Open-Source Tools to Analyze Temporal and Spatial Properties of Local Field Potentials.

Analysis of local field potentials (LFPs) is important for understanding how ensemble neurons function as a network in a specific region of the brain. Despite the availability of tools for analyzing LFP data, there are some missing features such as analysis of high frequency oscillations (HFOs) and spatial properties. In addition, accessibility of most tools is restricted due to closed source code and/or high costs. To overcome these issues, we have developed two freely available tools that make temporal and spatial analysis of LFP data easily accessible. The first tool, hfoGUI (High Frequency Oscillation Graphical User Interface), allows temporal analysis of LFP data and scoring of HFOs such as ripples and fast ripples which are important in understanding memory function and neurological disorders. To complement the temporal analysis tool, a second tool, SSM (Spatial Spectral Mapper), focuses on the spatial analysis of LFP data. The SSM tool maps the spectral power of LFPs as a function of subject's position in a given environment allowing investigation of spatial properties of LFP signal. Both hfoGUI and SSM are open-source tools that have unique features not offered by any currently available tools, and allow visualization and spatio-temporal analysis of LFP data.

Lateral Entorhinal Cortex Dysfunction in Alzheimer's disease Mice.

In Alzheimer's disease (AD), the formation of amyloid beta (A ß ) and neurofibrillary tangles (NFTs) leads to neuronal loss in entorhinal cortex (EC), a crucial brain region involved in memory and navigation. These pathological changes are concurrent with the onset of memory-related issues in AD patients with symptoms of forgetfulness such as misplacing items, disorientation in familiar environments etc. The lateral EC (LEC) is associated with non-spatial memory processing including object recognition. Since in LEC, neurons fire in response to objects (object cells) and at locations previously occupied by objects (trace cells), pathology in this region could lead to dysfunction in object location coding. In this paper we show that a transgenic mouse model, EC-App/Tau, which expresses both APP and tau primarily in the EC region, have deficits in LEC-specific memory tasks. Using in vivo single-unit electrophysiology recordings we show that the LEC neurons are hyperactive with low information content and high sparsity compared to the controls indicating poor firing fidelity. We finally show that object cells and trace cells fire less precisely in the EC-App/Tau mice compared to controls indicating poor encoding of objects. Overall, we show that AD pathology causes erratic firing of LEC neurons and object coding defects leading to LEC-specific memory impairment.

Beyond Correlation: Optimal Transport Metrics For Characterizing Representational Stability and Remapping in Neurons Encoding Spatial Memory.

Spatial representations in the entorhinal cortex (EC) and hippocampus (HPC) are fundamental to cognitive functions like navigation and memory. These representations, embodied in spatial field maps, dynamically remap in response to environmental changes. However, current methods, such as Pearson's correlation coefficient, struggle to capture the complexity of these remapping events, especially when fields do not overlap, or transformations are non-linear. This limitation hinders our understanding and quantification of remapping, a key aspect of spatial memory function. To address this, we propose a family of metrics based on the Earth Mover's Distance (EMD) as a versatile framework for characterizing remapping. Applied to both normalized and unnormalized distributions, the EMD provides a granular, noise-resistant, and rate-robust description of remapping. This approach enables the identification of specific cell types and the characterization of remapping in various scenarios, including disease models. Furthermore, the EMD's properties can be manipulated to identify spatially tuned cell types and to explore remapping as it relates to alternate information forms such as spatiotemporal coding. By employing approximations of the EMD, we present a feasible, lightweight approach that complements traditional methods. Our findings underscore the potential of the EMD as a powerful tool for enhancing our understanding of remapping in the brain and its implications for spatial navigation, memory studies and beyond.

Proteostasis failure exacerbates neuronal circuit dysfunction and sleep impairments in Alzheimer's disease.

