the absence of full-blown behavioral deficits, weak-hyperactive neuronal activity may induce impairments in sensory perception of changing environments.

Regional variation in cholinergic terminal activity determines the non-uniform occurrence of cortical slow waves during REM sleep in mice.

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 electroencephalogram (EEG) signals, while REM sleep is characterized by desynchronized cortical rhythms. Despite this, recent electrophysiological studies have suggested the presence of slow waves (SWs) in local cortical areas during REM sleep. Electrophysiological techniques, however, have been unable to resolve the regional structure of these activities because of relatively sparse sampling. Here, we map functional gradients in cortical activity during REM sleep using mesoscale imaging in mice and show 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 is also explored by calcium imaging of cholinergic activity within the cortex and analyzing structural data. We demonstrate weaker cholinergic projections and terminal activity in regions exhibiting frequent SWs during REM sleep.

Hippocampal conjunctive and complementary CA1 populations relate sensory events to movement.

Hippocampal CA1 neurons respond to sensory stimuli during enforced immobility, movement, and their transitions in a new conveyor belt task. Head-fixed mice were exposed to light flashes or air streams while at rest, spontaneously moving, or running a fixed distance. Two-photon calcium imaging of CA1 neurons revealed that 62% of 3341 imaged cells were active during one or more of 20 sensorimotor events. Of these active cells, 17% were active for any given sensorimotor event, with a higher proportion during locomotion. The study found two types of cells: Conjunctive cells that were active across multiple events, and complementary cells that were active only during individual events, encoding novel sensorimotor events or their delayed repetitions. The configuration of these cells across changing sensorimotor events may signify the role of hippocampus in functional networks integrating sensory information with ongoing movement making it suitable for movement guidance.

Hearing loss and impaired short-term memory in an Alzheimer's disease mouse model of amyloid-beta pathology.

Current evidence supports the link between hearing loss and Alzheimer's disease (AD). However, few studies report the hearing status of AD mice compared to wild-type mice. This study aimed to compare hearing thresholds and short-term memory (STM) performance of an AD (APPNL-G-F) mouse model of amyloid-beta (Aꞵ) pathology with C57BL/6 J and CBA/CaJ mice across age. The auditory brainstem response (ABR) test, using click and five tone-burst (TB) stimuli, was recorded at 2, 4, 6, 9, and 12 months. The novel object recognition (NOR) test, a measure of STM, was conducted at 6 and 12 months. While hearing thresholds were almost preserved in CBA/CaJ mice, they were not recorded at high frequencies with age in C57BL/6 J and AD mice, leading to island hearing (severe to profound hearing loss) at 9 and 12 months. AD mice showed increased hearing thresholds in TB8 and TB16 kHz at 6 and 9 months compared to C57BL/6 J mice. NOR findings were evidence of impaired STM in both C57BL/6 J and AD mice relative to CBA/CaJ mice, and a relationship was found between hearing thresholds and NOR measures in three groups. The findings were in support of the link between the degree of hearing loss and impaired STM.

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.

Sensory experience selectively reorganizes the late component of evoked responses.

In response to sensory stimulation, the cortex exhibits an early transient response followed by late and slower activation. 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 the mesoscale level using voltage and extracellular glutamate transient recordings over widespread regions of mouse 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 min and results in an increase in the amplitude of the late response after repeated stimulation and in an increase in the similarity between the spatiotemporal patterns of the late early evoked response. 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.

Tactile stimulation improves cognition, motor, and anxiety-like behaviors and attenuates the Alzheimer's disease pathology in adult APPNL-G-F/NL-G-F mice.

Alzheimer's disease (AD) is one of the largest health crises in the world. There are limited pharmaceutical interventions to treat AD, however, and most of the treatment options are not for cure or prevention, but rather to slow down the progression of the disease. The aim of this study was to examine the effect of tactile stimulation (TS) on AD-like symptoms and pathology in APPNL-G-F/NL-G-F mice, a mouse model of AD. The results show that TS reduces the AD-like symptoms on tests of cognition, motor, and anxiety-like behaviors and these improvements in behavior are associated with reduced AD pathology in APP mice. Thus, TS appears to be a promising noninvasive strategy for slowing the onset of dementia in aging animals.

