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.

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.

Miniaturized head-mounted microscope for whole-cortex mesoscale imaging in freely behaving mice.

The advent of genetically encoded calcium indicators, along with surgical preparations such as thinned skulls or refractive-index-matched skulls, has enabled mesoscale cortical activity imaging in head-fixed mice. However, neural activity during unrestrained behavior substantially differs from neural activity in head-fixed animals. For whole-cortex imaging in freely behaving mice, we present the 'mini-mScope', a widefield, miniaturized, head-mounted fluorescence microscope that is compatible with transparent polymer skull preparations. With a field of view of 8 × 10 mm2 and weighing less than 4 g, the mini-mScope can image most of the mouse dorsal cortex with resolutions ranging from 39 to 56 µm. We used the mini-mScope to record mesoscale calcium activity across the dorsal cortex during sensory-evoked stimuli, open field behaviors, social interactions and transitions from wakefulness to sleep.

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.

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.

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.

Spatial Information Encoding across Multiple Neocortical Regions Depends on an Intact Hippocampus.

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 STATEMENT Increasing 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.

Altered cortical processing of sensory input in Huntington disease mouse models.

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 reveals 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.

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.

Hearing Loss, Tinnitus, and Dizziness in COVID-19: A Systematic Review and Meta-Analysis.

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.

Tinnitus, sound intolerance, and mental health: the role of long-term occupational noise exposure.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Traffic noise exposure, cognitive decline, and amyloid-beta pathology in an AD mouse model.

Concerns are growing that exposure to environmental pollutants, such as traffic noise, might cause cognitive impairments and predispose individuals toward the development of Alzheimer's disease (AD) dementia. In this study in a knock-in mouse model of AD, we investigated how chronic traffic noise exposure (CTNE) impacts cognitive performance and amyloid-beta (Aß) pathology. A group of APPNL-G-F/NL-G-F mice was exposed to CTNE (70 dBA , 8 hr/day for 1 month) and compared with nonexposed counterparts. Following CTNE, an increase in hypothalamic-pituitary-adrenal (HPA) axis responsivity was observed by corticosterone assay of the blood. One month after CTNE, the CTNE group demonstrated impairments in cognitive and motor functions, and indications of anxiety-like behavior, relative to the control animals. The noise-exposed group also showed elevated Aß aggregation, as inferred by a greater number of plaques and larger average plaque size in various regions of the brain, including regions involved in stress regulation. The results support that noise-associated dysregulation of the neuroendocrine system as a potential risk factor for developing cognitive impairment and Aß pathology, which should be further investigated in human studies.

Life-Course Contribution of Prenatal Stress in Regulating the Neural Modulation Network Underlying the Prepulse Inhibition of the Acoustic Startle Reflex in Male Alzheimer's Disease Mice.

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 (Aß) 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 Aß 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 Aß 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 Aß deposition, especially in brain areas contributed to the PPI modulation network.

Hippocampus-dependent emergence of spatial sequence coding in retrosplenial cortex.

Retrosplenial cortex (RSC) is involved in visuospatial integration and spatial learning, and RSC neurons exhibit discrete, place cell-like sequential activity that resembles the population code of space in hippocampus. To investigate the origins and population dynamics of this activity, we combined longitudinal cellular calcium imaging of dysgranular RSC neurons in mice with excitotoxic hippocampal lesions. We tracked the emergence and stability of RSC spatial activity over consecutive imaging sessions. Overall, spatial activity in RSC was experience-dependent, emerging gradually over time, but, as seen in the hippocampus, the spatial code changed dynamically across days. Bilateral but not unilateral hippocampal lesions impeded the development of spatial activity in RSC. Thus, the emergence of spatial activity in RSC, a major recipient of hippocampal information, depends critically on an intact hippocampus; the indirect connections between the dysgranular RSC and the hippocampus further indicate that hippocampus may exert such influences polysynaptically within neocortex.

Auditory Dysfunction in Parkinson's Disease.

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.

Gestational Stress Augments Postpartum ß-Amyloid Pathology and Cognitive Decline in a Mouse Model of Alzheimer's Disease.