Failed proteostasis is a well-documented feature of Alzheimer's disease, particularly, reduced protein degradation and clearance. However, the contribution of failed proteostasis to neuronal circuit dysfunction is an emerging concept in neurodegenerative research and will prove critical in understanding cognitive decline. Our objective is to convey Alzheimer's disease progression with the growing evidence for a bidirectional relationship of sleep disruption and proteostasis failure. Proteostasis dysfunction and tauopathy in Alzheimer's disease disrupts neurons that regulate the sleep-wake cycle, which presents behavior as impaired slow wave and rapid eye movement sleep patterns. Subsequent sleep loss further impairs protein clearance. Sleep loss is a defined feature seen early in many neurodegenerative disorders and contributes to memory impairments in Alzheimer's disease. Canonical pathological hallmarks, ß-amyloid, and tau, directly disrupt sleep, and neurodegeneration of locus coeruleus, hippocampal and hypothalamic neurons from tau proteinopathy causes disruption of the neuronal circuitry of sleep. Acting in a positive-feedback-loop, sleep loss and circadian rhythm disruption then increase spread of ß-amyloid and tau, through impairments of proteasome, autophagy, unfolded protein response and glymphatic clearance. This phenomenon extends beyond ß-amyloid and tau, with interactions of sleep impairment with the homeostasis of TDP-43, α-synuclein, FUS, and huntingtin proteins, implicating sleep loss as an important consideration in an array of neurodegenerative diseases and in cases of mixed neuropathology. Critically, the dynamics of this interaction in the neurodegenerative environment are not fully elucidated and are deserving of further discussion and research. Finally, we propose sleep-enhancing therapeutics as potential interventions for promoting healthy proteostasis, including ß-amyloid and tau clearance, mechanistically linking these processes. With further clinical and preclinical research, we propose this dynamic interaction as a diagnostic and therapeutic framework, informing precise single- and combinatorial-treatments for Alzheimer's disease and other brain disorders.

Beyond correlation: optimal transport metrics for characterizing representational stability and remapping in neurons encoding spatial memory.

Introduction: Spatial representations in the entorhinal cortex (EC) and hippocampus (HPC) are fundamental to cognitive functions like navigation and memory. These representations, embodied in spatial field maps, dynamically remap in response to environmental changes. However, current methods, such as Pearson's correlation coefficient, struggle to capture the complexity of these remapping events, especially when fields do not overlap, or transformations are non-linear. This limitation hinders our understanding and quantification of remapping, a key aspect of spatial memory function. Methods: We propose a family of metrics based on the Earth Mover's Distance (EMD) as a versatile framework for characterizing remapping. Results: The EMD provides a granular, noise-resistant, and rate-robust description of remapping. This approach enables the identification of specific cell types and the characterization of remapping in various scenarios, including disease models. Furthermore, the EMD's properties can be manipulated to identify spatially tuned cell types and to explore remapping as it relates to alternate information forms such as spatiotemporal coding. Discussion: We present a feasible, lightweight approach that complements traditional methods. Our findings underscore the potential of the EMD as a powerful tool for enhancing our understanding of remapping in the brain and its implications for spatial navigation, memory studies and beyond.

Non-invasive optogenetics with ultrasound-mediated gene delivery and red-light excitation.

Optogenetics has revolutionized the capability of controlling genetically modified neurons in vitro and in vivo and has become an indispensable neuroscience tool. Using light as a probe for selective neuronal activation or inhibition and as a means to read out neural activity has dramatically enhanced our understanding of complex neural circuits. However, a common limitation of optogenetic studies to date is their invasiveness and spatiotemporal range. Direct viral injections into the brain tissue along with implantation of optical fibers and recording electrodes can disrupt the neuronal circuitry and cause significant damage. Conventional approaches are spatially limited around the site of the direct injection and insufficient in examining large networks throughout the brain. Lastly, optogenetics is currently not easily scalable to large animals or humans. Here, we demonstrate that optogenetic excitation can be achieved entirely non-invasively through the intact skull in mice. Using a needle-free combination of focused ultrasound-mediated viral delivery and extracorporeal illumination with red light, we achieved selective neuronal activation at depths up to 4 mm in the murine brain, confirmed through cFos expression and electrophysiology measurements within the treated areas. Ultrasound treatment significantly reduced freezing time during recall in fear conditioning experiments, but remote light exposure had a moderate effect on the freezing behavior of mice treated with viral vectors. The proposed method has the potential to open new avenues of studying, but also stimulating, neuronal networks, in an effort to elucidate normal or dysfunctional brain activity and treat neurological diseases. Finally, the same non-invasive methodology could be combined with gene therapy and applied to other organs, such as the eye and the heart.

Gestational immune activation disrupts hypothalamic neurocircuits of maternal care behavior.