Hippocampal gamma and sharp wave/ripples mediate bidirectional interactions with cortical networks during sleep.

Hippocampus-neocortex interactions during sleep are critical for memory processes: Hippocampally initiated replay contributes to memory consolidation in the neocortex and hippocampal sharp wave/ripples modulate cortical activity. Yet, the spatial and temporal patterns of this interaction are unknown. With voltage imaging, electrocorticography, and laminarly resolved hippocampal potentials, we characterized cortico-hippocampal signaling during anesthesia and nonrapid eye movement sleep. We observed neocortical activation transients, with statistics suggesting a quasi-critical regime, may be helpful for communication across remote brain areas. From activity transients, we identified, in a data-driven fashion, three functional networks. A network overlapping with the default mode network and centered on retrosplenial cortex was the most associated with hippocampal activity. Hippocampal slow gamma rhythms were strongly associated to neocortical transients, even more than ripples. In fact, neocortical activity predicted hippocampal slow gamma and followed ripples, suggesting that consolidation processes rely on bidirectional signaling between hippocampus and neocortex.

Dramatic impacts on brain pathology, anxiety, and cognitive function in the knock-in APPNL-G-F mouse model of Alzheimer disease following long-term voluntary exercise.

BACKGROUND: An active lifestyle is associated with improved cognitive functions in aged people and may prevent or slow down the progression of various neurodegenerative diseases including Alzheimer's disease (AD). To investigate these protective effects, male APPNL-G-F mice were exposed to long-term voluntary exercise. METHODS: Three-month-old AD mice were housed in a cage supplemented with a running wheel for 9 months for long-term exercise. At the age of 12 months, behavioral tests were completed for all groups. After completing behavioral testing, their brains were assessed for amyloid pathology, microgliosis, and cholinergic cells. RESULTS: The results showed that APPNL-G-F mice allowed to voluntarily exercise showed an improvement in cognitive functions. Furthermore, long-term exercise also improved anxiety in APPNL-G-F mice as assessed by measuring thigmotaxis in the Morris water task. We also found reductions in amyloid load and microgliosis, and a preservation of cholinergic cells in the brain of APPNL-G-F mice allowed to exercise in their home cages. These profound reductions in brain pathology associated with AD are likely responsible for the observed improvement of learning and memory functions following extensive and regular exercise. CONCLUSION: These findings suggest the potential of physical exercise to mitigate the cognitive deficits in AD.

A Systematic Review and Meta-Analysis of Extended High-Frequency Hearing Thresholds in Tinnitus With a Normal Audiogram.

OBJECTIVES: Current evidence supports the growing application of extended high-frequency (EHF: 9 to 20 kHz) audiometry in hearing research, which likely results from the high vulnerability of this frequency region to damage induced by known auditory risk factors. The present systematic review and meta-analysis were performed to investigate whether adults with a normal audiogram and tinnitus show increased EHF hearing thresholds relative to control peers. DESIGN: A comprehensive search was undertaken on electronic databases consisting of PubMed, ScienceDirect, Wiley, and Google Scholar using combined keywords: "tinnitus," "extended high frequency," "normal audiogram," and "hidden hearing loss." RESULTS: From 261 articles found by searching databases, nine studies met the inclusion criteria for the meta-analysis. A significant difference was observed between tinnitus and control groups in the effect size analysis of hearing thresholds at 10, 12.5, 14, 16, and 18 kHz ( p ≤ 0.001), and the I-square heterogeneity analysis was below 50% in all studies ( p ≥ 0.131). Visual inspection by the Funnel plot and Egger's regression test ( p ≥ 0.211) also exhibited no publication bias in the meta-analyses. CONCLUSIONS: Our findings are in support of the idea that in most cases, tinnitus is associated with some degree of cochlear mechanical dysfunction, which may not be detected by conventional audiometry alone. This finding underscores the significance of EHF audiometry in clinical practice, which may help both early identification of individuals susceptible to developing tinnitus and reduce the number of new cases through preventive counseling programs.