Besides well-known risk factors for Alzheimer's disease (AD), stress, and in particular noise stress (NS), is a lifestyle risk factor common today. It is known that females are at a significantly greater risk of developing AD than males, and given that stress is a common adversity in females during pregnancy, we hypothesized that gestational noise exposure could exacerbate the postpartum development of the AD-like neuropathological changes during the life span. Pregnant APPNL-G-F/NL-G-F mice were randomly assigned to either the stress condition or control group. The stress group was exposed to the NS on gestational days 12-16, which resulted in a markedly higher hypothalamic-pituitary-adrenal (HPA) axis responsivity during the postpartum stage. Higher amyloid-ß (Aß) deposition and larger Aß plaque size in the olfactory area were the early onset impacts of the gestational stress (GS) seen at the age of 4 months. This pattern of increased Aß aggregation and larger plaque size were observed in various brain areas involved in both AD and stress regulation, especially in limbic structures, at the age of 6 months. The GS also produced anxiety-like behavior, deficits in learning and memory, and impaired motor coordination. The findings suggest that environmental stresses during pregnancy pose a potential risk factor in accelerating postpartum cognitive decline and AD-like neuropathological changes in the dams (mothers) later in life.

Looking beyond the standard version of the Morris water task in the assessment of mouse models of cognitive deficits.

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.

Human string-pulling with and without a string: movement, sensory control, and memory.

String-pulling is a behavior that is allied to many daily acts and is an easily performed action featuring hand-over-hand movements to reel in a string (or rope). String-pulling has been used as a test of perceptual and cognitive functions in many animal species, including human children, but its movements and sensory control have not been characterized. Male and female university students (n = 68) performed target-based or memory-based string-pulling in which they pulled down a string suspended on an overhead pulley and immediately afterwards attempted to make the same movement in a memory-based test. Frame-by-frame video scoring was used to describe movements, eye-tracking and visual occluding glasses were used to assess sensory control, and a Matlab video-analysis procedure was used to describe kinematics. The string was advanced using five arm/hand movements: with lift and advance comprising fast up movements, and grasp, pull and push comprising slow down movements. Fingers closed 5 (pinky) through 1 (thumb) to make a whole-hand grasp and release in target-based string pulling but moved in a reverse sequence for the memory-based task. Target-based string pulling was not visually guided unless participants were instructed to grasp at a cue, and then vision featured eye-tracking of the target and pupil dilation with the grasp, but there was no relation between eye events for memory-based string-pulling. For target-based string-pulling the left and right hands advanced the string with both independent and concurrent movement but only independent movements were featured in a more symmetrical memory-based movement. The results are discussed in relation to the sensory control of hand movements, contemporary theories of the neural control of hand movements, and species differences in string-pulling.

New waves: Rhythmic electrical field stimulation systematically alters spontaneous slow dynamics across mouse neocortex.

The signature rhythm of slow-wave forebrain activity is the large amplitude, slow oscillation (SO: ∼1 Hz) made up of alternating synchronous periods of activity and silence at the single cell and network levels. On each wave, the SO originates at a unique location and propagates across the neocortex. Attempts to manipulate SO activity using electrical fields have been shown to entrain cortical networks and enhance memory performance. However, neural activity during this manipulation has remained elusive due to methodological issues in typical electrical recordings. Here we took advantage of voltage-sensitive dye (VSD) imaging in a bilateral cortical preparation of urethane-anesthetized mice to track SO cortical activity and its modulation by sinusoidal electrical field stimulation applied to frontal regions. We show that under spontaneous conditions, the SO propagates in two main opposing directional patterns along an anterior lateral - posterior medial axis, displaying a rich variety of possible trajectories on any given wave. Under rhythmic field stimulation, new propagation patterns emerge, which are not observed under spontaneous conditions, reflecting stimulus-entrained activity with distributed and varied anterior initiation zones and a consistent termination zone in the posterior somatosensory cortex. Furthermore, stimulus-induced activity patterns tend to repeat cycle after cycle, showing higher stereotypy than during spontaneous activity. Our results show that slow electrical field stimulation robustly entrains and alters ongoing slow cortical dynamics during sleep-like states, suggesting a mechanism for targeting specific cortical representations to manipulate memory processes.