Immune activation is one of the most common complications during pregnancy, predominantly evoked by viral infections. Nevertheless, how immune activation affects mother-offspring relationships postpartum remains unknown. Here, by using the polyinosinic-polycytidylic acid (Poly I:C) model of gestational infection we show that viral-like immune activation at mid-gestation persistently changes hypothalamic neurocircuit parameters in mouse dams and, consequently, is adverse to parenting behavior. Poly I:C-exposed dams favor non-pup-directed exploratory behavior at the expense of pup retrieval. These behavioral deficits are underlain by dendrite pruning and lesser immediate early gene activation in Galanin (Gal)+ neurons with dam-specific transcriptional signatures that reside in the medial preoptic area (mPOA). Reduced activation of an exclusively inhibitory contingent of these distal-projecting Gal+ neurons allows for increased feed-forward inhibition onto putative dopaminergic neurons in the ventral tegmental area (VTA) in Poly I:C-exposed dams. Notably, destabilized VTA output specifically accompanies post-pup retrieval epochs. We suggest that gestational immunogenic insults bias both threat processing and reward perception, manifesting as disfavored infant caregiving.

Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling.

Whether and how the pathogenic disruptions in endosomal trafficking observed in Alzheimer's disease (AD) are linked to its anatomical vulnerability remain unknown. Here, we began addressing these questions by showing that neurons are enriched with a second retromer core, organized around VPS26b, differentially dedicated to endosomal recycling. Next, by imaging mouse models, we show that the trans-entorhinal cortex, a region most vulnerable to AD, is most susceptible to VPS26b depletion-a finding validated by electrophysiology, immunocytochemistry, and behavior. VPS26b was then found enriched in the trans-entorhinal cortex of human brains, where both VPS26b and the retromer-related receptor SORL1 were found deficient in AD. Finally, by regulating glutamate receptor and SORL1 recycling, we show that VPS26b can mediate regionally selective synaptic dysfunction and SORL1 deficiency. Together with the trans-entorhinal's unique network properties, hypothesized to impose a heavy demand on endosomal recycling, these results suggest a general mechanism that can explain AD's regional vulnerability.

BrainWiki-A Wiki-Style, User Driven, Comparative Brain Anatomy Tool.

The mouse is the most important animal model within neuroscientific research, a position strengthened by the wide-spread use of transgenic mouse models. Discoveries in animals are followed by corroboration in humans, and the interchange between these fields of research is essential to our understanding of the human brain. With the advent of advanced technologies such as single-cell transcriptomics, epigenetic profiling and diffusion MRI, many prominent research institutes and collaborations have emerged, aiming to construct complete human or mouse brain atlases with data on gene expression, connectivity and cell types. These initiatives are indispensable resources, but frequently require extensive, time-consuming development, and rely on updates by the provider. They often come in the shape of applications which require practice or prior technical know-how. Importantly, none of them place the human and the mouse brain next to each other to allow for immediate comparison. We present BrainWiki, a user-friendly, web-based atlas that links the human and the mouse brain together, side-by-side. The platform gives the user a simple overview of brain anatomy along with published articles relating to each brain region that allows the user to delve deeper into the current state of research concerning circuitry, brain functions and pathology. The website relies on interactivity and supports user contributions resulting in a dynamic website that evolves at the pace of neuroscience. It is designed to allow for constant updates and new features in the future which will contain data such as gene expression and neuronal cell types.

Chemogenetic attenuation of neuronal activity in the entorhinal cortex reduces Aß and tau pathology in the hippocampus.

High levels of the amyloid-beta (Aß) peptide have been shown to disrupt neuronal function and induce hyperexcitability, but it is unclear what effects Aß-associated hyperexcitability may have on tauopathy pathogenesis or propagation in vivo. Using a novel transgenic mouse line to model the impact of human APP (hAPP)/Aß accumulation on tauopathy in the entorhinal cortex-hippocampal (EC-HIPP) network, we demonstrate that hAPP overexpression aggravates EC-Tau aggregation and accelerates pathological tau spread into the hippocampus. In vivo recordings revealed a strong role for hAPP/Aß, but not tau, in the emergence of EC neuronal hyperactivity and impaired theta rhythmicity. Chronic chemogenetic attenuation of EC neuronal hyperactivity led to reduced hAPP/Aß accumulation and reduced pathological tau spread into downstream hippocampus. These data strongly support the hypothesis that in Alzheimer's disease (AD), Aß-associated hyperactivity accelerates the progression of pathological tau along vulnerable neuronal circuits, and demonstrates the utility of chronic, neuromodulatory approaches in ameliorating AD pathology in vivo.

Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease.

The phosphoinositide phosphatase synaptojanin 1 (SYNJ1) is a key regulator of synaptic function. We first tested whether SYNJ1 contributes to phenotypic variations in familial Alzheimer's disease (FAD) and show that SYNJ1 polymorphisms are associated with age of onset in both early- and late-onset human FAD cohorts. We then interrogated whether SYNJ1 levels could directly affect memory. We show that increased SYNJ1 levels in autopsy brains from adults with Down syndrome (DS/AD) are inversely correlated with synaptophysin levels, a direct readout of synaptic integrity. We further report age-dependent cognitive decline in a mouse model overexpressing murine Synj1 to the levels observed in human sporadic AD, triggered through hippocampal hyperexcitability and defects in the spatial reproducibility of place fields. Taken together, our findings suggest that SYNJ1 contributes to memory deficits in the aging hippocampus in all forms of AD.

Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer's disease-like pathology.

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques-fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics-with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.

Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction, and Spatial Memory Deficits Reminiscent of Early Alzheimer's Disease.

The earliest stages of Alzheimer's disease (AD) are characterized by the formation of mature tangles in the entorhinal cortex and disorientation and confusion when navigating familiar places. The medial entorhinal cortex (MEC) contains specialized neurons called grid cells that form part of the spatial navigation system. Here we show in a transgenic mouse model expressing mutant human tau predominantly in the EC that the formation of mature tangles in old mice was associated with excitatory cell loss and deficits in grid cell function, including destabilized grid fields and reduced firing rates, as well as altered network activity. Overt tau pathology in the aged mice was accompanied by spatial memory deficits. Therefore, tau pathology initiated in the entorhinal cortex could lead to deficits in grid cell firing and underlie the deterioration of spatial cognition seen in human AD.

Non-invasive, Focused Ultrasound-Facilitated Gene Delivery for Optogenetics.

Optogenetics, a widely used technique in neuroscience research, is often limited by its invasive nature of application. Here, we present a noninvasive, ultrasound-based technique to introduce optogenetic channels into the brain by temporarily opening the blood-brain barrier (BBB). We demonstrate the efficiency of the method developed and evaluate the bioactivity of the non-invasively introduced channelrhodopsin channels by performing stimulation in freely behaving mice.

3D Visualization of the Temporal and Spatial Spread of Tau Pathology Reveals Extensive Sites of Tau Accumulation Associated with Neuronal Loss and Recognition Memory Deficit in Aged Tau Transgenic Mice.

3D volume imaging using iDISCO+ was applied to observe the spatial and temporal progression of tau pathology in deep structures of the brain of a mouse model that recapitulates the earliest stages of Alzheimer's disease (AD). Tau pathology was compared at four timepoints, up to 34 months as it spread through the hippocampal formation and out into the neocortex along an anatomically connected route. Tau pathology was associated with significant gliosis. No evidence for uptake and accumulation of tau by glia was observed. Neuronal cells did appear to have internalized tau, including in extrahippocampal areas as a small proportion of cells that had accumulated human tau protein did not express detectible levels of human tau mRNA. At the oldest timepoint, mature tau pathology in the entorhinal cortex (EC) was associated with significant cell loss. As in human AD, mature tau pathology in the EC and the presence of tau pathology in the neocortex correlated with cognitive impairment. 3D volume imaging is an ideal technique to easily monitor the spread of pathology over time in models of disease progression.

Neuronal activity enhances tau propagation and tau pathology in vivo.

Tau protein can transfer between neurons transneuronally and trans-synaptically, which is thought to explain the progressive spread of tauopathy observed in the brain of patients with Alzheimer's disease. Here we show that physiological tau released from donor cells can transfer to recipient cells via the medium, suggesting that at least one mechanism by which tau can transfer is via the extracellular space. Neuronal activity has been shown to regulate tau secretion, but its effect on tau pathology is unknown. Using optogenetic and chemogenetic approaches, we found that increased neuronal activity stimulates the release of tau in vitro and enhances tau pathology in vivo. These data have implications for disease pathogenesis and therapeutic strategies for Alzheimer's disease and other tauopathies.